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Taxonomy, Physiology, and Natural Products of Actinobacteria

November 2015
Microbiology and molecular biology reviews: MMBR 80(1):1-43

November 2015
80(1):1-43

Authors:

Essaïd Ait Barka

Université de Reims Champagne

Lisa Sanchez

Université de Reims Champagne-Ardenne

Nathalie Vaillant-Gaveau

Université de Reims Champagne-Ardenne

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Schematic representation of the life cycle of sporulating actinomycetes.

…

A genome-based phylogenetic tree based on 97 genome sequences of the phylum Actinobacteria. Type strain genome projects were selected as previously described (676), provided that they yielded at most 25 contigs. Phylogenetic reconstruction, including the assessment of branch support, was done using amino acid sequences according to the methods described by Meier-Kolthoff et al. (677, 678). The tree was visualized by using ITOL (679). Branch support values below 60% are not shown, but the tree generally reveals high support throughout.

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Major events during development of Streptomyces. Nutrient stress is a major trigger of development, leading to the accumulation of ppGpp, resulting in cessation of early growth and repression of the nutrient sensory DasR protein by cell wall-derived metabolites following PCD of the substrate mycelium. Bld proteins and environmental signals control the procession toward aerial growth and antibiotic production. The developmental master regulator BldD (when bound to tetrameric cyclic-di-GMP) represses the transcription of genes for many key developmental regulatory proteins, including WhiB, WhiG, SsgA, and SsgB, as well as FtsZ. Chaplins and SapB provide a supportive hydrophobic layer to allow aerial hyphae to become erect and break through the moist soil surface. White proteins control aerial growth, whereby WhiAB and SsgB likely play a role in growth cessation. Eventually, FtsZ accumulates and localizes to septum sites in an SsgAB-dependent manner. Ladders of FtsZ are formed, which subsequently delimit the spore compartments. Chromosome condensation and segregation are followed by septum closure and spore maturation. The onset of antibiotic production typically correlates temporally to the transition from vegetative to aerial growth. Solid black arrows represent major transitions in development. Dark dotted lines indicate transcriptional control (arrows for activation, ovals for repression).

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Scanning electron micrograph of the surface layer of mature spores, revealing a distinctive rodlet layer. This layer consists of hydrophobic chaplin (Chp) and rodlin (Rdl) proteins. Bar, 100 nm.

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Model for the control of sporulation-specific cell division in Streptomyces. When sporulation starts, SsgA localizes dynamically in young aerial hyphae, while SsgB and FtsZ are still diffuse at this stge. At this point, ParA is constrained to the hyphal tip. During early cell division, SsgA and SsgB colocalize temporarily at either side of the aerial hyphae, with ParA extending downward as filaments along the aerial hypha. ParB complexes are then formed over the uncondensed chromosomes, while FtsZ assembles in spirallike filaments. Subsequently, FtsZ and SsgB colocalize and stay together until FtsZ disperses, whereby SsgB recruits FtsZ and stimulate its polymerization into protofilaments. The way the SsgB-FtsZ complex is tethered to the membrane in the absence of a membrane domain in either protein is unclear, but a likely role is played by the SepG protein (SCO2078 in S. coelicolor) encoded by a gene upstream of divIVA (L. Zhang, J. Willemse, D. Claessen, and G. P. van Wezel, unpublished data). Z-rings are then formed at the sporulation stage, followed by chromosome condensation and segregation and the production of sporulation septa. SsgA eventually marks the future germination sites. The figure was adapted from references 277 and 316.

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Taxonomy, Physiology, and Natural Products of Actinobacteria

Essaid Ait Barka,

Parul Vatsa,

Lisa Sanchez,

Nathalie Gaveau-Vaillant,

Cedric Jacquard,

Hans-Peter Klenk,

Christophe Clément,

Yder Ouhdouch,

Gilles P. van Wezel

Laboratoire de Stress, Défenses et Reproduction des Plantes, Unité de Recherche Vignes et Vins de Champagne, UFR Sciences, UPRES EA 4707, Université de Reims

Champagne-Ardenne, Reims, France

; School of Biology, Newcastle University, Newcastle upon Tyne, United Kingdom

; Faculté de Sciences Semlalia, Université Cadi

Ayyad, Laboratoire de Biologie et de Biotechnologie des Microorganismes, Marrakesh, Morocco

; Molecular Biotechnology, Institute of Biology, Sylvius Laboratories,

Leiden University, Leiden, The Netherlands

SUMMARY .....................................................................................................................................................2

INTRODUCTION ...............................................................................................................................................2

BIOLOGY OF ACTINOBACTERIA................................................................................................................................2

Taxonomy of Actinobacteria.................................................................................................................................3

Morphological classiﬁcation ..............................................................................................................................3

(i) Mycelial morphology................................................................................................................................4

(ii) Spore chain morphology ...........................................................................................................................4

(iii) Spore chain length .................................................................................................................................4

(iv) Melanoid pigments ................................................................................................................................4

Chemotaxonomic classiﬁcation ..........................................................................................................................5

Molecular Classiﬁcation .....................................................................................................................................7

The genus Tropheryma ...................................................................................................................................7

The genus Propionibacterium.............................................................................................................................7

The genus Micromonospora ..............................................................................................................................7

The genus Salinispora ....................................................................................................................................7

The genus Mycobacterium................................................................................................................................9

The genus Nocardia ......................................................................................................................................9

The genus Corynebacterium ..............................................................................................................................9

The genus Gordonia.....................................................................................................................................10

The genus Rhodococcus.................................................................................................................................10

The genus Leifsonia .....................................................................................................................................10

The genus Biﬁdobacterium ..............................................................................................................................10

The genus Gardnerella ..................................................................................................................................11

The genus Streptomyces.................................................................................................................................11

The genus Frankia.......................................................................................................................................11

The genus Thermobiﬁda.................................................................................................................................11

PHYSIOLOGY AND ANTIBIOTIC PRODUCTION OF STREPTOMYCES ........................................................................................11

The Streptomyces Life Cycle ................................................................................................................................11

Environmental Control of Aerial Hypha Formation ........................................................................................................12

Facilitating Aerial Growth: the Roles of Chaplins, Rodlins, and SapB .......................................................................................13

From Aerial Hyphae to Spores: Sporulation-Speciﬁc Cell Division and the Cytoskeleton ..................................................................15

STREPTOMYCETES AS ANTIBIOTIC FACTORIES .............................................................................................................16

Correlation between Growth and Antibiotic Production ..................................................................................................16

Programmed cell death and the DasR system ..........................................................................................................16

Stringent control ........................................................................................................................................17

Morphological control ..................................................................................................................................17

From global control to the activation of speciﬁc gene clusters .........................................................................................18

ACTINOBACTERIA AS SOURCES OF NATURAL PRODUCTS .................................................................................................18

Actinobacteria as Sources of Antibiotics ...................................................................................................................18

Actinobacteria as Sources of Insecticides ..................................................................................................................18

Actinobacteria as Sources of Bioherbicide and Bioinsecticide Agents .....................................................................................18

Actinobacteria as Sources of Antifungal Agents............................................................................................................21

INTERACTIONS BETWEEN ACTINOBACTERIA AND OTHER ORGANISMS ...................................................................................21

(continued)

Published 25 November 2015

Citation Barka EA, Vatsa P, Sanchez L, Gaveau-Vaillant N, Jacquard C, Klenk H-P,

Clément C, Ouhdouch Y, van Wezel GP. 2016. Taxonomy, physiology, and natural

products of Actinobacteria. Microbiol Mol Biol Rev 80:1– 43.

doi:10.1128/MMBR.00019-15.

Address correspondence to Essaid Ait Barka, ea.barka@univ-reims.fr, or

Gilles P. van Wezel, g.wezel@biology.leidenuniv.nl.

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Interactions between Actinobacteria and Invertebrates ...................................................................................................21

Interaction with ants ....................................................................................................................................21

Interactions with beetles ................................................................................................................................21

Interactions with protozoans............................................................................................................................21

Interactions between Actinobacteria and Vertebrates .....................................................................................................21

Interactions between Actinobacteria and Plants ...........................................................................................................22

Plant-Actinobacteria deleterious interactions ...........................................................................................................22

(i) Actinobacteria as plant pathogens .................................................................................................................22

(ii) Traits of pathogenicity.............................................................................................................................23

Plant-Actinobacteria beneﬁcial interactions .............................................................................................................24

(i) Actinobacteria as biological control agents ........................................................................................................24

(ii) Actinobacteria as plant growth-promoting rhizobacteria .........................................................................................24

(iii) Actinobacteria as symbionts ......................................................................................................................25

(iv) Actinobacteria as endophytes.....................................................................................................................25

(v) Actinobacteria as elicitors of plant defense ........................................................................................................25

CONCLUSIONS AND FUTURE PERSPECTIVES ...............................................................................................................25

ACKNOWLEDGMENTS .......................................................................................................................................26

REFERENCES .................................................................................................................................................26

AUTHOR BIOS ................................................................................................................................................43

SUMMARY

Actinobacteria are Gram-positive bacteria with high G⫹C DNA

content that constitute one of the largest bacterial phyla, and they

are ubiquitously distributed in both aquatic and terrestrial ecosys-

tems. Many Actinobacteria have a mycelial lifestyle and undergo

complex morphological differentiation. They also have an exten-

sive secondary metabolism and produce about two-thirds of all

naturally derived antibiotics in current clinical use, as well as

many anticancer, anthelmintic, and antifungal compounds. Con-

sequently, these bacteria are of major importance for biotechnol-

ogy, medicine, and agriculture. Actinobacteria play diverse roles in

their associations with various higher organisms, since their mem-

bers have adopted different lifestyles, and the phylum includes

pathogens (notably, species of Corynebacterium,Mycobacterium,

Nocardia,Propionibacterium, and Tropheryma), soil inhabitants

(e.g., Micromonospora and Streptomyces species), plant commen-

sals (e.g., Frankia spp.), and gastrointestinal commensals (Biﬁdo-

bacterium spp.). Actinobacteria also play an important role as

symbionts and as pathogens in plant-associated microbial com-

munities. This review presents an update on the biology of this

important bacterial phylum.

INTRODUCTION

The phylum Actinobacteria is one of the largest taxonomic units

among the major lineages currently recognized within the

Bacteria domain (1). The actinobacterial genomes sequenced to

date belong to organisms relevant to human and veterinary med-

icine, biotechnology, and ecology, and their observed genomic

heterogeneity is assumed to reﬂect their biodiversity (2). The ma-

jority of the Actinobacteria are free-living organisms that are

widely distributed in both terrestrial and aquatic (including ma-

rine) ecosystems (3). Actinobacteria are Gram-positive ﬁlamen-

tous bacteria with a high guanine-plus-cytosine (G⫹C) content in

their genomes. They grow by a combination of tip extension and

branching of the hyphae. This is what gave them their name,

which derives from the Greek words for ray (aktis or aktin) and

fungi (muke៮s). Traditionally, actinomycetes were considered

transitional forms between fungi and bacteria. Indeed, like ﬁla-

mentous fungi, many Actinobacteria produce a mycelium, and

many of these mycelial actinomycetes reproduce by sporulation.

However, the comparison to fungi is only superﬁcial: like all bac-

teria, actinomycetes’ cells are thin with a chromosome that is or-

ganized in a prokaryotic nucleoid and a peptidoglycan cell wall;

furthermore, the cells are susceptible to antibacterial agents (Fig.

1). Physiologically and ecologically, most Actinobacteria are aero-

bic, but there are exceptions. Further, they can be heterotrophic or

chemoautotrophic, but most are chemoheterotrophic and able to

use a wide variety of nutritional sources, including various com-

plex polysaccharides (4,5). Actinobacteria may be inhabitants of

soil or aquatic environments (e.g., Streptomyces,Micromonospora,

Rhodococcus, and Salinispora species), plant symbionts (e.g.,

Frankia spp.), plant or animal pathogens (e.g., Corynebacterium,

Mycobacterium,orNocardia species), or gastrointestinal com-

mensals (e.g., Biﬁdobacterium spp.).

BIOLOGY OF ACTINOBACTERIA

Most of the Actinobacteria (the streptomycetes in particular) are

saprophytic, soil-dwelling organisms that spend the majority of

their life cycles as semidormant spores, especially under nutrient-

limited conditions (6). However, the phylum has adapted to a

wide range of ecological environments: actinomycetes are also

present in soils, fresh and salt water, and the air. They are more

abundant in soils than other media, especially in alkaline soils

and soils rich in organic matter, where they constitute an im-

portant part of the microbial population. Actinobacteria can be

found both on the soil surface and at depths of more than 2 m

below ground (7).

The population density of Actinobacteria depends on their

habitat and the prevailing climate conditions. They are typically

present at densities on the order of 10

to 10

cells per gram of soil

(7); soil populations are dominated by the genus Streptomyces,

which accounts for over 95% of the Actinomycetales strains iso-

lated from soil (8). Other factors, such as temperature, pH, and

soil moisture, also inﬂuence the growth of Actinobacteria. Like

other soil bacteria, Actinobacteria are mostly mesophilic, with op-

timal growth at temperatures between 25 and 30°C. However,

thermophilic Actinobacteria can grow at temperatures ranging

from 50 to 60°C (9). Vegetative growth of Actinobacteria in the soil

is favored by low humidity, especially when the spores are sub-

merged in water. In dry soils where the moisture tension is greater,

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growth is very limited and may be halted. Most Actinobacteria

grow in soils with a neutral pH. They grow best at a pH between 6

and 9, with maximum growth around neutrality. However, a few

strains of Streptomyces have been isolated from acidic soils (pH

3.5) (10). The ﬁrst study on the effect of climate on the distribu-

tion of Actinobacteria was done by Hiltner and Strömer (11), who

showed that these bacteria account for 20% of the microbial ﬂora

of the soil in spring and more than 30% in the autumn because of

the large amounts of crop residues available at this time of year.

However, during the winter, frost reduces their relative abun-

dance to only 13%.

Taxonomy of Actinobacteria

Actinobacteria represent one of the largest taxonomic units among

the 18 major lineages currently recognized within the Bacteria

domain, including 5 subclasses, 6 orders, and 14 suborders (1).

The genera of this phylum exhibit enormous diversity in terms of

their morphology, physiology, and metabolic capabilities. The

taxonomy of Actinobacteria has evolved signiﬁcantly over time

with the accumulation of knowledge. The order Actinomycetales,

established by Buchanan in 1917 (12), belongs to this group of

prokaryotic organisms.

The phylum Actinobacteria is delineated on the basis of its

branching position in 16S rRNA gene trees. However, rRNA se-

quences do not discriminate well between closely related species

or even genera, which can create ambiguity. For instance, the tax-

onomic status of the genus Kitasatospora (13) within the family

Streptomycetaceae has been disputed for many years (1,14,15),

although a recent detailed genetic analysis provided strong evi-

dence that it should be regarded as a separate genus (16). A similar

close relationship exists between Micromonospora,Verrucosispora,

and Salinispora. Additional genetic markers have therefore been

used to discriminate between closely related genera, including

rpoB and, most recently, ssgB, which is particularly useful for dis-

criminating between closely related genera (17). Moreover, the

massive recent increase in the availability of genome sequence

information has provided detailed insights into genome evolution

and made it possible to identify genes speciﬁc to organisms at the

level of genera and family (18).

An updated taxonomy of the phylum Actinobacteria that is

based on 16S rRNA trees was recently reported (1). That update

eliminated the taxonomic ranks of subclasses and suborders, ele-

vating the former subclasses and suborders to the ranks of classes

and orders, respectively (19). The phylum is thus divided into six

classes: Actinobacteria,Acidimicrobiia,Coriobacteriia,Nitrilirup-

toria,Rubrobacteria,and Thermoleophilia.

The class Actinobacteria contains 16 orders, including both of

the previously proposed orders, Actinomycetales and Biﬁdobacte-

riales (20). The order Actinomycetales is now restricted to the

members of the family Actinomycetaceae, and the other suborders

that were previously part of this order are now designated distinct

orders (19). Consequently, 43 of the 53 families within the phylum

Actinobacteria are assigned to a single class, Actinobacteria, whereas

the other ﬁve classes together contain only 10 families (21).

Morphological classiﬁcation. The main characteristics used to

delineate the taxonomy of Actinobacteria at the genus and species

levels are microscopic morphology and chemotaxonomy. The lat-

ter of these characteristics primarily relates to the composition of

the cell wall and the whole-cell sugar distribution, although phos-

pholipid composition and menaquinone type may also be consid-

ered for ﬁne-tuning purposes (22).

FIG 1 Schematic representation of the life cycle of sporulating actinomycetes.

Biology of Actinobacteria

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Mycelial fragmentation can be regarded as a special form of

vegetative reproduction. However, the Actinobacteria with pri-

marily mycelial lifestyles usually reproduce by forming asexual

spores. Actinobacteria exhibit a wide variety of morphologies, dif-

fering mainly with respect to the presence or absence of a substrate

mycelium or aerial mycelium, the color of the mycelium, the pro-

duction of diffusible melanoid pigments, and the structure and

appearance of their spores (Fig. 1).

(i) Mycelial morphology. Except for Sporichthya sp., which

produces aerial hyphae that are initiated upright on the surface of

the medium by holdfasts, Actinobacteria form a substrate myce-

lium in both submerged and solid-grown cultures. However, on

solid surfaces, many differentiate to form aerial hyphae, whose

main purpose is to produce reproductive spores (23,24). The

substrate mycelium develops from outgrowth of a germinating

spore. The branching substrate mycelium is often monopodial,

but in some rare cases, Actinobacteria, such as Thermoactinomyces,

exhibit dichotomous branching (25). On the other hand, mem-

bers of the Micromonosporaceae family produce an extensive sub-

strate mycelium with an absent or rudimentary aerial mycelium.

Actinobacteria exhibit a wide variety of morphologies, includ-

ing coccoid (Micrococcus) and rod-coccoid (Arthrobacter), as well

as fragmenting hyphal forms (Nocardia spp.) and also forms with

permanent and highly differentiated branched mycelia (e.g.,

Streptomyces spp., Frankia)(

26). Rhodococci form elongated ﬁl-

aments on the substrate and do not produce a true mycelium (27),

while corynebacteria do not produce mycelia at all. However, as in

other Actinobacteria, the ﬁlaments grow at the apex instead of by

lateral wall extension (28,29). Actinobacteria belonging to the ge-

nus Oerskovia are characterized by the formation of branched sub-

strate hyphae that break up into ﬂagellated motile elements (30).

Further, mycobacteria and rhodococci do not usually form aerial

hyphae, although some exceptions exist (31).

(ii) Spore chain morphology. Spores are extremely important

in the taxonomy of Actinobacteria (32). The initial steps of sporu-

lation in several oligosporic Actinobacteria can be regarded as bud-

ding processes, because they satisfy the main criteria used to deﬁne

budding in other bacteria (Fig. 2). Spores may be formed on the

substrate and/or the aerial mycelium as single cells or in chains of

different lengths. In other cases, spores may be harbored in special

vesicles (sporangia) and endowed with ﬂagella.

Thus, in the genera Micromonospora,Micropolyspora, and

Thermoactinomycètes, spore formation occurs directly on the sub-

strate mycelium (33), whereas in Streptomyces the spores grow out

from the aerial mycelium. The Actinoplanes and Actinosynnema

groups are characterized by motile spores, while Thermoactinomy-

ces has unique heat-resistant endospores (33). Some other Actino-

bacteria genera have sclerotia (Chainia), synnemas (Actinosyn-

nema), vesicles that contain spores (Frankia), or vesicles that are

devoid of spores (Intrasporangium). Other genera, such as Actino-

planes,Ampulariella,Planomonospora,Planobispora,Dactylospo-

rangium, and Streptosporangium, are classiﬁed based on their spo-

rangial morphology. Figure 2 illustrates the different types of

spores that can be found in actinomycetal genera. Finally, the

morphology of the spores themselves can also be used to charac-

terize species: they may have smooth, warty, spiny, hairy, or ru-

gose surfaces (34).

(iii) Spore chain length. The number of spores per spore chain

varies widely from genus to genus. The genera Micromonospora,

Salinispora,Thermomonospora,Saccharomonospora, and Promi-

cromonospora produce isolated spores, while Microbispora pro-

duces spores in longitudinal pairs. Members of the genera Actino-

madura,Saccharopolyspora,Sporicthya, and some Nocardia spp.

have short spore chains, while members of the genera Streptomy-

ces,Nocardioides,Kitasatospora,Streptoverticillium, and some No-

cardia spp. produce very long chains of up to 100 spores. In con-

trast, Frankia species produce sporangia, which are essentially

bags of spores. Streptomycetes’ spore chains can be classiﬁed as

being straight to ﬂexuous (Rectus-Flexibilis), open loops (Reli-

naculam-Apertum), open or closed spirals (spira), or verticillate

(35).

(iv) Melanoid pigments. Melanins are polymers with diverse

molecular structures that typically appear black or brown and are

formed by the oxidative polymerization of phenolic and indolic

compounds. They are produced by a broad range of organisms,

ranging from bacteria to humans. Actinobacteria have long been

known to produce pigments, which may be red, yellow, orange,

pink, brownish, distinct brown, greenish brown, blue, or black,

depending on the strain, the medium used, and the age of the

culture (4).

Generally referred to as melanins, or melanoid pigments, these

brown-black metabolic polymers are important not only because

of their usefulness in taxonomic studies but also because of their

similarity to soil humic substances (36,37). Melanins are not es-

sential for the organisms’ growth and development, but they play

a crucial role in improving their survival and competitiveness.

FIG 2 Schematic drawings of the different types of spore chains produced by

actinomycetes.

Barka et al.

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Chemotaxonomic classiﬁcation. Chemotaxonomy is the use

of the distribution of chemical components to group organisms

according to the similarities of their cellular chemistries (38,39).

The most commonly used chemical components in such system-

atics are cell wall amino acids, lipids, proteins, menaquinones,

muramic acid types, sugars, and the base composition of DNA

(40,41). Chemotaxonomic classiﬁcation and identiﬁcation can

also be performed on the basis of information derived from

whole-organism chemical ﬁngerprinting techniques. Below, we

discuss chemotaxonomic markers that have been reported to be of

particular value for the classiﬁcation and identiﬁcation of actino-

mycetes (1).

Analysis of the cell wall composition of Actinobacteria is taxo-

nomically valuable because it differs between suborders (42). In

particular, information on the chemical architecture of the pepti-

doglycan in the cell wall is valuable for classifying actinomycetes

because it facilitates discrimination between groups of Actinobac-

teria above the genus level. Multiple discriminatory characteristics

relating to the structure and composition of their peptidoglycans

have been identiﬁed (43), including the identity of the amino acid

in position 3 of the tetrapeptide side chain, the presence or ab-

sence of glycine in interpeptide bridges, and the peptidoglycan’s

sugar content (43). The presence or absence of speciﬁc optical

isomers of the chiral nonproteinogenic amino acid 2,6-diamin-

opimelic acid (DAP) is another chemotaxonomically important

characteristic of the cell walls of Gram-positive bacteria: the

peptidoglycan of Actinobacteria may contain either LL-orDL-

(meso)-DAP, depending on the genus. By considering DAP

isomerism and the presence/absence of other amino acids and

(amino)sugars, Lechevalier and Lechevalier (44) identiﬁed

nine distinct actinobacterial cell wall chemotypes (Table 1).

However, it is important to realize that while DAP analysis and

other chemotaxonomic methods are extremely important in

the taxonomy of Actinobacteria, diverse groups share the same

DAP proﬁle. For example, the genera Streptomyces,Streptoverti-

cillium,Arachnia, and Nocardioides share the same chemotype

(chemotype I), even though their different morphologies indi-

cate that they belong to different families. Therefore, when

assessing the phenotypic diversity of Actinobacteria, DAP pro-

ﬁling should be used in combination with other phenotypic or

genotypic criteria (45). To this end, a system for classifying

Actinobacteria based on both morphological and chemical char-

acteristics has been proposed (4).

Cellular fatty acid patterns are also very useful chemotaxo-

nomic indicators for the identiﬁcation of speciﬁc Actinobacteria

genera (46). Bacterial fatty acids range in chain length from two

) to over 90 (C

) carbon atoms, but only those in the range of

to C

are of particular taxonomic value (47). Three major

types of fatty acid proﬁles have been identiﬁed in Actinobacteria

(46).

Several types of isoprenoid quinones have been characterized

in bacteria (48), of which menaquinones are most commonly

found in actinomycete cell envelopes (46–49). Menaquinone

analysis has provided valuable information for the classiﬁcation of

Actinomadura,Microtetraspora, and Streptomyces strains (46,50–

52). In addition, cyclic menaquinones are characteristic of mem-

bers of the genus Nocardia (53,54), while fully saturated cyclic

menaquinones have been reported for Pyrobaculum organotro-

phum (54).

Different types of phospholipids are discontinuously distrib-

uted in actinomycetes’ cytoplasmic membranes, providing useful

information for the classiﬁcation and identiﬁcation of actinomy-

cete genera (41,55). Actinobacteria have been classiﬁed into ﬁve

phospholipid groups based on semiquantitative analyses of major

phospholipid markers found in whole-organism extracts (56–58).

This classiﬁcation system was used in the identiﬁcation of Aero-

microbium (59) and Dietzia (60). Importantly, it has been re-

ported that members of the same Actinobacteria genus have the

same phospholipid type.

Finally, sugar composition analysis is also important in che-

motaxonomy. At the suprageneric level, neutral sugars (the

major constituents of actinomycete cell envelopes) are useful

taxonomic markers (Table 2). On the basis of the discontinu-

ous distribution of major diagnostic sugars, Actinomycetes can

be divided into ﬁve groups. Group A comprises those species

whose cell walls contain arabinose and galactose; group B cell

walls contain madurose (3-O-methyl-D-galactose); group C

consists of those with no diagnostic sugars; group D cell walls

contain arabinose and xylose; group E cell walls contain galac-

tose and rhamnose (22,61). In addition, the presence of 3=-O-

methyl-rhamnose in Catellatospora (62) and of tyvelose in Agro-

TABLE 1 Different types of cell wall components in Actinomycetes

Cell wall type Major parietal constituent(s) Genera

ILL-DAP, glycine, no sugar Arachnia,Nocardioides,Pimelobacter,Streptomyces

II meso-DAP, glycine, arabinose, xylose Actinomyces,Actinoplanes,Ampulariella,Catellatosporia,Dactylosporangium,Glycomyces,

Micromonospora,Pilimelia

III meso-DAP, madurose (3-O-methyl-D-galactose) Actinocorallia,Actinomadura,Dermatophylus,Frankia,Geodermatophilus,Kitasatospora,

Maduromycetes,Microbispora,Microtetraspora,Nonomuraea,Planobispora,

Planomonospora,Planotetraspora, some Frankia spp., Spirillosporia,

Streptosporangium,Thermoactinomyces,Thermomonospora

IV meso-DAP, arabinose, galactose Micropolyspora,Nocardioforms

V Deprived of DAP; possesses lysine and ornithine Actinomyces

VI Deprived of DAP; variable presence of aspartic

acid, galactose

Arcanobacterium,Actinomyces,Microbacterium,Oerskovia,Promicromonospora

VII Deprived of DAP; diaminobutyric acid, glycine,

with lysine variable

Agromyces,Clavibacter

VIII Deprived of DAP; ornithine Aureobacterium,Curtobacterium,Cellulomonas

Information summarized in this table was obtained from references 14,45,61, and 602.

Biology of Actinobacteria

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TABLE 2 Taxonomic markers used as characteristics to differentiate the genera of Actinomycetes

Amino acid present Sugar(s) Morphological characteristics Genus

No diaminopimelic

acid

Xylose, madurose Only substrate mycelium, breaks into motile elements Oerskovia

Sterile aerial mycelium, breaks into nonmotile elements Promicromonospora

Sporangia with motile spores Actinoplanes

Short chains of conidia on aerial mycelium Actinomadura

L-Diaminopimelic

acid

Xylose, madurose Both aerial and substrate mycelia that break up into rods and coccoid

elements

Nocardioides

Only substrate mycelium, bearing terminal or subterminal vesicles Intrasporangium

Aerial mycelium with long chains of spores Streptomyces,Kitasatospora

Sclerotia Streptomyces

Very short chains of large conidia on the vegetative and aerial mycelia Streptomyces

Whorls of small chains of spores Streptoverticillium

No aerial mycelium, sporangia on the vegetative mycelium Kineosporia

meso-Diaminopimelic

acid

Xylose, arabinose Conidia isolated on the vegetative mycelium Micromonospora

No sporangia, short chains of conidia Cattellatospora

Chains of conidia on the aerial mycelium Glycomyces

Dactyloid oligosporic sporangia, motile spores Dactylosporangium

Sporangia with spherical and motile spores formed on the surfaced of colonies Actinoplanes

Sporangia with rod-shaped spores, motility via polar ﬂagella Ampullariella

Sporangia with lateral ﬂagellated spores Pilimelia

Multilocular sporangia, spores are nonmotile Frankia

Madurose Short chains of conidia on the aerial mycelium Actinomadura

Chains of conidia with spores Microbispora

Chains of conidia with 2 to 6 spores Microtetraspora

Sporangia with 2 motile spores Planobispora

Sporangia with 1 motile spore Planomonospora

Mycelium with spherical sporangia containing many rod-shaped, motile

spores

Spirillospora

Fructose Multilocular sporangia Frankia

Sporangia with motile spores Actinoplanes

Rhamnose, galactose Both substrate and aerial mycelia that break into nonmotile elements Saccharothrix

Rhamnose, galactose,

mannose

Same as Streptomyces Streptoalloteichus

Galactose Same as Streptomyces Kitasatospora

Arabinose, galactose Presence of nocardiomycolic acid (NMA) in whole cells; both substrate and

aerial mycelia fragment into rods and coccoid elements

Nocardia

Presence of NMA; rods and extensively branched substrate mycelium that

fragments into irregular rods and cocci

Rhodococcus

Presence of NMA; straight to slightly curved rods occur singly, in pairs, or in

masses; cells are nonmotile, non-spore forming, and do not produce aerial

hyphae

Tsukamurella

Presence of NMA; paired spores borne in longitudinal pairs on vegetative

hyphae; aerial mycelium is sparse

Actinobispora

No NMA, spores are long, cylindrical on aerial mycelium, formed by budding Pseudonocardia

No NMA; long chains of conidia on aerial mycelium Saccharomonospora

No NMA; aerial mycelium bearing long chains of conidia; halophilic Actinopolyspora

No NMA; substrate mycelium tends to break into nonmotile elements; aerial

hyphae may form and may also segment

Amycolata,Amycolatopsis

No NMA; aerial mycelium bearing curled hyphae embedded in amorphous

matrix

Kibdelosporangium

No NMA; both aerial and substrate mycelia bearing long chains of motile

spores

Aktinokineospora

No NMA; aerial mycelium tends to fragment into rods and cocci, short chains

of spores

Pseudoamycolata

Spores formed are not heat resistant Thermomonospora

Long chains of spores on aerial mycelium Nocardiopsis

Columnar hyphal structures called synnemata bearing chains of conidia

capable of forming ﬂagella

Actinosynnema

Multilocular sporangia containing motile spores Geodermatophilus

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myces (63) has been valuable for the classiﬁcation of some

actinomycete taxa.

Molecular Classiﬁcation

More recently, the morphological and chemical classiﬁcation of

actinomycetes have been challenged by molecular taxonomic

data, much of which were obtained thanks to the rapid advance-

ment of genome sequencing. Notably, some organisms that were

inappropriately placed in certain taxonomic groups have recently

been reclassiﬁed on the basis of molecular analyses (20). A recent

example is the ﬁnal deﬁnition of Kitasatospora as a separate genus

within the Streptomycetaceae (17); genome sequencing resolved a

long-running debate about this group’s relationship with the ge-

nus Streptomyces and conclusively demonstrated that it is in fact a

separate genus (15,16,64,65).

At present, a new species cannot be claimed without genetic

analysis based on sequencing the 16S rRNA gene and DNA-DNA

hybridization, and even genome sequencing is becoming routine.

Molecular and chemical composition criteria have been used to

group the order Actinomycetales into 14 suborders: Actinomy-

cineae,Actinopolysporineae,Catenulisporineae,Corynebacterineae,

Frankineae,Glycomycineae,Jiangellineae,Kineosporineae,Micro-

coccineae,Micromonosporineae,Propionibacterineae,Pseudonocar-

dineae,Streptomycineae, and Streptosporangineae (66). Moreover,

sequencing of 16S rRNA genes has led to the recognition of 39

families and 130 genera (Fig. 3). All groups previously assigned to

the taxonomic rank of “order” were recovered as being strictly

monophyletic based on these molecular and chemical criteria, but

some paraphyletic groups were found within the rank “suborder.”

This might be because the classiﬁcation was mainly based on 16S

rRNA gene trees, which were generated without bootstrap sup-

port and may thus include misleading results. The features of

some of these genera are summarized below.

The genus Tropheryma.The most-studied member of the ge-

nus Tropheryma is T. whipplei, the causative agent of Whipple’s

disease, which is characterized by intestinal malabsorption leading

to cachexia and death. T. whipplei isolates are typically found in

human intracellular niches, such as inside intestinal macrophages

and circulating monocytes (67,68). It has a condensed genome of

only 925,938 bp, with a G⫹C content of only 46% (69,70),

whereas other actinomycete genomes have much larger genomes

(up to 10 MBp) and higher G⫹C contents. T. whipplei has a tro-

pism for myeloid cells, particularly macrophages, although it can

be found in various cell types. Further, genome sequencing re-

vealed a lack of key biosynthetic pathways and a lower capacity for

energy metabolism. Its small genome and lack of metabolic capa-

bilities suggest that T. whipplei has a host-restricted lifestyle (69).

Recent ﬁndings have shown that T. whipplei survives phagocyte

killing and replicates in macrophages by interfering with innate

immune activation (71).

The genus Propionibacterium.The genus Propionibacterium

includes various species belonging to the human cutaneous pro-

pionibacteria, including P. acnes,P. avidum,P. granulosum,P.

innocuum, and P. propionibacterium.Propionibacterium acnes is a

non-spore-forming, anaerobic, pleomorphic rod whose end

products of fermentation include propionic acid. The bacterium

is omnipresent on human skin, predominantly within sebaceous

follicles, where it is generally a harmless commensal. Nonetheless,

P. acnes may be an opportunistic pathogen (72). Indeed, the bac-

terium has been isolated from sites of infection and inﬂammation

in patients suffering from acne and other diverse conditions, in-

cluding corneal ulcers, synovitis, hyperostosis, endocarditis, pul-

monary angitis, and endophthalmitis (73,74). Recently, Campi-

sano et al. (75) reported a unique example of horizontal

interkingdom transfer of P. acnes to the domesticated grapevine,

Vitis vinifera L.

The genus Micromonospora.Micromonospora species are

widely distributed in nature, living in different environments.

They have long been known as a signiﬁcant source of secondary

metabolites for medicine, and it was recently demonstrated that

Micromonospora species may also inﬂuence plant growth and de-

velopment (76); Micromonospora strains have been identiﬁed as

natural endophytes of legume nodules, although the precise na-

ture and mechanism of their effects on plant development and

productivity are currently unclear. While the genus exhibits con-

siderable physiological and biochemical diversity, Micromono-

spora constitutes a well-deﬁned group in terms of morphology,

phylogeny, and chemotaxonomy. Its colonies can be a variety of

colors, including white, orange, rose, or brown. However, species

of the genus Micromonospora are not always easy to differentiate

on the basis of morphology alone. Consequently, phylogenies and

species identiﬁcations are now more commonly derived by ana-

lyzing the sequence of the 16S rRNA gene or gyrB (the gene en-

coding DNA topoisomerase). The genus Micromonospora consists

primarily of soil actinobacteria, which account for 32 of its species,

according to the latest version of Bergey’s manual (77), although

50 soil actinobacteria in this genus have been validly described as

of the time of writing. Most of these species were isolated from

alkaline or neutral soils and to a lesser extent from aquatic envi-

ronments. The spore population of M. echinospora is known to be

heterogeneous with respect to its heat response characteristics,

suggesting that routine heat activation could be utilized to elimi-

nate the natural variability that exists within populations of this

species and its relatives (78). Further, analysis of the genome of M.

lupini Lupac 08 revealed a diverse array of genes that may help the

bacterium to survive in the soil or in plant tissues. However, de-

spite having many genes that encode putative plant material-de-

grading enzymes, this bacterium is not regarded as a plant patho-

gen (79). In addition, genome comparisons showed that M. lupini

Lupac 08 is metabolically closely related to Frankia sp. strains

ACN14a, CcI3, and EAN1pec. These results suggest that the Mi-

cromonospora genus has undergone a previously unidentiﬁed pro-

cess of adaptation from a purely terrestrial to a facultative endo-

phytic lifestyle.

The genus has also been reported to produce a large number of

antibiotics (80) and is second only to Streptomyces in this respect,

synthesizing up to 500 different molecules with various properties

(77). Micromonospora species can produce hydrolytic enzymes,

which allows them to play an active role in the degradation of

organic matter in their natural habitats. Marine Micromonospora

species have recently been reviewed with respect to their broad

distribution and their potential use as probiotics (76,81). Like

other endophytic actinobacteria, Micromonospora can suppress a

number of pathogens both in vitro and in planta by activating key

genes in the systemic acquired resistance (SAR) or jasmonate/

ethylene (JA/ET) pathways (76). Unfortunately, there have been

few genomic studies on Micromonospora species, and there is a

lack of tools for their genetic analysis despite their acknowledged

capacity for secondary metabolite production (76).

The genus Salinispora.Salinispora belongs to the Micromono-

Biology of Actinobacteria

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FIG 3 A genome-based phylogenetic tree based on 97 genome sequences of the phylum Actinobacteria. Type strain genome projects were selected as previously

described (676), provided that they yielded at most 25 contigs. Phylogenetic reconstruction, including the assessment of branch support, was done using amino

acid sequences according to the methods described by Meier-Kolthoff et al. (677,678). The tree was visualized by using ITOL (679). Branch support values below

60% are not shown, but the tree generally reveals high support throughout.

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sporaceae and is the ﬁrst Actinobacteria genus known to require

seawater for growth (82). The genus is widely distributed in trop-

ical and subtropical marine sediments (83) and includes three

distinct but closely related clades corresponding to the species S.

arenicola,S. paciﬁca, and S. tropica. Like their terrestrial actinomy-

cete counterparts, Salinispora spp. produce numerous secondary

metabolites with diverse potential pharmaceutical applications.

For instance, salinosporamide A, isolated from S. tropica, is cur-

rently in phase 1 clinical trials in patients with multiple myeloma,

lymphomas, leukemia, and solid tumors (84).

Although the three currently known species of Salinispora

cooccur at six widely separated and distinct locations (82), only

strains of S. tropica isolated from the Caribbean produce the po-

tent anticancer compound salinosporamide A (85). In addition to

its production of various secondary metabolites, this genus has

attracted major interest for the novel phenomenon of species-

speciﬁc secondary metabolite production (86,87). Although it is

clear that many of the genes for secondary metabolite production

in the Salinispora genome were acquired via horizontal gene trans-

fer, the ecological and evolutionary signiﬁcance of these mecha-

nisms remain unclear (86).

The genus Mycobacterium.The relatively simple morphology

of mycobacteria partly explains why it is sometimes overlooked

when considering criteria for classifying actinomycetes (88,89).

With the genera Corynebacterium and Nocardia,Mycobacterium

forms a monophyletic taxon within the Actinobacteria, the so-

called CMN group (90). This group shares an unusual waxy cell

envelope that contains mycolic acids, meaning these bacteria are

unusual in being acid fast and alcohol fast. The mycobacterial cell

wall contains various polysaccharide polymers, including arabi-

nogalactan, lipomannan, lipoarabinomannan, and phosphatidyl-

inositol mannosides (91,92). Representatives of the genus Myco-

bacterium have been the subjects of three major 16S rRNA

sequencing studies (93–95). Mycobacteria are generally free-liv-

ing saprophytes (96), and they are the causative agents of a broad

spectrum of human diseases. Mycobacterial diseases are very often

associated with immunocompromised patients, especially those

with AIDS. In addition, M. bovis and M. tuberculosis, isolated ini-

tially from infected animals, are most likely obligate parasites of

humans (97). Both species can survive within macrophages and

cause pulmonary disease, although organs other than lungs may

be affected. M. leprae, which causes leprosy, lives in Schwann cells

and macrophages; infection with this species results in a chronic

granulomatous disease of the skin and peripheral nerves (98). In-

terestingly, the pathogenic M. ulcerans, which is the third most

common causative agent of mycobacterial disease, has also been

isolated as a soil inhabitant in symbiosis with roots of certain

plants living in tropical rain forests and similar environments (99,

100). Mycobacterium marinum was initially identiﬁed as a caus-

ative organism of tuberculosis in ﬁsh in 1926 (101) and was sub-

sequently shown to also cause skin disease in humans (102). M.

marinum is a nontuberculosis mycobacterium that is a causative

agent of human skin infections acquired through aquatic sources.

Most cases of M. marinum infection are reported to have occurred

after exposure to contaminated aquarium water or contact with

ﬁsh and shellﬁsh (103).

The genus Nocardia.The genus Nocardia is a ubiquitous group

of environmental bacteria that is most widely known as the caus-

ative agent of opportunistic infection in immunocompromised

hosts. It forms a distinct clade that is associated with the genus

Rhodococcus. Both the Nocardia and Rhodococcus genera belong to

the family Nocardiaceae, which is a suborder of the “aerobic acti-

nomycetes.” Nocardia species are ubiquitous soilborne aerobic

actinomycetes, with more than 80 different species identiﬁed, of

which at least 33 are pathogenic (104). Nocardia infections are

mainly induced through inhalation or percutaneous inoculation

from environmental sources (105), but nosocomial transmission

has also been reported. The pathogen can spread to the brain,

kidneys, joints, bones, soft tissues, and eyes, causing disseminated

nocardiosis in humans and animals (106). Although Nocardia

species are rare, they now account for 1 to 2% of all reported brain

abscesses. However, the mortality rate for brain abscesses associ-

ated with Nocardia infection is substantially higher (31%) than

that for brain abscesses in general (⬍10%) (107).

Moreover, Nocardia species produce industrially important

bioactive molecules, such as antibiotics and enzymes (108,109).

Within the Nocardia clade, two sublines distinguishable by nucle-

otide differences in helix 37-1 are recognized; one consists of No-

cardia asteroides and allied taxa, while the second consists of No-

cardia otitidiscaviarum and related species. N. asteroides, the causal

agent for most clinical human nocardial infections, was reorga-

nized into multiple species on the basis of drug susceptibility pat-

terns: Nocardia abscessus, the Nocardia brevicatena-Nocardia pau-

civorans complex, the Nocardia nova complex, the Nocardia

transvalensis complex, Nocardia farcinica, and N. asteroides (104).

Recently, Nocardia cyriacigeorgica was differentiated from N. as-

teroides (110).

In the last 2 decades, Nocardia infections have become re-

garded as an emerging disease among humans and domestic

animals worldwide because of improved methods for pathogen

isolation and molecular identiﬁcation and a growing immuno-

compromised population (111). Nocardia species are recognized

as opportunistic pathogens (112) and are known to compromise

immune function. Moreover, they have been associated with or-

gan and bone marrow transplants (113), long-term steroid use,

connective tissue diseases, human immunodeﬁciency virus (HIV)

infections, chronic obstructive pulmonary disease, alcoholism,

cirrhosis, systemic vasculitis, ulcerative colitis, and renal failure

(114).

In companion animals, Nocardia infections are usually re-

ported as coinfections with immunosuppressive infectious dis-

eases such as distemper in dogs and leukemia and immunodeﬁ-

ciency in cats (115).

The genus Corynebacterium.The genus Corynebacterium was

initially deﬁned in 1896 to accommodate mainly pathogenic spe-

cies exhibiting morphological similarity to the diphtheroid bacil-

lus (116). Therefore, the genus comprised, for several decades, an

extremely diverse collection of morphologically similar Gram-

positive microorganisms, including nonpathogenic soil bacteria

(117). Following chemotaxonomic studies and 16S rRNA se-

quence analysis, there are currently almost 70 recognized Coryne-

bacterium species. Some well-known representatives include C.

glutamicum, which (like the thermostable C. efﬁciens) is widely

used in industry for the production of amino acids such as L-glu-

tamic acid and L-lysine for human and animal nutrition, respec-

tively (118). Several genome sequences of Corynebacterium spe-

cies have been reported, including those of C. ulcerans (119), C.

kutscheri (120), C. kroppenstedtii (121), and C. argentoratense

(122), providing important new insights into the genomic archi-

tecture of the genus. A prophage, CGP3, that integrates into the

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genome of C. glutamicum and encodes an actin-like protein, AlpC,

was recently described (123). CGP3 appears to be inactive in terms

of cell lysis and virion production and is therefore referred to as a

cryptic prophage, which likely became trapped in the genome in

the course of evolution (123). This suggests that bacterial phages

use an actin-based transport system similar to that found in ver-

tebrate viruses, such as the herpesvirus. Among the known patho-

genic members of Corynebacterium are C. diphtheria, which is a

notorious strictly human-adapted species and the causative agent

of the acute, communicable disease diphtheria, which is charac-

terized by local growth of the bacterium in the pharynx along with

the formation of an inﬂammatory pseudomembrane (124). The

virulence factor in diphtheria is an exotoxin that targets host pro-

tein synthesis (125). Another important Corynebacterium patho-

gen is C. ulcerans, which is increasingly acknowledged as an

emerging pathogen in various countries; infections with this spe-

cies can mimic diphtheria because it harbors lysogenic-␤-cory-

nephages that carry the the diphtheria toxin (DT) gene, which is

responsible for most of the systemic symptoms of diphtheria

(126). C. ulcerans also induces clinical symptoms in the lower

respiratory tract, including pneumonia (127) and pulmonary

granulomatous nodules (128). However, its pathogenicity does

not necessarily depend on the production of DT (129). A ﬁnal

important pathogen in this genus is C. jeikeium, which was ini-

tially isolated from human blood cultures and is associated with

bacterial endocarditis contracted following cardiac surgery (130).

It was subsequently shown to be a natural inhabitant of human

skin and has been implicated in a variety of nosocomial infections

(131).

The genus Gordonia.Initially proposed by Tsukamura (132),

this genus has been isolated from the sputum of patients with

pulmonary disease and also from soil samples. There are currently

29 validly described species in this genus (1). Bacteria of this genus

are aerobic and catalase positive, forming rods and cocci. The

gordonae are widely distributed and are common in soil, but some

strains have been linked with foams found in activated sludge at

sewage treatment plants. Three species originally assigned to Rho-

dococcus, namely, R. bronchialis (132), R. rubropertinctus (133),

and R. terrae (132), have more recently been reafﬁliated to the

genus Gordona as Gordona bronchialis (132), Gordona rubroper-

tincta (133), and Gordona terrae (132). The original spelling Gor-

dona (sic) was corrected to Gordonia by Stackebrandt et al. (134).

The genus Rhodococcus.The genus Rhodococcus is a heteroge-

neous group of microorganisms whose members are more closely

related to those of the genus Nocardia than to those of the genus

Mycobacterium. Rhodococcus species include symbionts (Rhodo-

coccus rhodnii) and pathogens to animals (e.g., R. equi), plants

(Rhodococcus fascians), and humans (e.g., R. equi,R. rhodochrous,

and R. erythropolis)(

135). Rhodococcus equi is the Rhodococcus

species that is most likely to act as a pulmonary pathogen in young

horses and HIV-infected humans (136).

The Rhodococcus genus has had a long and confused taxonomic

pedigree (137,138). However, many of the early uncertainties

have been resolved satisfactorily through the application of che-

motaxonomic and phylogenetic character analyses. In the last edi-

tion of Bergey’s Manual of Systematic Bacteriology, rhodococci

were assigned to two aggregate groups based primarily on chem-

ical and serological properties (21). Key diagnostic characteristics

for rhodococci are the presence of tuberculostearic acid, mycolic

acids with lengths of between 34 and 64 carbon atoms, and with

the major menaquinone type being dihydrogenated menaquino-

nes that possess eight isoprenoid units but which lack the cyclic

element that is the characteristic motif of the Nocardia genus

(135).

Rhodococci are aerobic, Gram-positive, catalase-positive, par-

tially acid-fast, nonmotile actinomycetes that can grow as rods but

also as extensively branched substrate hyphae. Some strains pro-

duce sparse, aerial hyphae that may be branched or form aerial

synnemata, which consist of unbranched ﬁlaments that coalesce

and project upwards (53). Rhodococci are very important organ-

isms with remarkably catabolic versatility, because they carry

genes encoding enzymes that can degrade an impressive array of

xenobiotic and organic compounds (139). In addition to their

bioremediation potential, they produce metabolites of industrial

potential, such as carotenoids, biosurfactants, and bioﬂocculation

agents (140). Some species, such as Rhodococcus rhodochrous, also

synthesize commercially valuable products, such as acrylamide

(135).

The nomenclature of Rhodococcus equi remains controversial.

In a commentary on the nomenclature of this equine pathogen,

Goodfellow et al. (141) noted that the taxon is regrettably left

without a valid name, because Rhodococcus itself is an illegitimate

name and, according to the nomenclature code, should not be

used. “Prescottella equi” was suggested as a new name for the taxon

that would provide nomenclatural stability; consequently, clini-

cians and scientists working on this taxon should adopt the name

“P. equi.”

The genus Leifsonia.Evtushenko et al. (142) introduced the

genus Leifsonia to accommodate Gram-positive, non-spore-

forming, irregular rod- or ﬁlament-shaped, motile, mesophilic,

catalase-positive bacteria containing DL-2,4-diaminobutyric acid

in their peptidoglycan layer. Currently, the genus harbors 12 spe-

cies and two subspecies, with Leifsonia aquatica as the type species.

Members of the genus Leifsonia have been isolated from different

ecological niches, including plants (L. poae and L. xyli), soil (L.

naganoensis and L. shinshuensis), distilled water (e.g., L. aquatica),

Himalayan glaciers, and Antarctic ponds (L. rubra and L. aurea)

(142–146).

Leifsonia xyli comprises two subspecies: L. xyli subsp. cynodon-

tis, a pathogen that causes stunting in Bermuda grass (Cynodon

dactylon), and L. xyli subsp. xyli (142). Information on the biology

and pathogenicity of L. xyli subsp. xyli is limited. Like the gamma-

proteobacterium Xylella fastidiosa,L. xyli subsp. xyli belongs to a

unique group of xylem-limited and fastidious bacterial pathogens

and is the causative agent of ratoon stunting disease, the main

sugarcane disease worldwide (147).

The genus Biﬁdobacterium.Biﬁdobacteria, ﬁrst isolated by

Tissier (148), are the only family of bacteria in the order Biﬁdo-

bacteriales. The Biﬁdobacteriaceae family contains the type genus

Biﬁdobacterium (149), and members of the family Biﬁdobacteri-

aceae have different shapes, including curved, short, and bifur-

cated Y shapes. They were initially classiﬁed as Bacillus biﬁdus

communis. The cells have no capsule and they are non-spore-

forming, nonmotile, and nonﬁlamentous bacteria. The genus en-

compasses bacteria with health-promoting or probiotic proper-

ties, such as antimicrobial activity against pathogens that is

mediated through the process of competitive exclusion (150), and

also bile salt hydrolase activity, immune modulation, and the abil-

ity to adhere to mucus or the intestinal epithelium (151). For

commercial exploitation, biﬁdobacterial strains are typically se-

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lected for fast growth, antibacterial activity, good adhesion prop-

erties, and utilization of prebiotic substrates (151). Among the

many probiotic features that have been attributed to biﬁdobacte-

ria are (i) the induction of immunoglobulin production, (ii) im-

provement of a food’s nutritional value by assimilation of sub-

strates not metabolized by the host, (iii) anticarcinogenic activity,

and (iv) folic acid synthesis (152–154). Some biﬁdobacteria pro-

duce antimicrobials (155) and notably, also bacteriocins (156,

157).

The genus Gardnerella.Classiﬁcation for the genus Gardnerella

is controversial: the genus has often been described as Gram vari-

able but has a Gram-positive wall type (158). Gardnerella vaginalis

is a facultative anaerobic bacterium and the only species of this

genus belonging to the Biﬁdobacteriaceae family (159). G. vaginalis

is strongly associated with bacterial vaginosis, a disease character-

ized by malodorous vaginal discharge, but it also occurs frequently

in the vaginal microbiota of healthy individuals (160). G. vagina-

lis-associated vaginosis is a risk factor for poor obstetric and gy-

necologic outcomes, as well as the acquisition of some sexually

transmitted diseases. In addition, clinical studies have demon-

strated a relationship between G. vaginalis and preterm delivery

(161). The issue of G. vaginalis commensalism is still ambiguous,

as the vaginal bacterial community is dynamic and tends to

change over the menstrual cycle, leading to a transient dominance

of G. vaginalis even in healthy women (162).

The genus Streptomyces.The various mycelial genera of Acti-

nobacteria harbor some of the most complex known bacteria

(163), such as Streptomyces,Thermobiﬁda,and Frankia.Ofthe

three genera, Streptomyces has received particular attention for

three main reasons. First, streptomycetes are abundant and im-

portant in the soil, where they play major roles in the cycling of

carbon trapped in insoluble organic debris, particularly from

plants and fungi. This action is enabled by the production of di-

verse hydrolytic exoenzymes. Second, the genus exhibits a fairly

wide phylogenetic spread (164). Third, streptomycetes are among

Nature’s most competent chemists and produce a stunning mul-

titude and diversity of bioactive secondary metabolites; conse-

quently, they are of great interest in medicine and industry (165).

Streptomycetes are the only morphologically complex Actinobac-

teria whose development has been considered in detail. For more

details on this genus, which serves as a model system for bacterial

antibiotic production, see the section on “Physiology and Antibi-

otic Production of Streptomyces,” below.

The genus Frankia.Frankia is the only nitrogen-ﬁxing actino-

bacterium and can be distinguished by its ability to enter into

symbiotic associations with diverse woody angiosperms known

collectively as actinorhizal plants. The most notable plant genera

in this group are Alnus,Casuarina, and Elaeaginus, and their sym-

biosis with Frankia enables them to grow well in nitrogen-poor

soils (166,167). Like Streptomyces, the DNA of Frankia has a par-

ticularly high G⫹C content of 72 to 73% (2). Frankia can form

three different cell types, growing as mycelia or as multilocular

sporangia. Under nitrogen-limited and aerobic conditions,

Frankia develops so-called vesicles at the tips of hyphae or at the

ends of short side hyphae (168). For a long time, Frankia spp. were

believed to be the only bacteria within the Actinobacteria able to ﬁx

atmospheric nitrogen. However, Gtari et al. (169) recently re-

viewed the sparse physiological and biochemical studies con-

ducted on Actinobacteria over the last 50 years and concluded that

nitrogen ﬁxation within this group is unlikely to be restricted to

frankiae.

The genus Thermobiﬁda.The genus Thermobiﬁda, established

by Zhang et al. (170), was originally assigned to the highly heter-

ogeneous genus Thermomonospora. A phylogenetic analysis based

on 16S rRNA sequences prompted the reclassiﬁcation of Thermo-

biﬁda alba and Thermobiﬁda fusca, which were previously classi-

ﬁed as Thermomonospora species (33,137). Later, Thermobiﬁda

cellulolytica was added to this genus (171). More recently, Ther-

mobiﬁda halotolerans sp. nov. was proposed as representative of a

novel species of Thermobiﬁda (172). Members of the genus Ther-

mobiﬁda are Gram-positive, non-acid-fast, chemo-organotrophic

aerobic organisms that form an extensively branched substrate

mycelium. Thermobiﬁda species are moderately thermophilic,

growing optimally at 55°C, and act as major degraders of plant cell

walls in heated organic materials, such as compost heaps, rotting

hay, manure piles, or mushroom growth medium.

PHYSIOLOGY AND ANTIBIOTIC PRODUCTION OF

STREPTOMYCES

The Streptomyces Life Cycle

Streptomycetes play key roles in soil ecology because of their abil-

ity to scavenge nutrients and, in particular, to hydrolyze a wide

range of polysaccharides (cellulose, chitin, xylan, and agar) and

other natural macromolecules (173). The life cycle of the multi-

cellular mycelial Streptomyces starts with the germination of a

spore that grows out to form vegetative hyphae, after which a

process of hyphal growth and branching results in an intricately

branched vegetative mycelium (174). A prominent feature of the

vegetative hyphae of Streptomyces is that they grow by tip exten-

sion (28). This in contrast to unicellular bacteria, like Bacillus

subtilis and Escherichia coli, where cell elongation is achieved by

incorporation of new cell wall material in the lateral wall (175).

Exponential growth of the vegetative hyphae is achieved by a com-

bination of tip growth and branching. The fact that cell division

during vegetative growth does not lead to cell ﬁssion but rather to

cross-walls that separate the hyphae into connected compart-

ments (176) makes streptomycetes a rare example of a multicel-

lular bacterium, with each compartment containing multiple cop-

ies of the chromosome (177,178). The spacing of the vegetative

cross-walls varies signiﬁcantly, both between different Streptomy-

ces species and within individual species between different growth

conditions and mycelial ages.

Under adverse conditions, such as nutrient depletion, the veg-

etative mycelium differentiates to form erected sporogenic struc-

tures called aerial hyphae. This is also the moment in the life cycle

when most antibiotics are produced (179,180). Streptomyces and

other ﬁlamentous microorganisms are sessile; when nutrient de-

pletion occurs, the vegetative or substrate mycelium is autolyti-

cally degraded by a programmed cell death (PCD)-like mecha-

nism to acquire the building blocks needed to erect a second mass

of (aerial) mycelium (181–183). PCD results in the accumulation

of amino acids, aminosugars, nucleotides, and lipids around the

lysing substrate mycelium (184–186), which inevitably attract

motile competing microbes in the habitat; it is logical to assume

that antibiotics are produced at this time to protect the pool of

nutrients. One well-studied system revolves around the PCD-re-

sponsive nutrient sensory regulator DasR, which controls early

development and antibiotic production and responds to the accu-

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mulation of cell wall-derived N-acetylglucosamine (186,187).

The role of DasR as a regulator of antibiotic production is dis-

cussed in more detail in the section on controlling antibiotic pro-

duction. A cascade of extracellular proteases and protease inhibi-

tors also plays a well-established role in PCD and development in

streptomycetes, as reviewed elsewhere (173,188).

Two rounds of PCD occur during the Streptomyces life cycle

(189). After spore germination, a compartmentalized mycelium

grows out and then undergoes a ﬁrst round of PCD that affects the

material formed during early vegetative growth. This is then fol-

lowed by a second round of PCD that is initiated during the onset

of development (189). At this stage, the vegetative or substrate

hyphae are lysed so as to provide nutrients for the next round of

biomass formation, i.e., the growth of the aerial mycelium. The

aerial hyphae give the colonies their characteristic ﬂuffy appear-

ance and eventually differentiate to form chains of unigenomic

spores (23). Genes that are required for the formation of aerial

hyphae are referred to as bld genes, in reference to the bald (“hair-

less”) phenotype of mutants lacking the ﬂuffy aerial hyphae (190),

while mutants whose development is blocked at a stage prior to

sporulation are called whi (white), due to their failure to produce

the gray spore pigment (174,191).

Genes that are required for aerial growth or for sporulation

were originally identiﬁed by screening for mutants after random

mutagenesis by using UV irradiation or treatment with chemical

mutagens, or by transposon-mediated mutagenesis, resulting in a

collection of bld and whi mutants that were subsequently classiﬁed

on the basis of their morphology (174,190–195). Several new

classes of developmental genes have been identiﬁed on the basis of

physiological criteria, such as the acceleration of aerial mycelium

formation in S. lividans (ram genes, for rapid aerial mycelium

[196]), complementation of mutants of S. griseus with disturbed

sporulation (ssgA-like genes, for sporulation of Streptomyces gri-

seus [197]), or disruptions in sugar metabolism (186,198,199).

Most bld and whi genes that have been identiﬁed to date have a

(predicted) regulatory function at the transcriptional or transla-

tional level, with many encoding predicted transcription factors.

Some of the best-studied examples are bldD, a highly pleiotropic

transcription factor that controls hundreds of development-re-

lated genes (200–202), the RNA polymerase ␴factors bldN (203)

and whiG (204,205), which control early events during sporula-

tion (although bldN is also strongly transcribed during aerial

growth), and whiH, which controls the onset of sporulation-spe-

ciﬁc cell division (206,207). There is also extensive control at the

translational level. A wonderful example is bldA, which speciﬁes a

tRNA molecule responsible for the translation of the rare leucine

codon UUA (208,209). Deletion of bldA has a pleiotropic effect on

gene expression in streptomycetes (210,211). A major target of

bldA-mediated translational control is bldH (adpA), which en-

codes an important global regulator of development and antibi-

otic production (212–215). Transcription of adpA is activated in

response to the ␥-butyrolactone A-factor in S. griseus and to the

related molecule SCB1 in S. coelicolor (216–220). An interesting

feedback loop exists whereby the translation of the adpA mRNA

depends on BldA (221,222), while AdpA in turn controls bldA

transcription (223).

Recently, it was elegantly shown by the group of Mark Buttner

that the activity of BldD, which represses many developmental

genes during vegetative growth, is controlled posttranslationally

by the signaling molecule cyclic-di-GMP (CDG) (224). Binding of

tetrameric CDG to BldD brings together the DNA binding do-

mains of the BldD dimer, thus enabling the protein to bind to its

target sites (224). An example of metabolic control is presented by

the pleiotropic nutrient sensory regulator DasR, which is essential

for development and pleiotropically represses antibiotic produc-

tion (see below). DNA binding by DasR is controlled by the bind-

ing of GlcNAc-related metabolites as ligands (186,225). An over-

view of key developmental events and regulatory networks in

streptomycetes is presented in Fig. 4. An extensive overview of the

very complex and intriguing regulatory networks that control

the onset of sporulation is beyond the scope of this review; we refer

the reader to the excellent previously published reviews of this

ﬁeld for further information (23,173,188,226,227).

Environmental Control of Aerial Hypha Formation

In addition to being defective in aerial hypha formation, early

developmental (bld) mutants also exhibit disrupted antibiotic

production. This underlines the connection between develop-

ment and secondary metabolism (see below). Most bld mutants

fail to produce antibiotics, although some, in particular bldF, are

antibiotic overproducers. By deﬁnition, all of the nonessential

genes that are required for aerial hypha formation are bld genes.

Extracellular complementation experiments where bld mutants

were grown in close proximity to one another without physical

contact suggested the existence of a hierarchical relationship be-

tween at least some of the bld genes (228–231). Aerial hypha for-

mation could be restored from one bld mutant to another, which

is consistent with the idea of a signaling cascade that generates a

signal that ultimately leads to the onset of development. However,

these experiments were almost exclusively performed on a single

reference medium, namely, nutrient-rich R2YE agar plates with

glucose, and many bld mutants have a conditional bald pheno-

type—in other words, they are able to produce at least some aerial

hyphae and spores on minimal media with nonrepressive carbon

sources, such as mannitol (192,198,227). A logical assumption is

that this is the result of carbon catabolite repression (CCR),

whereby favorable carbon sources such as glucose signal the pres-

ence of abundant food, thus favoring growth over development

and antibiotic production (232,233).

In streptomycetes, CCR largely depends on the glycolytic en-

zyme glucose kinase, and deletion of the glkA gene encoding glu-

cose kinase therefore abolishes CCR (232,234,235). Suggestively,

deleting glkA in bldA mutants of S. coelicolor restores their ability

to sporulate on glucose-containing media (236). Conversely, mu-

tants that lack the bldB gene (which encodes a small 99-amino-

acid [aa] protein) are defective in CCR, although the mode of

action of BldB is as yet unclear (192,237). It should be noted that

Glk-independent pathways of CCR that affect development and

antibiotic production also exist, adding further complexity to the

picture (238). Other bld genes relevant to sugar metabolism are

ptsH,ptsI, and crr, which encode the global components HPr,

enzyme I (EI), and enzyme IIA (EIIA

Crr

), respectively, of the

phospohoenolpyruvate (PEP)-dependent phosphotransferase

system (PTS), which transports sugars such as N-acetylgluco-

samine and fructose in S. coelicolor (239,240). Other examples are

dasABC, which encodes a chitobiose sugar transporter (199,241),

and the pleiotropic sugar regulators atrA (242) and dasR (186,

187). Perhaps surprisingly, the nonsporulating phenotype of the

das and pts transport mutants is independent of the carbon source

and thus probably also of the transport activity (186,199,241).

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These examples highlight the important and complex connections

between carbon utilization and development in streptomycetes.

Metals also play a key role in the onset of development. Strep-

tomyces lividans requires a large amount of copper for proper aer-

ial growth (243). This defect can be rescued by enhanced expres-

sion of the ram cluster (196), which ultimately leads to the

production of the surfactant SapB (see the next section). Recently,

Sébastien Rigali and colleagues showed that development can be

restored to bldJ and bldK mutants by supplementing R2YE agar

with iron (244). The bldK gene cluster encodes an oligopeptide

transporter (228,245), while the function of bldJ is unknown

(228). Interestingly, mass spectrometric analysis revealed that all

of the bld mutants that were tested showed either severely reduced

(for bldA,bldJ, and ptsH mutants) or enhanced (for bldF,bldK,crr,

and ptsI mutants) production of the iron-binding siderophore

desferrioxamine (244). The same paper also mentioned unpub-

lished data suggesting that deregulated desferrioxamine produc-

tion occurs in bldB,bldC,bldD,dasA, and adpA mutants when

grown on R2YE agar plates and may thus be a more general feature

of many bld mutants (244). Further complications arise from the

fact that both bldJ mutants and mutants lacking the citA gene for

citrate synthase (which also fail to develop on R2YE under “stan-

dard” conditions), do successfully develop on R2YE when the me-

dium is strongly buffered (246). Besides shedding more light on

the nature of bld mutations, these experiments also show that

environmental factors, such as metal availability, pH, and carbon

and nitrogen sources, have profound effects on the onset of devel-

opment, and so the composition of the medium should be con-

sidered very carefully when planning experiments to study devel-

opment in streptomycetes.

Facilitating Aerial Growth: the Roles of Chaplins, Rodlins,

and SapB

Aerial hyphae differ substantially from vegetative hyphae. One

major difference is that aerial hyphae of wild-type cells typically do

not branch extensively, are nearly twice as wide as vegetative hy-

phae, and undergo rapid growth. The aerial hyphae are also sur-

rounded by a sheath that later becomes part of the spore coat

(247–251). This sheath is hydrophobic on the air-facing side, al-

lowing the aerial hyphae to break through the moist soil-air sur-

face with the assistance of the turgor pressure generated by the

hyphae (252,253), similarly to what has been proposed for fungi

(254). Chaplins are potent surfactants, reducing the surface ten-

sion from 72 to 24 mJ m

⫺2

(247,255). An important function of

the sheath may also be to create a channel along the outer hyphal

wall that can facilitate nutrient transport, as proposed by Keith

FIG 4 Major events during development of Streptomyces. Nutrient stress is a major trigger of development, leading to the accumulation of ppGpp, resulting in

cessation of early growth and repression of the nutrient sensory DasR protein by cell wall-derived metabolites following PCD of the substrate mycelium. Bld

proteins and environmental signals control the procession toward aerial growth and antibiotic production. The developmental master regulator BldD (when

bound to tetrameric cyclic-di-GMP) represses the transcription of genes for many key developmental regulatory proteins, including WhiB, WhiG, SsgA, and

SsgB, as well as FtsZ. Chaplins and SapB provide a supportive hydrophobic layer to allow aerial hyphae to become erect and break through the moist soil surface.

White proteins control aerial growth, whereby WhiAB and SsgB likely play a role in growth cessation. Eventually, FtsZ accumulates and localizes to septum sites

in an SsgAB-dependent manner. Ladders of FtsZ are formed, which subsequently delimit the spore compartments. Chromosome condensation and segregation

are followed by septum closure and spore maturation. The onset of antibiotic production typically correlates temporally to the transition from vegetative to aerial

growth. Solid black arrows represent major transitions in development. Dark dotted lines indicate transcriptional control (arrows for activation, ovals for

repression).

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Chater (173,256). This argument suggests that nutrients and

other metabolites might diffuse from the vegetative hyphae in the

basal part of the colony up to the growing tips of the aerial hyphae

(173,256), which would be an attractive alternative to transport

through hyphae and could potentially resolve the longstanding

debate about how nutrients are transported efﬁciently across long

distances over the cross-walls (188).

The sheath consists of a number of hydrophobic proteins, in

particular chaplins and rodlins (230,247,249,257–260). To-

gether, these proteins form the so-called rodlet layer, which

decorates the spores with a seemingly random pattern of small

lines running in all directions; high-resolution electron mi-

croscopy shows that these lines consist of small protein assem-

blies (Fig. 5). Typical rodlet layer formation depends on the

rodlin proteins RdlA and RdlB; deletion of the rdl genes instead

results in decoration with ﬁne lines consisting of the chaplins

(248). S. coelicolor contains eight chaplins, three large ones

(ChpABC) with two chaplin domains and a sortase domain and

ﬁve smaller chaplins (ChpDEFGH) bearing a single chaplin

domain (247,249). The chaplins assemble on the hyphal sur-

face into an amphipathic protein layer that consists of amyloid-

like ﬁbrils. Of the chaplins, the vegetatively expressed ChpC,

ChpE, and ChpH proteins are sufﬁcient for sporulation (261).

ChpE and ChpH are secreted into the surrounding medium to

reduce the surface tension so as to enable the hyphae to grow

into the air (247,255).

Closer analysis of the ChpH protein showed that it has two

amyloidogenic domains at its N and C termini, which are both

required for aerial hypha formation, while only the C-terminal

domain is required for assembly of the rodlet ultrastructure

(262). In addition to the chaplins, there are two rodlin proteins

that also contribute to the development of the sheath’s rodlet

ultrastructure and the spore surface (258). Suggestively, most

of the genes for the chaplins and the two rodlin genes lie in

close proximity on the genome (263). However, the rodlins are

not required for sporulation, even though they are needed for

the sheath’s development into paired rodlet structures (258). It

is clear that these hydrophobic structural proteins play key

roles in the aerial development of streptomycetes, but the pre-

cise role of each of the individual components remains to be

resolved.

In addition to ChpE and ChpH, the onset of aerial growth

requires the extracellular accumulation of yet another hydro-

phobic surfactant, SapB (230,264). SapB-type proteins are

widespread in streptomycetes; well-studied examples include

AmfS in S. griseus and SapT in S. tendae (265,266). In S. coelicolor,

SapB is encoded by the ramS gene in the ramCSAB gene cluster

(196,267), which is controlled by the orphan response regulatory

gene ramR (268–270). In turn, at least in S. griseus, transcription of

the amf operon, and thus of amfS, depends on AdpA and therefore

ultimately also on BldA (215). RamS is produced as a 42-aa pro-

peptide that is subsequently modiﬁed and exported in a way very

similar to that for lantibiotics, although the way the propeptide is

processed is yet unknown. During modiﬁcation by RamC, four

dehydroalanine residues and two lanthionine bridges are intro-

duced (271). Thus, a highly modiﬁed 21-aa molecule of 2,027 Da

is produced (271), with all the structural and genetic features of

type II lantibiotics (259,272). Despite the exciting insights that

have been obtained into the biological role of SapB so far, the

precise mechanism by which it controls the developmental growth

of streptomycetes awaits further elucidation, as do the transcrip-

tional and posttranscriptional control mechanisms underlying its

biosynthesis (273).

As a ﬁnal comment on this topic, it is important to note that

even the extracellular addition of the fungal hydrophobin SC3

(obtained from the basidiomycete Schizophyllum commune) re-

stores aerial growth to several bld mutants of S. coelicolor that are

deﬁcient in the production of chaplins and/or SapB (264,265).

FIG 5 Scanning electron micrograph of the surface layer of mature spores, revealing a distinctive rodlet layer. This layer consists of hydrophobic chaplin (Chp)

and rodlin (Rdl) proteins. Bar, 100 nm.

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This again underlines the importance of the extracellular accumu-

lation of a hydrophobic layer for the early stages of aerial growth.

From Aerial Hyphae to Spores: Sporulation-Speciﬁc Cell

Division and the Cytoskeleton

Like vegetative hyphae, aerial hyphae grow by tip extension. Once

sufﬁcient aerial biomass is generated, a signal is transmitted that

results in growth cessation, followed by the onset of sporulation.

The signal for growth cessation is not yet known but likely relates

to the Whi regulatory proteins WhiA and WhiB, as well as the cell

division activator SsgB. Mutations of whiA and whiB produce

identical phenotypes, with hypercoiling and very long aerial hy-

phae that fail to initiate cell division (23,174,274), while ssgB

mutations produce a large colony phenotype, forming an ex-

tremely large aerial biomass (275).

The landmark event in the onset of sporulation is the initiation

of sporulation-speciﬁc cell division, which is notable because the

process of cell division is completely different between vegetative

and aerial hyphae. Wonderful movies of septum formation during

early growth of the hyphae of S. coelicolor show how irregular the

placement of septa is in vegetative hyphae, with cross-walls divid-

ing the vegetative hyphae into multigenomic compartments

(276). In contrast, during sporulation-speciﬁc cell division in aer-

ial hyphae, many septa are formed almost simultaneously and in a

highly symmetrical fashion, followed by the formation of spore

compartments and cell ﬁssion, resulting in chains of spores that

each contain a single copy of the chromosome (reviewed in refer-

ences 277 and 278). Most bacteria divide by binary ﬁssion,

whereby a single mother cell symmetrically divides into identical

daughter cells. This process involves the formation of a cytokinetic

ring structure, of which the scaffold is formed by the polymeriza-

tion of thousands of copies of the tubulin homolog FtsZ at divi-

sion sites (279–283). However, in streptomycetes, the long aerial

hyphae differentiate into chains of spores after a uniquely coordi-

nated cell division event. Distinctive ladders of FtsZ are thereby

produced that consist of up to 100 septa, and this eventually leads

to the production of chains of haploid spores (284–286). Sufﬁ-

cient accumulation of FtsZ is required to support sporulation, and

developmental ftsZ transcription is largely dependent on the

“early” whi regulatory genes whiA,whiB,whiG,whiH,whiI, and

whiJ (287). Consistent with the notion that the control of ftsZ

transcription may be a key event, at least in S. coelicolor, the non-

sporulating phenotype of many of these early whi mutants could

be overruled by constitutive expression of ftsZ during develop-

ment (288). This also suggests that no other genes that are re-

quired for sporulation completely depend on these whi genes, at

least not when FtsZ is overexpressed.

A unique feature of Streptomyces biology is that cell division is

not required for growth and ftsZ null mutants are viable (289).

While the ftsZ mutant also fails to make cross-walls, most of the

other cell division mutants are only defective in sporulation-spe-

ciﬁc cell division (278,290–293). This illustrates a major differ-

ence between vegetative and aerial cell division.

While sporulation-speciﬁc cell division is mechanistically very

similar to that in bacteria that divide by binary ﬁssion, the way

septum site localization is controlled is completely different, in-

volving actinomycete-speciﬁc proteins (177,277,278). In unicel-

lular bacteria, the positioning and timing of the formation of a

septum involves the action of negative-control systems such as

Min, which prevents Z-ring assembly at the cell poles (294,295),

and nucleoid occlusion, which prevents DNA damage by blocking

Z-ring formation over nonsegregated chromosomes (296). The

Z-ring is tethered to the membrane by dedicated anchoring pro-

teins, such as FtsA and ZipA in Escherichia coli (297,298). All of

these systems are absent in streptomycetes. It is therefore unclear

how streptomycetes avoid DNA damage in the multinucleoid hy-

phae. Elegant work on DNA partitioning revealed the important

role of the ParAB proteins in DNA segregation during growth and

development (299–301). FtsK helps to avoid “guillotining” of the

DNA by pumping chromosomes into the spore compartments

prior to septum closure, and ftsK mutants frequently generate

spores with incomplete chromosomes (302–304). Other proteins

that should be considered are SmeA and SffA, which play key roles

in DNA translocation during sporulation (302), and also the

DNA-packaging proteins HupS (305), sIHF (306,307), Smc

(308), and Dps (309).

In terms of septum site localization, a key role is played by the

SsgA-like proteins (SALPs), which only occur in sporulating acti-

nobacteria (310,311). SsgA activates sporulation-speciﬁc cell di-

vision (312,313), and both ssgA and ssgB are required for sporu-

lation (275,314,315). The symmetrical spacing of the many

Z-rings is achieved by SsgB, which directly recruits FtsZ and also

stimulates its polymerization (316). SsgB localizes to future divi-

sion sites prior to and independent of FtsZ (316). Thus, cell divi-

sion is positively controlled in streptomycetes (Fig. 6). The next

obvious question is how SsgB itself is localized, especially given

that it lacks a membrane domain. Another important cell division

protein that controls sporulation-speciﬁc cell division in Strepto-

FIG 6 Model for the control of sporulation-speciﬁc cell division in Strepto-

myces. When sporulation starts, SsgA localizes dynamically in young aerial

hyphae, while SsgB and FtsZ are still diffuse at this stge. At this point, ParA is

constrained to the hyphal tip. During early cell division, SsgA and SsgB colo-

calize temporarily at either side of the aerial hyphae, with ParA extending

downward as ﬁlaments along the aerial hypha. ParB complexes are then

formed over the uncondensed chromosomes, while FtsZ assembles in spiral-

like ﬁlaments. Subsequently, FtsZ and SsgB colocalize and stay together until

FtsZ disperses, whereby SsgB recruits FtsZ and stimulate its polymerization

into protoﬁlaments. The way the SsgB-FtsZ complex is tethered to the mem-

brane in the absence of a membrane domain in either protein is unclear, but a

likely role is played by the SepG protein (SCO2078 in S. coelicolor) encoded by

a gene upstream of divIVA (L. Zhang, J. Willemse, D. Claessen, and G. P. van

Wezel, unpublished data). Z-rings are then formed at the sporulation stage,

followed by chromosome condensation and segregation and the production of

sporulation septa. SsgA eventually marks the future germination sites. The

ﬁgure was adapted from references 277 and 316.

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myces is CrgA, which affects sporulation-speciﬁc cell division by

inﬂuencing Z-ring assembly (317). In contrast to the SALPs, CrgA

also occurs in nonsporulating actinomycetes, and it interacts with

FtsZ, FtsI, and FtsQ in Mycobacteria (318). The phenotypes of crgA

null mutants and overexpressing strains suggest that CrgA affects

both cell division and the cytoskeleton, although its precise mode

of action is still unknown.

Streptomycetes probably have a much more elaborate cytoskel-

eton than most other bacteria, which may be explained by their

hyphal rather than planktonic growth (319). Besides the tubulin

homolog FtsZ and the actin-like proteins MreB and Mbl (320,

321), a large number of proteins with coiled-coil structural ele-

ments occur in these bacteria, and evidence is accumulating re-

garding their important role in growth, cell shape, and morpho-

genesis (319,322–324). The protein FilP forms intermediate

ﬁlament-like structures that contribute to mechanical stress resis-

tance (322). In addition, the Scy protein, encoded by a gene im-

mediately adjacent to ﬁlP, apparently functions as a “molecular

assembler” and sequesters DivIVA (323). DivIVA is essential for

growth in streptomycetes and localizes to tips to drive apical

growth, although the molecular mechanism of this process is still

unclear (325,326). In this way, Scy establishes growth nuclei for

apical growth and branching. It also interacts with the chromo-

some-partitioning protein ParA (327) and the intermediate ﬁla-

ment-like protein FilP, which in turn interacts with DivIVA. The

apical assembly that drives tip growth was termed the tip organiz-

ing complex (TIPOC) by Gabriella Kelemen and colleagues (323,

328,329). SsgA (330) and the polysaccharide synthase CslA (323,

328,329) are other proteins that are part of this TIPOC. Clearly,

we can only see the tip of the iceberg at present, and future discov-

eries will undoubtedly shed new light on these processes.

STREPTOMYCETES AS ANTIBIOTIC FACTORIES

Actinomycetes produce approximately two-thirds of all known

antibiotics, the majority of which are produced by streptomycetes.

Consequently, these microorganisms are very important in the

ﬁght against emerging multidrug-resistant pathogens (331–333).

Streptomyces coelicolor is a model system for studying (the control

of) antibiotic production. Scientists have marveled for decades at

the ability of single streptomycetes species to produce a plethora of

different antibiotic compounds. For example, those produced by

S. coelicolor include actinorhodin (Act [334]), undecylprodigiosin

(Red [335]), calcium-dependent antibiotic (CDA [336]), and

methylenomycin (Mmy [337]), the latter of which is carried on a

plasmid. However, when the genome sequence of S. coelicolor was

published (263), it became apparent that this species’ true poten-

tial as a producer of natural products had actually been underes-

timated: over 20 biosynthetic gene clusters for secondary metab-

olites were identiﬁed (338), including one that appears to be for

the production of a cryptic polyketide antibiotic (Cpk [339]). It

rapidly became apparent that such “concealment” of antibiotic-

producing capabilities is the norm rather than the exception, with

some streptomycetes harboring more than 50 different secondary

metabolite gene clusters (340–343). It therefore appears that the

potential of these organisms for novel drug production is much

greater than originally anticipated. This has prompted extensive

research in applied genomics into so-called cryptic, silent, or

sleeping antibiotics (reviewed in references 344 to 347) and meth-

ods for activating their biosynthesis (348–352).

Correlation between Growth and Antibiotic Production

Programmed cell death and the DasR system. The production of

antibiotics (and other secondary metabolites) is temporally cor-

related to the onset of development in the Streptomyces life cycle

(179,180). This correlation may exist because of the need to de-

fend the colony when it is undergoing PCD. Evidence supporting

such a direct link between PCD and antibiotic production was

provided by the observation that cell wall-derived N-acetylgluco-

samine (GlcNAc) acts as a signal for the onset of development and

as a global elicitor molecule for antibiotic production (186,187).

In competitive soil habitats, the timing of development is crucial.

However, it is not clear how colonies know when to initiate this

process, which has such major consequences for the colony. As

long as sufﬁcient nutrients are available, growth should prevail

over development, while during starvation, sporulation and sub-

sequent spore dispersal are essential for the survival of the prog-

eny. The signals that trigger such events should be unmistakable,

and GlcNAc may serve this purpose well. In nature, GlcNAc can be

obtained from hydrolysis of the abundant natural polymer chitin

by the chitinolytic system, or from hydrolysis of microorganism

cell walls. For bacteria, GlcNAc is a favorable C and N source and

a major constituent of the cell wall peptidoglycan. Some 13 chiti-

nases and chitosanases have been identiﬁed in S. coelicolor (353–

355).

Interestingly, under poor nutritional conditions, supplement-

ing with GlcNAc accelerates both the onset of development and

antibiotic production, suggesting that under these conditions

GlcNAc signals nutrient stress, resulting in accelerated develop-

ment. Conversely, in rich media, higher concentrations of GlcNAc

block development and antibiotic production, thus inducing a

response typical of vegetative growth (187). The different growth

conditions of minimal and rich media likely resemble conditions

of feast or famine in the natural environment (i.e., the soil), with

GlcNAc acting as an important signaling molecule that would

typically be derived from chitin in nutrient-rich soil during feast

periods or from the Streptomyces cell walls during PCD (famine),

respectively. The secret of this dual signaling role appears to lie in

the nature of the sugar transporters. Monomeric GlcNAc enters

the cell via the NagE2 permease (356), which is part of the PEP-

dependent phosphotransferase system (PTS) (357,358), while

chitobiose (dimeric GlcNAc), which is the subunit of chitin, en-

ters via the ABC transporters DasABC or NgcEFG (241,353,359).

Subsequently, internalized GlcNAc is converted by the enzymes

NagA and NagB to glucosamine-6-phosphate (GlcN-6-P) (360), a

central metabolite that can then enter glycolysis (as fructose-6P)

or the pathway toward peptidoglycan synthesis.

GlcNAc-derived GlcN-6-P acts as an allosteric effector of the

GntR family regulator DasR (186), a global regulator that controls

the GlcNAc regulon (186,360,361), and also the production of

antibiotics (187) and siderophores (362). GlcNAc-dependent nu-

tritional signaling is most likely mediated through changes in the

intracellular level of GlcN-6-P, which binds as a ligand to the GntR

family regulator DasR, leading to derepression of DasR-mediated

control of antibiotic production (187). As shown by genome-wide

transcription and ChIP-on-chip analysis, all pathway-speciﬁc ac-

tivator genes for antibiotic biosynthetic gene clusters are con-

trolled by DasR (363). Thus, antibiotic biosynthesis and secretion

is induced by adding GlcNAc to minimal medium with a poor

carbon source. As mentioned above, these conditions activated

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the cpk gene cluster (187), which encodes genes that for the cryptic

polyketide Cpk and was more recently established as coelimycin

P1 (364). This suggests that similar conditions could be used to

activate other cryptic antibiotic gene clusters which are expressed

poorly (or not at all) under normal growth conditions.

It was recently shown that “hostile” interactions between

streptomycetes such as antibiosis and suppression of production

by competitors primarily occur under nutrient-limiting condi-

tions; conversely, under nutrient-rich conditions, social interac-

tions are favored (365). These observations suggest that antibiot-

ics are indeed used as weapons in nature. This concept is in

contrast with studies suggesting that antibiotics act as signals for

intercellular communication (366–368). The latter hypothesis is

based on the rationale that the secreted antibiotics may not reach

sufﬁciently high concentrations to cause appreciable growth inhi-

bition and the observation that subinhibitory concentrations of

antibiotics induce responses such as bioﬁlm formation (369)or

virulence (370) that may beneﬁt the target cells (371). In terms of

concentrations in the soil, the same argument can be made for

GlcNAc, which only activates antibiotic production at millimolar

concentrations on agar plates. Presumably, small molecules reach

higher local concentrations, for instance, in close proximity to a

producing colony or, in the case of natural products, by binding to

dead plant or animal material. In this context, it is worth remem-

bering that cellulose is a preferred column material for the puriﬁ-

cation of natural products. Information on the interactions be-

tween microbes is not just of ecological and evolutionary

importance, since it could also be useful in drug discovery efforts.

Indeed, data on the interactions between microbes could provide

key clues concerning the activation of cryptic biosynthetic path-

ways (372–376).

Stringent control. As discussed, nutrient deprivation and the

resulting growth cessation are the primary triggers for the onset of

antibiotic production. Starvation results in the depletion of amino

acids and hence uncharged tRNAs, which then occupy the ribo-

somal A-site. This in turn induces the production of the small

molecules guanosine tetraphosphate and pentaphosphate (377).

However, (p)ppGpp, or “magic spot,” as it was originally known,

is produced in response to basically all processes that relate to

changes in nutrient availability and might affect growth, adapta-

tion, secondary metabolism, survival, persistence, cell division,

motility, bioﬁlm formation, development, competence, and viru-

lence (378). The synthesis of (p)ppGpp from GTP and ATP can be

carried out by either RelA, which is ribosome associated and acti-

vated by the binding of uncharged tRNAs to the ribosome, or by

SpoT, which produces (p)ppGpp in response to nutrient starva-

tion (378). The ribosomal protein L11, encoded by rplI (relC),

activates RelA and thus ppGpp synthesis (379). Deletion of the

relA gene suppresses antibiotic production, underlining the im-

portant role of the stringent response in controlling antibiotic

production (380). Indeed, under nitrogen-limiting conditions

ppGpp causes a dramatic switch in the physiology of streptomy-

cetes, activating the expression of genes involved in morphologi-

cal and chemical differentiation, including the production of CDA

and actinorhodin, and at the same time repressing genes involved

in normal growth (381). The exact mechanism by which ppGpp

acts upon such a wide range of genes remains to be elucidated.

However, the response to fatty acid starvation involves the direct

binding of the unacylated (“uncharged”) fatty acid acyl carrier

protein (ACP) to SpoT (382), and it has been suggested (180) that

perhaps the ACPs of polyketide synthases help to control the strin-

gent response in a similar fashion, providing a possible explana-

tion of the relationship between the stringent response and sec-

ondary metabolism.

Morphological control. A complex relationship exists between

morphology and antibiotic production. Streptomycetes display a

great many different morphologies in submerged cultures, rang-

ing from fragmented growth to dense clumps, and this can have a

major inﬂuence on their production levels (24). For example, in

Saccharopolyspora erythraea, erythromycin production is favored

by clumps with a minimum size of around 90 ␮m in diameter

(383). The connection between mycelial morphology and produc-

tion is further exempliﬁed by avermectin production by S. aver-

mitilis, which is favored by small dense pellets (384), and by S.

coelicolor,in which forced fragmentation by overexpression of the

cell division activator protein SsgA abolishes actinorhodin pro-

duction. However, it is dangerous to generalize, as the same strain

shows a 20- to 50-fold increase in undecylprodigiosin production

in a fermentor (310,313,315), and chloramphenicol production

by Streptomyces venezuelae is not hampered by the extremely frag-

mented growth of the producing organism (385,386). It was pre-

viously suggested that antibiotics that are produced during expo-

nential growth may beneﬁt from fragmented growth, while those

produced during the transition or stationary phases are produced

much more efﬁciently by clumps (236).

More insights into the genetic factors that control mycelial

growth should allow scientists to signiﬁcantly improve the yield of

natural product formation by actinomycetes. A novel set of genes

was recently discovered in Streptomyces that control pellet growth,

called mat, for mycelial aggregation (387). The genes were discov-

ered 30 years ago via reverse engineering of a strain of S. lividans

that was selected for fragmented growth in a chemostat (388).

Deletion of the mat genes (SCO2962 and SCO2963 in S. coelicolor)

prevented pellet formation and increased both growth rate and

enzyme production in S. lividans (387). The mat genes are prob-

ably responsible for the production of a secreted polysaccharide,

which presumably glues the hyphae together and thus promotes

pellet aggregation.

In silico models have been developed to better understand my-

celial growth (389–391), although many were primarily based on

physiological and nutritional parameters. Helped by the strong

increase in computing power in the modern era, new models were

developed recently (392,393). In particular, a three-dimensional

model was developed that includes parameters such as hyphal

growth, branching, fragmentation, cross-wall formation, and col-

lision detection, as well as oxygen diffusion (392). For the rational

design of actinomycetes as production hosts, it is imperative that

we better understand how morphology correlates with produc-

tion. For example, when and especially where are natural products

(and enzymes) secreted? Secretion at apical sites would imply that

fragmented growth is favorable because it increases the number of

hyphal tips per length unit, as opposed to when production pri-

marily takes place inside mycelial clumps. Interestingly, produc-

tion of enzymes through the twin arginine translocation (Tat)

exporter occurs closely behind the hyphal tips in S. coelicolor (16,

394); in line with this concept, Tat substrates are secreted more

efﬁciently in fragmenting strains of S. coelicolor and S. lividans

(313). An extensive review of the industrial implications of the

correlation between growth and natural product formation is be-

Biology of Actinobacteria

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yond the scope of this review, so we refer the interested reader

elsewhere (24,395–398).

From global control to the activation of speciﬁc gene clusters.

The global regulatory networks ultimately relay information to-

ward the individual biosynthetic gene clusters, acting at the level

of pathway-speciﬁc control. Transcription of antibiotic biosyn-

thetic gene clusters typically depends on a pathway-speciﬁc acti-

vator gene inside the cluster. Many of these are controlled in a

growth phase-dependent manner, with the SARP family regula-

tors (399) being the best-known examples. Particularly well-

known members of this family are ActII-ORF4 and RedD, which

activate the production of the pigmented antibiotics actinorhodin

and undecylprodigiosin, respectively, in S. coelicolor, and StrR for

production of the aminoglycoside streptomycin in S. griseus (400–

402). As exempliﬁed by the actinorhodin biosynthetic activator

gene actII-ORF4, transcription of which is controlled by over 15

different regulatory proteins, the timing and accumulation of a

pathway-speciﬁc activator may be very complex (236,395). How-

ever, once activated, there appears to be little additional control

downstream, as long as the necessary precursors are present. In-

deed, when redD, the pathway-speciﬁc activator gene for produc-

tion of prodigionines in S. coelicolor, is placed under the control of

another regulatory element, the result is that control of prodi-

gionin production becomes dictated by the regulatory network

controlling that element (275,314,315). In other words, placing

redD under the control of the promoter for the global nitrogen

regulator (glnR) or the sporulation-speciﬁc sigma factor (sigF)

ensures that production is controlled by nitrogen or produced in

aerial hyphae, respectively. This implies that there may be few

genetic limitations regarding the production of natural products

in time and space once an appropriate activator is expressed. From

a production point of view this is an advantage, because restric-

tions due to growth phase-related control mechanisms can be

dealt with by changing the regulatory element. This is particularly

important for heterologous expression of biosynthetic gene clus-

ters that are being uncovered at a high rate in actinomycetes in the

era of genome sequencing. In particular, the combination of syn-

thetic biology approaches with expression in optimized heterolo-

gous Streptomyces production platforms is a promising develop-

ment (403–408).

ACTINOBACTERIA AS SOURCES OF NATURAL PRODUCTS

Actinobacteria as Sources of Antibiotics

Actinobacteria are of great importance in the ﬁeld of biotechnol-

ogy, as producers of a plethora of bioactive secondary metabolites

with extensive industrial, medical, and agricultural applications

(Table 3 provides examples and corresonding references). In par-

ticular, Actinobacteria produce the majority of the naturally oc-

curring antibiotics. The ﬁrst antibiotics discovered in Actinobac-

teria were actinomycin from a culture of Streptomyces antibioticus

in 1940 (409), streptothricin from Streptomyces lavendulae in 1942

(410), and streptomycin from Streptomyces griseus in 1944 (411),

all of which were discovered by Waksman and colleagues. Strep-

tomycetes have been the major source of clinical antibiotics and

are responsible for over 80% of all antibiotics of actinobacterial

origin (333). That actinomycin, streptomycin, and streptothricin

were the ﬁrst to be found is not surprising, as these molecules

occur at much higher frequencies than many other antibiotics. For

example, streptothricin is found in some 10% of all streptomyce-

tes isolated randomly from soil and streptomycin is found in 1%

and actinomycin in 0.1%, while conversely, erythromycin and

vancomycin are found in around 10

⫺5

soil isolates, and daptomy-

cin is found only at a frequency of around 10

⫺7

(412). Major

classes of clinical antibiotics produced by actinomycetes are the

following: aminoglycosides (neomycin, kanamycin, streptomycin

(413–415), angucyclines (auricin; also, antitumor agents like lan-

domycin and moromycin (416), ansamycins (rifamycin, geldana-

mycin) (417), anthracyclines (primarily antitumor agents, e.g.,

daunorubicin) (418,419), ␤-lactams (cephamycins) (420) and

also the important ␤-lactamase inhibitor clavulanic acid (421,

422), chloramphenicol (423), glutarimides (cycloheximide)

(424), glycopeptides (vancomycin, teichoplanin) (425,426), lipo-

peptides (daptomycin) (427), lantibiotics (mersacidin, actagar-

dine) (272), macrolides (clarythromycin, erythromycin, tylosin,

clarithromycin) (428,429), oxazolidinones (cycloserine) (430),

streptogramins (streptogramin) (431), and tetracyclines (432).

The producing capacity of individual actinomycetes can also vary

enormously. Some Streptomyces species produce a single antibi-

otic, while others produce a range of different compounds and

compound classes.

Besides antibiotics, Actinobacteria also produce a wide variety of

other secondary metabolites with activity as herbicides (54), anti-

fungals, antitumor or immunosuppressant drugs, and anthel-

mintic agents (433). Examples are given below.

Actinobacteria as Sources of Insecticides

Macrotetrolides are active against mites, insects (434–436), coc-

cidia (437), and helminths (438), and they also show immunosup-

pressive effects (439). They are produced by a variety of Strepto-

myces species (for a review, see Jizba et al. [434]). However, with

regard to the composition of the macrotetrolide complex, only S.

aureus S-3466 (440), which produces a mixture of tetranactin (the

most active member of the compound group) with dinactin and

trinactin (435,441), has been utilized for commercial purposes

(442). Tetranactin, a cyclic antibiotic produced by Streptomyces

aureus with a molecular structure related to cyclosporine, is used as

emulsion against carmine mites of fruits and tea. A true success story

in terms of anthelmintics is ivermectin (443), which is a dehydro

derivative of avermectin produced by Streptomyces avermitilis. After

its appearance in the late 1970s, ivermectin was the world’s ﬁrst en-

dectocide, which at the time was a completely novel class of antipar-

asitic agents, with strong and broad-spectrum activity against both

internal and external nematodes and arthropods. Recently, the Nobel

Prize for Physiology or Medicine 2015 was awarded to Satoshi

Omura and William C. Campbell for their discovery of avermectin,

jointly with Youyou Tu for the discovery of the antimalarial drug

artemisinin.

Actinobacteria as Sources of Bioherbicide and Bioinsecticide

Agents

Mildiomycin, an antifungal metabolite isolated from cultures of

Streptoverticillium rimofaciens Niida, is strongly active against sev-

eral powdery mildews on various crops (444) and inhibits fungal

protein biosynthesis (445). The primary sites of action of these

antibiotics are at locations where chitin synthesis occurs in the cell

wall, there is cation leakage from mitochondria, inositol biosyn-

thesis is occurring, or sites of protein and DNA synthesis. The

compounds mentioned above are a few examples of agroactive

compounds isolated from Actinobacteria. Validamycin A was

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TABLE 3 Examples of bioactive molecules produced by Actinobacteria genera and their activities

Type of compound and producing species Bioactive agent(s) Source or reference

Antibacterial agent producers

Verrucosispora spp. Abyssomycin 603

Streptomyces anulatus Actinomycins 409

Streptomyces canus Amphomycin 604

Micromonospora spp. Anthracyclin 605

Streptomyces cattley Antibiotics and ﬂuorometabolites 606

Streptomyces canus Aspartocins 607

Streptomyces avermitilis Avermectin 608

Streptomyces venezuelae Chloramphenicol 609

Micromonospora spp. Clostomicins 609

Streptomyces griseus Cycloheximide 620

Streptomyces orchidaceus Cycloserine 610

Streptomyces roseosporus Daptomycin 611

Saccharopolyspora erythraea Erythromycin (Ilotycin) 612

Micromonospora purpurea Gentamicin 613

Streptomyces hygroscopicus Hygromycin 614

Streptomyces kanamyceticus Kanamycin 615

Streptomyces kitasoensis Leucomycin 616

Streptomyces lincolnensis Lincomycin 617

Marinispora spp. Marinomycin 618

Streptomyces fradiae Neomycins 619

Micromonospora spp. Netamicin 80

Streptomyces niveus Novobiocin 620

Streptomyces antibioticus Oleandomycin 621

Streptomyces rimosus Oxytetracycline 622

Streptomyces spp. Pristinamycin 623

Streptomyces lindensis Retamycin 624

Streptomyces mediterranei Rifamycin 625

Nocardia lurida Ristocetin 621

Streptomyces ambofaciens Spiramycin 626

Streptomyces virginiae Staphylomycin 627

Streptomyces endus Stendomycin 628

Streptomyces lydicus Streptolydigin 629

Streptomyces griseus Streptomycin 411

Streptomyces lavendulae Streptothricin 410

Streptomyces aureofaciens Tetracycline 630

Micromonospora spp. Thiocoraline 631

Amycolatopsis orientalis Vancomycin 632

Antifungal agent producers

Streptomyces anulatus Actinomycins 603

Streptomyces nodosus Amphotericin B 633

Streptomyces griseochromogenes Blasticidin 634

Streptomyces griseus Candicidin 635

Streptomyces spp. Carboxamycin 636

Streptomyces venezuelae Chloramphenicol 637

Streptomyces padanus Fungichromin 638

Streptomyces galbus Galbonolides 675

Streptomyces violaceusniger YCED-9 Guanidylfungin 564

Streptomyces venezuelae Jadomycin 639

Streptomyces kasugaensis Kasugamycin 452

Streptomyces spp. Kitamycin 640

Streptomyces natalensis Natamycin 641

Streptomyces tendae Nikkomycin 642

Streptomyces diastatochromogenes Oligomycin 643

Streptomyces humidus Phenylacetate 644

Streptomyces cacaoi Polyoxin B 453

Streptomyces canus Resistomycin 645

Streptomyces lavendulae Streptothricin 410

Streptomyces canus Tetracenomycin 645

Nocardia transvalensis Transvalencin 646

Streptomyces hygroscopicus Validamycin 647

(Continued on following page)

Biology of Actinobacteria

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commercialized by Takeda for the control of pathogens in rice and

other plants and as a tool for damping off diseases in vegetable

seedlings. On the other hand, some secreted metabolites are cyto-

toxic and can include chemical structures such as macrolides,

␣-pyrones, lactones, indoles, terpenes, and quinones (446). For

instance, resistomycin, a quinone-related antibiotic, has a unique

structure and exhibits bactericidal and vasoconstrictive activity

based on the inhibition of RNA and protein synthesis (447,448).

The genome sequences of important Actinobacteria species re-

ported to date indicate that as much as 90% of the chemical po-

tential of these organisms remains undiscovered and that the bio-

synthetic machinery encoded by many of these genetic loci may be

activatable under laboratory conditions (449). The predictive

models of Watve et al. (450) suggested that over 150,000 bioactive

metabolites from members of the genus Streptomyces alone within

this order are still waiting to be discovered (328,451). Molecular

techniques such as combinatorial biosynthesis may lead to the

discovery of drugs that cannot be found naturally and of biosyn-

thetic components that can be interchanged and modiﬁed to pro-

duce bioactive products with unique properties.

TABLE 3 (Continued)

Type of compound and producing species Bioactive agent(s) Source or reference

Bioherbicide/biopesticide producers

Actinomadura spp. 2,4-Dihydro-4-(␤-D-ribofuranosyl)-1, 2, 4 (3H)-triazol-3-one (herbicide) 648

Streptomyces hygroscopicus Herbimycin 649

Streptomyces avermitilis Ivermectin (derivative of avermectin) 650

Streptomyces prasinus Prasinons 651

Saccharopolyspora spinosa Spinosad (neurotoxic insecticides) 652

Antiparasitic agent producers

Streptomyces avermitilis Avermectins 608

Streptomyces coelicolor Prodiginine 653

Streptomyces bottropensis Trioxacarcin 654

Antiviral agent producers

Streptomyces antibioticus 9-␤-D-Arabinofuranosyladénine 655

Streptomyces hygroscopicus Hygromycin 614

Streptomyces spp. Panosialins 656

Hypercholesterolemia agent producer

Streptomyces hygroscopicus Rapamycin 674

Antitumor agent producers

Micromonospora spp. Anthraquinones 657

Nocardia asteroides Asterobactine 658

Streptomyces spp. Borrelidine 659

Micromonospora spp. Diazepinomicin 660

Actinomadura spp. IB-00208 661

Micromonospora spp. LL-E33288 complex 76

Micromonospora spp. Lomaiviticins 76

Micromonospora spp. Lupinacidins 657

Thermoactinomyces spp. Mechercharmycin 662

Marinospora spp. Marinomycin 618

Salinispora tropica Salinosporamide 621

Streptomyces peucetius Doxorubicin (adriamycin) 664

Streptomyces peucetius Daunorubicin (daunomycin) 665

Micromonospora spp. Tetrocarcin 76

Micromonospora spp. Thiocoraline 666

Immunostimulatory agent producers

Nocardia rubra Rubratin 667

Streptomyces olivoreticuli Bestatin 668

Kitasatospora kifunense FR-900494 669

Immunosuppressive agent producers

Nocardia brasiliensis Brasilicardin 670

Streptomyces ﬁlipinensis Hygromycin 671

Streptomyces ﬁlipinensis Pentalenolactone 671

Therapeutic enzyme (antitumor) producers

Streptomyces spp. L-Asparaginase 672

Streptomyces olivochromogenes L-Glutaminase 673

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Actinobacteria as Sources of Antifungal Agents

Kasugamycin is a bactericidal and fungicidal metabolite secreted

by Streptomyces kasugaensis (452) that acts as an inhibitor of pro-

tein biosynthesis in microorganisms but not in mammals. The

systemically active kasugamycin was marketed to control rice blast

(Pyricularia oryzae cavara) and bacterial Pseudomonas diseases in

several crops. In 1965, Isono et al. (453) isolated the ﬁrst members

of a new class of natural fungicides, polyoxins B and D, from

metabolites of Streptomyces cacaoi var. asoensis. These substances

act by interfering with fungal cell wall synthesis by inhibiting chi-

tin synthase (454). Polyoxin B is applied against a number of fun-

gal pathogens in fruits, vegetables, and ornamentals, while

polyoxin D is used to control the causative agent of rice sheath

blight, Rhizoctonia solani (455).

In 1968, the validamycin family was detected by researchers at

Takeda Chemical Industries in a greenhouse assay for the treat-

ment of sheath blight disease in rice plants caused by the fungus

Rhizoctonia solani. Validamycin A, the major and most active

component of the complex, was isolated from Streptomyces hygro-

scopicus var. limoneus. Within the fungal cell, validamycin is con-

verted to validoxylamine A, a particularly strong inhibitor of tre-

halose that suppresses the breakdown of intracellular trehalose

(456). Trehalose is well known as a storage carbohydrate, and

trehalase plays an essential role in the transport of glucose in in-

sects and fungi (457). This mode of action gives validamycin A a

favorable biological selectivity, since vertebrates do not depend on

the hydrolysis of the disaccharide trehalose for their metabolism

(457).

INTERACTIONS BETWEEN ACTINOBACTERIA AND OTHER

ORGANISMS

Interactions between Actinobacteria and Invertebrates

Insect-bacterium symbioses are widespread in the environment

(458), and antibiotic-producing bacterial symbionts are often re-

cruited to protect the host and/or their resources (459,460). Many

insects (e.g., ants, termites, gall midges, and beetles) have devel-

oped a speciﬁc association with their microbial communities.

These interactions are diverse, ranging from antagonism and

commensalism to mutualism, and from obligate to facultative

(461).

Interaction with ants. Microbial communities of many groups

of insects have been widely studied (462), and particularly com-

plex associations have been documented between gut bacteria and

insects (463,464). Attine ants have evolved a mutualism with Ac-

tinobacteria that produce antibiotics that the ants use as weedkill-

ers to keep their fungal gardens free of other microbes (460,465).

For instance, the ants (genera Atta and Acromyrmex) cut leaves

and then masticate them into a ﬁne biomass that is fed to the

symbiotic fungus (Leucoagaricus gongylophorus) which, in turn,

provides lipid- and carbohydrate-rich hyphae known as gongy-

lidia that will be used by the ants (466).

The ants rely on a similar mutualistic association with mem-

bers of the Actinobacteria (genus Pseudonocardia) that produce

antibiotics that help suppress Escovopsis, which has a devastating

effect on the fungus gardens of leaf-cutting ants in the absence of

the bacterium (467–470), by signiﬁcantly reducing the colony ﬁt-

ness or even inducing colony death (471). Other Actinobacteria

genera may play a similar role (472,473). The presence and main-

tenance of Streptomyces bacteria seems to be of prime importance,

as the bacteria appear to be the primary defense against Escovopsis,

which ants possess (467,474).

Interactions with beetles. Multiple bacterial genera of the

Gammaproteobacteria and Actinobacteria classes were found in the

larvae, pupae, and adult guts of the bark beetle Dendroctonus rhi-

zophagus. The class of Actinobacteria was represented by Ponticoc-

cus gilvus and Kocuria marina, both of which can degrade car-

boxymethylcellulose in vitro. Neither Actinobacteria species has

ever been reported in other bark beetles, suggesting that these

bacteria could be involved in the degradation of cellulosic sub-

strates such as pine bark and phloem, enabling them to serve as a

carbon source (475). This postulate is supported by the presence

of cellulose-degrading bacteria in the gut of insects that feed on

woody tree tissues, such as wood-boring beetles, including

Saperda vestita and Agrilus planipennis (476,477).

Interactions with protozoans. Mycobacterium ulcerans is re-

sponsible for a necrotizing cutaneous infection called Buruli ulcer,

which has been reported in more than 30 countries worldwide,

mainly in tropical and subtropical climates. However, M. ulcerans

can probably not live freely due to its natural fragility, slow-

growth development, and inability to withstand exposure to direct

sunlight. Further, M. ulcerans is sensitive to several antibiotics,

such as streptomycin and rifampin. M. ulcerans therefore rarely

occurs as a free-living microorganism, even though Streptomyces

griseus and Amycolatopsis rifamycinica, producers of streptomycin

and rifampin, thrive under such conditions (478,479).

To survive, Mycobacterium has adapted to a more protected

niche by utilizing free-living amoebae (FLA) as carriers. In their

protozoan hosts, “hidden” mycobacteria might ﬁnd easier oppor-

tunities to infect vertebrate end hosts, multiplying within proto-

zoans to escape immune reactions (480). This ability to persist

within amoebae has been widely documented (481–483). The in-

ternalization of infectious agents inside other parasites represents

an evolutionary strategy for survival that may sometimes enhance

pathogenesis or transmissibility (480).

Interactions between Actinobacteria and Vertebrates

Actinobacteria,Bacteroidetes,Firmicutes,Fusobacteria, and Proteo-

bacteria dominate the gut microbiota, demonstrating a similar

overall composition at the phylum level in various gastrointestinal

tract locations, including human gastric ﬂuid, intraoral niches

(484,485), throat (486), distal esophagus (487), stomach mucosa

(486), and feces (488). Further, Actinobacteria are prominent

among the identiﬁed microbiota of the oral cavity but are signiﬁ-

cantly less abundant in the lower gastrointestinal and genital

tracts.

Children with diabetes reportedly exhibit substantially lower

numbers of Actinobacteria and Firmicutes compared to healthy

children. Further, within the Actinobacteria, the number of Biﬁ-

dobacterium was signiﬁcantly lower in children with diabetes

(489).

Metagenomic studies of mucosal and fecal samples retrieved

from healthy subjects demonstrated the presence of six dominant

phylogenetic phyla, including Actinobacteria (490). The role of

biﬁdobacteria in gut ecology illustrates the importance of Actino-

myces and other Actinobacteria (491). The phyla Actinobacteria,

Bacteroidetes,Firmicutes,Fusobacteria,and Proteobacteria consti-

tute more than 99% of all gut microbiota in dogs and cats. Com-

pared with the case in humans, which harbor 10

bacterial cells,

Biﬁdobacteria is less abundant in cats and dogs (492,493).

Biology of Actinobacteria

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Although the aerobic Actinobacteria are infrequently encoun-

tered in clinical practice, they are important potential causes of

serious human and animal infections. These bacteria have

emerged as unusual but important potential human pathogens

that cause signiﬁcant disease, affecting not only immunocompe-

tent hosts but also severely immunocompromised patients. Mc-

Neil and Brown (494) reviewed the data on medically important

aerobic Actinobacteria and epidemic diseases that these organisms

cause in animals and humans. For instance, the genus Nocardia

comprises several species that are known to be unusual causes of a

wide spectrum of clinical diseases in both humans and animals,

infecting cattle, horses, dogs, and swine (494). While the majority

of nocardial infections have been attributed to Nocardia asteroides,

other pathogenic Nocardia species that have been reported in-

clude N. brasiliensis,N. otitidiscaviarum, and N. transvalensis.Ina

taxonomic revision of the N. asteroides taxon, two new species, N.

farcinica and Nocardia nova, were separated (495).

Reports of human infection with Rhodococcus spp. have been

rare (494). The disease they cause can have a variable clinical pre-

sentation depending upon the host’s underlying immune status

and possibly upon the site of inoculation and the virulence of the

infecting microorganism. Consequently, in severely immuno-

compromised patients, primary pulmonary Rhodococcus equi in-

fections (pneumonia and lung abscesses) have been reported most

frequently (494).

Only a few invasive humans infections, such as mycetoma

caused by Streptomyces spp., have been documented to date (496).

They can, however, be caused by S. somaliensis and S. sudanensis

(497,498). The majority of invasive Streptomyces infections are

associated with bacteremia and lung infections, namely, pneumo-

nia, abscess, and pneumonitis (499). Streptomycetes are infre-

quent pathogens, although S. somaliensis and S. sudanensis can

cause infections.

As for Rhodococcus, most of the infected patients had some un-

derlying immunosuppressive condition, such as HIV infection,

cancer, systemic lupus erythematosus (SLE), Crohn’s disease, etc.

Moreover, S. pelletieri,S. griseus,S. lanatus, and S. albus have been

isolated from various patients with lung pathology (496,500–

502). Other opportunistic pathogenic Actinobacteria include

Amycolata autotrophica,A. orientalis,Micromonospora spp., N.

dassonvillei, and Oerskovia spp. (494).

Interactions between Actinobacteria and Plants

As stated previously, actinomycetes are abundantly present in

soils and represent a high proportion of the microbial ﬂora of the

rhizosphere (503). Actinobacteria thus unsurprisingly play diverse

roles in plant-associated microbial communities. Some genera are

viewed predominantly as soil saprophytes with crucial roles in

nutrient cycling, while others are endophytes, beneﬁcial symbi-

onts, or even pathogens of plants.

Plant-Actinobacteria deleterious interactions. (i) Actinobac-

teria as plant pathogens. The successful infection of a plant host is

a complex multistep process, requiring the pathogen to sense the

presence of a suitable host, penetrate and colonize the plant tissue,

and survive in the presence of host defense mechanisms. In com-

parison to other bacteria, actinomycetes play a relatively minor

role in plant diseases. However, they represent major pathogens of

certain crops in particular areas, and under special conditions

affect the quality and the quantity of agricultural products. This

may result in huge agricultural losses, especially of potatoes but

also of other root crops, such as beet, carrot, parsnip, radish, sweet

potato, and turnip (504,505).

Recent progress in molecular genetics and the understanding

of the genomics of plant pathogenicity has been made for the

Actinobacterial genera Clavibacter,Streptomyces,Leifsonia, and

Rhodococcus. Further, plant-pathogenic Actinobacteria in the gen-

era Streptomyces and Rhodococcus have very wide host ranges, in-

cluding economically important crops and model plants. For in-

stance, in the genus Streptomyces, plant pathogenicity is rare, with

only a dozen or so species possessing this trait of the more than 900

species described. Nevertheless, such species have a signiﬁcant im-

pact on agricultural economies throughout the world due to their

ability to cause important crop diseases, such as potato common

scab, which is characterized by lesions that form on the potato

tuber surface. The most well-known phytopathogenic Actinobac-

teria are Streptomyces scabiei,S. acidiscabies, and S. turgidiscabies,

which induce devastating scab diseases on a broad spectrum of

plants. Streptomyces scabiei, the most ancient of these pathogens, is

found worldwide, whereas S. turgidiscabies and S. acidiscabies are

emergent pathogens that were ﬁrst described in Japan and the

northeastern United States, respectively (506–508).

S. scabiei and S. turgidiscabies both cause “common” scab in

potatoes (Solanum tuberosum); the disease is characterized by gray

spores borne in spiral chains and that produce melanin (509).

Another disease, the “acid scab,” is associated with S. acidiscabies

(510). The typical and acid scab strains differ with respect to pig-

mentation, spore chain morphology, rafﬁnose utilization, and tol-

erance of low pH. In addition, S. acidiscabies differs from S. scabiei

in phenotype and ecology by having ﬂexuous spore chains, a

growth medium-dependent spore mass color ranging from white

to salmon-pink, a red or yellow pH-sensitive diffusible pigment,

and no melanin.

Russet scab is commonly restricted to nature of the potato’s

skin and affects the quality of the crop. This disease caused by

soilborne streptomycetes different from S. scabies has been re-

ported in Europe and the United States since the beginning of the

century (511). The disease is divided into two types. The ﬁrst type

is American russet scab, caused by the genus Streptomyces and

species different from S. scabiei (which forms a pigmented myce-

lium, ﬂexuous spore chains, and no melanin) and from S. acidis-

cabies (mass spore color, inability to grow at pH 4.5). The second

type is European russet (or netted) scab, which is apparently dis-

tinct from the American variant (512) with respect to cultivar

susceptibility, root attack, and optimum soil temperature.

No speciﬁc taxonomic investigations have been carried out on

S. ipomoeae, the causal agent of the sweet potato soil rot disease

characterized by dwarfed plants with little or no growth and mi-

nor discolored leaves, with many plants dying before the end of

the season. The organism apparently persists for long periods,

even in the absence of the host plant.

In the 1980s, Actinobacteria were reported to plug the xylem

vessels of silver, sugar, and Norway maples, leading to early decay

and dieback of the tree branches (513,514). A variety of strepto-

mycetes of different species (S. parvus,S. sparsogenes,Streptomyces

sp.) were isolated from the plugs. The isolates were capable of

growing within the tree vessels and in vitro in the presence of

several phenols. Although sugar maples in the northeastern

United States are routinely tapped to collect maple sap for conver-

sion to maple syrup, the mode of penetration of the Actinobacteria

into the host is not known. Similarly, a lignocellulose-degrading

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streptomycete (S. ﬂavovirens) was found to decompose the intact

cell walls of the phloem of Douglas ﬁrs, and hyphae were found in

the cavities deriving from the destruction of the walls of the pa-

renchyma and sclereids (515).

Rhodococcus fascians was ﬁrst isolated and identiﬁed in 1930 as

the causal agent of sweet pea fasciations (516). Since then, the

symptoms caused by R. fascians in diverse plant species have been

described (reviewed by Goethals et al. [517]). The bacterium in-

fects both monocot and dicot hosts, many of which are econom-

ically important (518). Extensive epiphytic growth precedes inter-

cellular invasion through stomata. R. fascians causes various

effects in its hosts, including leaf deformation and formation of

witches’ broom, fasciations, and leafy galls (517,519). The symp-

toms are caused by the hyperinduction of shoots through activa-

tion of dormant axillary meristems and de novo meristem forma-

tion, probably as the result of elaborate manipulation of host

hormone balances and pathogen-derived auxins and cytokinins

(520,521). In contrast to Streptomyces and Rhodococcus,plant-

pathogenic species in the Actinobacteria genera Clavibacter and

Leifsonia are host speciﬁc at the species or subspecies level.

Clavibacter michiganensis is another aerobic nonsporulating

Gram-positive plant-pathogenic member of the Actinobacteria

and is currently the only known species within the genus Clavibac-

ter. C. michiganensis is composed of a number of host-speciﬁc

subspecies, all of which colonize the xylem. Currently, C. michi-

ganensis is represented by ﬁve subspecies: C. michiganensis subsp.

insidiosus,C. michiganensis subsp. michiganensis,C. michiganensis

subsp. nebraskensis,C. michiganensis subsp. sepedonicus, and C.

michiganensis subsp. tesselarius.

C. michiganensis subsp. michiganensis provokes bacterial can-

ker formation in tomatoes, a serious emerging disease of tomatoes

wherever tomato plants are grown. This disease has caused sub-

stantial economic losses worldwide (522). Another important

plant pathogen is C. michiganesis subsp. sepedonicus, which causes

a disease in potatoes known as ring rot, due to the way it rots the

vascular tissue inside potato tubers. C. michiganensis subsp. ne-

braskensis causes wilt and blight in maize. C. michiganensis subsp.

tesselarius induces leaf freckles and leaf spots in wheat. Wilting and

stunting in alfalfa (Medicago sativa) are induced by C. michiganen-

sis subsp. insidiosus (523). The severity of these diseases and the

difﬁculty of controlling the spread of the corresponding patho-

gens has resulted in the pathogens being classiﬁed as quarantine

organisms under the European Union Plant Health Legislation, as

well as the laws of many other countries.

The genus Leifsonia includes xylem-limited, fastidious, bacte-

rial pathogens. The best-known of these pathogens is L. xyli subsp.

xyli, the causative agent of a systemic disease called ratoon stunt-

ing of sugarcane. Plant growth inhibition, the hallmark of this

disease, may be due to a putative fatty acid desaturase that modi-

ﬁes the carotenoid biosynthesis pathway to produce abscisic acid,

a growth inhibitor (524).

(ii) Traits of pathogenicity. The mechanisms by which a patho-

gen can induce the development of lesions on the host are still not

well known, although recent advances in this ﬁeld have provided

some ideas. An important feature in the interaction of a pathogen

and its host is the establishment of an equilibrium that allows both

partners to survive in nature. If no resistant or tolerant plant

cultivars are available, pathogen infection will inevitably lead to

disease outbreaks. Despite the economic importance of plant-

pathogenic Streptomyces species, very little is known about the

molecular mechanisms used by these organisms to sense the pres-

ence of a suitable plant host, colonize the host’s tissues, and resist

its defense mechanisms.

The virulence factors of C. michiganensis subsp. michiganensis

seem to be extracellular enzymes, particularly proteases. Dreier et

al. (525) reported the participation of three proteases (Pat-1,

ChpC, and ChpG) in the pathogen’s initial interactions with the

host plant, but their exact target remains unknown. Several po-

tential virulence genes are clustered in the chp-tomA region of the

bacterial genome, which may be a pathogenicity island and crucial

for successful colonization. It was recently shown that the viru-

lence of Clavibacter michiganensis subsp. michiganensis toward to-

mato plants can be modulated by three different mechanisms: loss

of plasmids accompanied by the loss of the pathogenicity factors

celA and pat-1, resulting in reduced virulence or even nonviru-

lence in a plasmid-free derivative; transfer of plasmids to plasmid-

free C. michiganensis subsp. michiganensis derivatives, which re-

stores full virulence; and loss of the pathogenicity island due to

stress-activated recA-dependent recombination events, which

leads to a low-titer colonizer that may carry the plasmids and the

pathogenicity factors necessary for effective colonization but

which can be considered a nonvirulent endophyte (526).

Ammonium assimilation and nitrogen control in M. tubercu-

losis have been studied intensively, with a particular focus on glu-

tamine synthetase I (GSI), an enzyme whose extracellular release

was identiﬁed as a potentially important determinant of pathoge-

nicity (527).

Phytotoxin production is commonly involved in the pathoge-

nicity of Streptomyces. Some early work on potato scab disease

demonstrated that darkening of tuber cells during pathogen col-

onization was a response to the action of a toxin or enzyme se-

creted by the scab organism. A key virulence determinant in scab-

causing streptomycetes is a family of phytotoxic secondary

metabolites called thaxtomins, of which thaxtomin A is the most

abundant (528). Thaxtomin production is usually positively cor-

related with pathogenicity. Further, thaxtomin induces a variety

of phenotypic changes in the plant host, including cell hypertro-

phy, root and shoot stunting, tissue necrosis, alterations in plant

2⫹

and H

⫹

ion inﬂuxes, inhibition of cellulose synthesis, pro-

grammed cell death, and production of the antimicrobial plant

phytoalexin scopoletin (529–533). In addition, thaxtomin helps S.

scabiei,S. turgidiscabies, and S. acidiscabies penetrate plant cell

walls by inhibiting cellulose biosynthesis (reviewed by Loria et al.

[505]), which presumably enables the bacterium to secrete pro-

teins onto the host cell membrane. An additional virulence deter-

minant that has been described in plant-pathogenic streptomyce-

tes is a secreted necrogenic protein called Nec1. Thaxtomin and

Nec1 were the ﬁrst virulence determinants to be identiﬁed and are

thought to contribute to tissue penetration and suppression of

plant defense responses, respectively. Thaxtomins are cyclic di-

peptides (2,5-diketopiperazines) derived from L-phenylalanine

and L-tryptophan, and they contain a 4-nitroindole moiety that is

essential for their phytotoxicity (528). The production of thaxto-

min A was positively correlated with disease severity (534). Mu-

tants of S. scabiei and S. acidiscabies that were deﬁcient in thaxto-

min A biosynthesis did not cause symptoms on potato tubers,

establishing the thaxtomins as important pathogenicity determi-

nants (535,536). Eleven family members have been isolated and

characterized and are distinguished by the presence or absence of

N-methyl and/or hydroxyl groups. Thaxtomin A, the predomi-

Biology of Actinobacteria

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nant family member produced by S. scabiei,S. turgidiscabies, and

S. acidiscabies, is required for scab disease development (536–

538). The S. scabiei coronafacic acid-like biosynthetic cluster con-

tributes to host-pathogen interactions, as demonstrated recently

by Bignell et al. (504). In addition, an extracellular esterase from S.

scabiei has been characterized, sequenced, and identiﬁed as a po-

tential virulence factor whose activity may be regulated by the

availability of zinc (539).

Several bacterial and fungal genomes have been reported to

encode proteins with distant homology to plant expansins (540).

These proteins are required for virulence, have C-terminal expan-

sin-like domains, and are found in many plant-associated micro-

organisms, including the phytopathogenic Actinobacteria organ-

isms Clavibacter michiganensis subsp. sepedonicus (526,541). The

S. scabiei expansin-like proteins exhibit 66% homology with each

other at the amino acid level and are also closely related to putative

expansin-like proteins from two nonpathogenic Streptomyces spe-

cies. It is tempting to speculate that SCAB44951 might be impor-

tant for plant-microbe interactions, because it can mimic speciﬁc

plant PR-1 proteins and thus manipulate plant defense responses

during infection. Interestingly, the PR-1-type protein identiﬁed in

S. scabiei is part of the pathogenome and is conserved in S. ipo-

moeae, further supporting a potential role for this protein in

Streptomyces-plant interactions.

Propionibacterium acnes produces abundant porphyrins,

which might contribute to skin damage (542). The interaction of

porphyrins with oxygen is thought to contribute to keratinocyte

damage and consequently to have implications regarding the

pathogenesis of progressive macular hypomelanosis (543).

Concanamycins are produced by several Streptomyces species,

including S. diastatochromogenes (544), S. neyagawaensis (545), S.

graminofaciens (546), and S. scabiei (547,548). For instance, con-

canamycins A and B, produced by S. scabiei, exhibit phytotoxic

activity (549) and have been proposed (but not proven) to be

virulence determinants in that organism. It should be noted that

the other concanamycin family members are not produced in S.

acidiscabies or S. turgidiscabies (548–550).

Plant-Actinobacteria beneﬁcial interactions. Actinobacteria

are microorganisms capable of colonizing the rhizosphere

through their antagonistic and competitive characteristics con-

cerning other soil microorganisms (503). Like other beneﬁcial mi-

croorganisms, Actinobacteria can affect plant growth in two gen-

eral ways, either directly or indirectly. Indirect promotion occurs

when they prevent the harmful effects of one or more deleterious

microorganisms. This is chieﬂy done through biocontrol or an-

tagonism toward soil plant pathogens. Speciﬁcally, colonization

or the biosynthesis of antibiotics (551) and other secondary me-

tabolites can prevent pathogen invasion and establishment. Direct

promotion of plant growth occurs when the plant is supplied with

a compound that is synthesized by the bacteria, or when the latter

otherwise facilitates plant uptake of soil nutrients. Possible con-

tributions of this sort include nitrogen ﬁxation, siderophore syn-

thesis, phytohormone synthesis, and solubilization of minerals to

make them available for plant uptake and use (552).

(i) Actinobacteria as biological control agents. The Actinobac-

teria are widely recognized for their potential in biocontrol (553–

555) because they are important producers of bioactive com-

pounds (556). Over the past 50 years, there have been many

studies on the mechanisms by which Actinobacteria might inhibit

pathogens in soil, including antibiosis, nutrient competition, pro-

duction of degradative enzymes, nitrous oxide production, and

quorum quenching (557–559). Their adaptability to different en-

vironments in the rhizosphere makes them a strong competitor.

Some are known for their production of siderophores, which can

chelate iron, depriving other organisms of this important micro-

nutrient (560,561). Siderophore production by S. griseorubigi-

nouse is effective in the ﬁght against Fusarium wilt of banana

caused by Fusarium oxysporum f. sp. cubenese (561). Actinobacte-

ria have also been reported to secrete enzymes that degrade the

mycelial cell walls of fungal parasites, as described in several stud-

ies (556,562–565). Several chitinolytic enzymes have been identi-

ﬁed in some species of Actinobacteria, including S. antibioticus

(566), S. aureofaciens (566), S. lividens (567), S. plicatus (568), S.

halsteii AJ-7 (569), and S. lydicus WYEC108 (570). A biofungicide

containing Streptomyces lydicus WYEC 108 was approved by AG

(Natural Industries Inc., TX, USA) and registered in 2004 as Ac-

tinovate soluble (EPA registration number 73314-1). The prod-

uct, which is completely water soluble, is a biofungicide that effec-

tively protects against and controls many common foliar and

soilborne diseases.

Actinobacteria are also widely known for their ability to pro-

duce antibiotics that allow them to inhibit plant pathogens (556,

571,572). Trejo-Estrada et al. (564) have shown a correlation

between the production of antibiotics in soil Actinobacteria and

effectiveness in the ﬁght against plant pathogens. For example,

Streptomyces violaceusniger YCED9 produces three antifungal

compounds, including nigrecine, geltanamycine, and guanidylf-

ingine, that ﬁght against plant pathogens (564). Similarly, several

antibiotics produced by Actinobacteria are currently used in bio-

logical control (Table 3).

Millard (573) reported that green manures, or crops grown

speciﬁcally for biomass to be incorporated into soil, could reduce

the infection of potatoes by pathogenic Streptomyces scabiei. Later,

in 1926, Sanford (574) noted that Actinomyces scabiei was “very

sensitive to the secreted products of many molds and bacteria,

some of which prevent its growth,” and suggested that green ma-

nures favored the antagonistic bacteria that inhibited the patho-

gen. Subsequently, Millard and Taylor (575) showed that soil in-

oculation with a saprophytic (nonpathogenic) Actinomycete

isolate could signiﬁcantly reduce both disease (potato scab) and

pathogen populations, concluding that the saprophytic inocu-

lated strain outcompetes the pathogen in soil, thereby reducing

plant disease.

Antibiotic-mediated inhibition of pathogens is generally the

primary focus in efforts to suppress plant diseases. However, the

diversity of secondary metabolites produced by Streptomyces and

other species also offers great potential for suppressing fungal,

bacterial, oomycete, and nematode pathogens.

(ii) Actinobacteria as plant growth-promoting rhizobacteria.

In attempts to develop commercial biocontrol and plant growth-

promoting products using rhizobacteria, it is important to recog-

nize the speciﬁc challenges they present. To begin with, the inter-

action between plant growth-promoting rhizobacteria (PGPR)

species and their plant symbionts appears to be speciﬁc, even

within a crop or cultivar (552,576). While a rhizobacterium

screened for growth promotion may reveal positive effects on one

crop, it may have no effect or even retard the growth of another

(577,578). Although rhizobacteria may present unique challenges

to our attempts to harness their beneﬁcial attributes, the prospects

for improving agriculture by using PGPR for biocontrol seem to

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be excellent. The ﬁrst step toward exploiting PGPR species to en-

hance plant growth will be to better understand the systems that

enable them to act as efﬁcient plant growth enhancers.

Since the 1990s, several nitrogen-ﬁxing Actinobacteria have

been recognized and found to be associated with plants. Coryne-

bacterium sp. AN1 isolated from the plant forest phyllosphere re-

duces acetylene and can be regarded as a substitute for nitroge-

nous fertilizer as a means of promoting maize growth (579).

Pseudonocardia dioxanivorans CB1190 isolates, which can grow

on 1,4-dioxane as their sole source of carbon and energy, have also

been shown to ﬁx dinitrogen (580). Despite the well-documented

history of Streptomyces in biocontrol and preliminary evidence of

their capacity to enhance plant growth (581), the potential of

Streptomyces species as PGPR has not been widely studied. This is

surprising because streptomycetes, which generally account for an

abundant percentage of the soil microﬂora, are particularly effec-

tive colonizers of plant root systems and are able to endure unfa-

vorable growth conditions by forming spores (582).

Merriman et al. (583) reported the use of Streptomyces griseus

(Krainsky) Waksman and Henrici isolates to treat the seeds of

barley, oat, wheat, and carrot, in order to increase their growth.

The isolate was originally selected for the biological control of the

pathogen Rhizoctonia solani. Though the S. griseus isolate did in-

crease the average grain yield, dry foliage weight, tiller number,

and advanced head emergence for both wheat and oat relative to

controls, the differences were not statistically signiﬁcant. How-

ever, the isolate was more successful as a seed treatment for car-

rots. Marketable yields were increased over controls by 17% and

15% in two separate ﬁeld trials. In addition, both trials also pro-

vided an improved yield of large- and very-large-grade carrots

relative to controls (583). Nearly 20 years later, El-Abyad et al.

(584) described the use of three Streptomyces spp. in the control of

bacterial, Fusarium, and Verticillium wilts, early blight, and bacte-

rial canker of tomato. In addition, tomato growth was signiﬁ-

cantly improved by the use of the antagonistic Streptomyces spp.

for a seed coating. An increased availability of growth regulators

produced by the inoculum was the reason proposed for the im-

provement in tomato growth, although this has not yet been for-

mally tested (584). While studies conducted by El-Abyad et al.

(584) and Merriman et al. (583) reported plant growth enhance-

ment to be a function of the magnitude of inoculation with Strep-

tomyces, but the behavior of the inocula under gnotobiotic condi-

tions and the possible mechanisms of streptomycete-mediated

growth promotion should be investigated further.

(iii) Actinobacteria as symbionts. Streptomyces spp. constitute

protective mutualistic symbioses in which the host feeds and pro-

tects the bacteria and in return the bacteria provide antibiotics to

protect the host, or their resources, from pathogens (585). Other

genera of Actinobacteria, namely, Frankia and Micromonospora,

form mutualistic symbioses with higher organisms via nitrogen-

ﬁxing actinonodules in trees and shrubs (586,587).

For a long time, diazotrophy in the Actinobacteria was thought

to be limited to the genus Frankia. However, molecular studies

have increased the number of known nifH-containing Actinobac-

teria beyond Frankia spp. (587–591). The discovery of these acti-

nobaceria has stimulated further discussion and inquiries on the

origin and emergence of diazotrophy among Actinobacteria. Ni-

trogen-ﬁxing Actinobacteria in the genus Frankia live as soil sap-

rophytes and as endophytic symbionts in over 200 plant species

(592). The genus Frankia has a special signiﬁcance as the nitrogen-

ﬁxing partner in a symbiosis with certain nonleguminous plants,

most notably of the genera Alnus,Casuarina, and Elaeaginus, per-

mitting these plants to grow well in nitrogen-poor soils. Some

species of higher plants are symbiotic, forming endophytic asso-

ciations with actinomycetes to achieve actinorhizal nitrogen ﬁxa-

tion (168). The genus Frankia establishes a symbiotic relationship

with many ﬂowering plants. The best-known example is the alder

(Alnus), where these Actinobacteria are found in the roots, in nod-

ules where nitrogen gas is allowed to reach the nitrogenase (168).

(iv) Actinobacteria as endophytes. Endophytic Actinobacteria

have been isolated from a wide variety of plants. The most fre-

quently observed species belong to the genera Microbispora,No-

cardia,Micromonospora, and Streptomyces, the most abundant

(566,593). Unlike pathogenic streptomycetes, endophytic species

persist inside the plant host for long periods of time without caus-

ing observable disorder symptoms and lack known virulence de-

terminants shared with phytopathogenic Streptomyces spp. (503).

Endophytic streptomycetes may improve the growth of their plant

host by producing auxins that promote root growth and develop-

ment (594,595). Moreover, endophytic colonization of Pisum sa-

tivum with the endophyte S. lydicus improves the frequency of

root nodulation by Rhizobium spp., causing enhanced iron and

molybdenum assimilation and vigorous plant growth (596).

(v) Actinobacteria as elicitors of plant defense. In addition to

direct toxic effects on other microbes, nitrous oxide production by

Streptomyces has been suggested to activate plant defenses, im-

proving the plant’s protection against pathogens (597). Recently,

Mahmoudi et al. (559) reported that streptomycetes can degrade

the signaling compounds that coordinate the expression of genes

required for pathogenicity in Pectobacterium carotovorum, sug-

gesting a further mechanism for disease suppression. In addition,

the production of chitinases or plant growth-promoting com-

pounds has been reported to contribute to disease suppression by

some Streptomyces isolates (598–601).

CONCLUSIONS AND FUTURE PERSPECTIVES

In this review, we have provided a comprehensive overview of the

current knowledge concerning the biology of the phylum Actino-

bacteria and applications of its members in medicine, agriculture,

and industry. Distributed in both terrestrial and aquatic ecosys-

tems, its members play a crucial role in the recycling of refractory

biomaterials. The diversity of this phylum is large and includes

many beneﬁcial but also some pathogenic species. Mycobacterium

tuberculosis is carried by 2 billion people in the world and is the

causative agent of tuberculosis, killing several million people every

year. There are also the scab-causing streptomycetes, which have a

broad host range, infect plants, and are known for their ability to

cause necrotic scab-like lesions on economically important root

and tuber crops, such as potato. On the other hand, the Actino-

bacteria have numerous clear potential beneﬁts for humans as

sources of novel antibiotics, antifungals, anticancer agents, and

other secondary metabolites that might be used in medicine or to

improve plant growth and resistance to diseases. Actinobacteria

are also very promising for biocontrol of pests and as plant growth

promoters. With the rapid developments in the ﬁelds of genomics,

synthetic biology, and ecology and the strong requirement for new

antimicrobial compounds to combat antimicrobial resistance, the

biology of the Actinobacteria is a highly dynamic research ﬁeld and

we expect to see many new advances in this ﬁeld in the years to

come.

Biology of Actinobacteria

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on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

ACKNOWLEDGMENTS

We are grateful to Dennis Claessen for discussions.

This work is supported by the research program “Assessing and reduc-

ing environmental risks from plant protection products” funded by the

French Ministries in charge of Ecology and Agriculture.

REFERENCES

1. Ludwig W, Euzéby J, Schumann P, Buss HJ, Trujillo ME, Kämpfer P,

Whiteman WB. 2012. Road map of the phylum Actinobacteria, p 1–28.

In Goodfellow M, Kämpfer P, Busse HJ, Trujillo ME, Suzuki KI, Ludwig

W, Whitman WB (ed), Bergey’s manual of systematic bacteriology, vol 5.

Springer-Verlag, New York, NY.

2. Ventura M, Canchaya C, Fitzgerald GF, Gupta RS, van Sinderen D.

2007. Genomics as a means to understand bacterial phylogeny and eco-

logical adaptation: the case of biﬁdobacteria. Antonie Van Leeuwenhoek

91:351–372. http://dx.doi.org/10.1007/s10482-006-9122-6.

3. Macagnan D, Romeiro RDS, de Souza JT, Pomella AWV. 2006.

Isolation of actinomycetes and endospore-forming bacteria from the ca-

cao pod surface and their antagonistic activity against the witches’ broom

and black pod pathogens. Phytoparasitica 3:122–132. http://dx.doi.org

/10.1007/BF02981312.

4. Lechevalier HA, Lechevalier MP. 1965. Classiﬁcation des actinomycètes

aérobies basée sur leur morphologie et leur composition chimique. Ann

Inst Pasteur 108:662– 673. (In French.)

5. Zimmerman W. 1980. Degradation of lignin by bacteria. J Biotechnol

13:199–130.

6. Mayﬁeld CI, Williams ST, Ruddick SM, Hatﬁeld HL. 1972. Studies on

the ecology of actinomycetes in soil. IV. Observations on the form and

growth of streptomycetes in soil. Soil Biol Biochem 4:79–91.

7. Goodfellow M, Williams ST. 1983. Ecology of actinomycetes. Annu

Rev Microbiol 37:189 –216. http://dx.doi.org/10.1146/annurev.mi.37

.100183.001201.

8. Williams ST, Vickers JC. 1988. Detection of actinomycetes in the nat-

ural environment: problems and perspectives, p 165–270. In Okami Y,

Beppu T, Ogawara H (ed), Biology of actinomycetes. Japan Scientiﬁc

Societies Press, Tokyo, Japan.

9. Edwards C. 1993. Isolation properties and potential applications of ther-

mophilic actinomycetes. Appl Biochem Biotechnol 42:161–179. http:

//dx.doi.org/10.1007/BF02788050.

10. Kim SB, Lonsdale J, Seong C-N, Goodfellow M. 2003. Streptacidiphilus

gen. nov., acidophilic actinomycetes with wall chemotype I and emen-

dation of the family Streptomycetaceae (Waksman and Henrici

(1943)AL) emend. Rainey et al. 1997. Antonie Van Leeuwenhoek 83:

107–116. http://dx.doi.org/10.1023/A:1023397724023.

11. Hiltner L, Störmer K. 1903. Studien über die Bakterienﬂora des Acker-

bodens, mit besonderer Berücksichtigung ihres Verhaltens nach einer

Behandlung mit Schwefelkohlenstoff und nach Brache. Arb Biol Reich-

sanst Land-Forstwirtsch 3:443–545. (In German.)

12. Buchanan RE. 1917. Studies in the nomenclature and classiﬁcation of

the bacteria. II. The primary subdivisions of the Schizomycetes. J Bacteriol

2:155–164.

13. Omura S, Takahashi Y, Iwai Y, Tanaka H. 1982. Kitasatosporia, a new

genus of the order Actinomycetales. J Antibiot 35:1013–1019. http://dx

.doi.org/10.7164/antibiotics.35.1013.

14. Wellington EM, Stackebrandt E, Sanders D, Wolstrup J, Jorgensen

NO. 1992. Taxonomic status of Kitasatosporia, and proposed uniﬁcation

with Streptomyces on the basis of phenotypic and 16S rRNA analysis and

emendation of Streptomyces Waksman and Henrici 1943, 339AL. Int J

Syst Bacteriol 42:156–160. http://dx.doi.org/10.1099/00207713-42-1

-156.

15. Zhang Z, Wang Y, Ruan J. 1997. A proposal to revive the genus Kita-

satospora (Omura, Takahashi, Iwai, and Tanaka 1982). Int J Syst Bacte-

riol 47:1048–1054. http://dx.doi.org/10.1099/00207713-47-4-1048.

16. Girard G, Willemse J, Zhu H, Claessen D, Bukarasam K, Goodfellow

M, van Wezel GP. 2014. Analysis of novel kitasatosporae reveals signif-

icant evolutionary changes in conserved developmental genes between

Kitasatospora and Streptomyces. Antonie Van Leeuwenhoek 106:365–

380. http://dx.doi.org/10.1007/s10482-014-0209-1.

17. Girard G, Traag BA, Sangal V, Mascini N, Hoskisson PA, Goodfellow

M, van Wezel GP. 2013. A novel taxonomic marker that discriminates

between morphologically complex actinomycetes. Open Biol 3:130073.

http://dx.doi.org/10.1098/rsob.130073.

18. Kirby R. 2011. Chromosome diversity and similarity within the Actino-

mycetales. FEMS Microbiol Lett 319:1–10. http://dx.doi.org/10.1111/j

.1574-6968.2011.02242.x.

19. Gao B, Gupta RS. 2012. Phylogenetic framework and molecular signa-

tures for the main clades of the phylum Actinobacteria. Microbiol Mol

Biol Rev 76:66–112. http://dx.doi.org/10.1128/MMBR.05011-11.

20. Zhi XY, Li WJ, Stackebrandt E. 2009. An update of the structure and

16S rRNA gene sequence-based deﬁnition of higher ranks of the class

Actinobacteria, with the proposal of two new suborders and four new

families and emended descriptions of the existing higher taxa. Int J Syst

Evol Microbiol 59:589 –608. http://dx.doi.org/10.1099/ijs.0.65780-0.

21. Goodfellow M, Kämpfer P, Busse HJ, Trujillo ME, Suzuki K, Ludwig

W, Whitman WB (ed). 2012. Bergey’s manual of systematic bacteriol-

ogy, vol 5. The Actinobacteria, part A and B. Springer, New York, NY.

22. Labeda D. 1987. Actinomycete taxonomy: generic characterization. Dev

Ind Microbiol 28:115–121.

23. Flärdh K, Buttner MJ. 2009. Streptomyces morphogenetics: dissecting

differentiation in a ﬁlamentous bacterium. Nat Rev Microbiol 7:36–49.

http://dx.doi.org/10.1038/nrmicro1968.

24. van Dissel D, Claessen D, van Wezel GP. 2014. Morphogenesis of

Streptomyces in submerged cultures. Adv Appl Microbiol 89:1–45. http:

//dx.doi.org/10.1016/B978-0-12-800259-9.00001-9.

25. Kalakoutskii LV, Agre NS. 1976. Comparative aspects of development

and differentiation in actinomycetes. Bacteriol Rev 40:469–525.

26. Atlas R. 1997. Principles of microbiology. WCB McGraw-Hill, New

York, NY.

27. Locci R, Schaal KP. 1980. Apical growth in facultative anaerobic acti-

nomycetes as determined by immunoﬂuorescent labeling. Zentralbl

Bakteriol A 246:112–118.

28. Flärdh K. 2003. Growth polarity and cell division in Streptomyces. Curr

Opin Microbiol 6:564–571. http://dx.doi.org/10.1016/j.mib.2003.10

.011.

29. Letek M, Ordonez E, Vaquera J, Margolin W, Flärdh K, Mateos LM,

Gil JA. 2008. DivIVA is required for polar growth in the MreB-lacking

rod-shaped actinomycete Corynebacterium glutamicum. J Bacteriol 190:

3283–3292. http://dx.doi.org/10.1128/JB.01934-07.

30. Prauser H, Lechevalier MP, Lechevalier H. 1970. Description of Oers-

kovia gen. n. to harbor Orskov’s motile Nocardia. Appl Microbiol 19:534.

31. Ochi K. 1995. Phylogenetic analysis of mycolic acid-containing wall-

chemotype IV actinomycetes and allied taxa by partial sequencing of

ribosomal protein AT-L30. Int J Syst Bacteriol 45:653– 660. http://dx.doi

.org/10.1099/00207713-45-4-653.

32. Locci R, Sharples G. 1984. Morphology, p 165–199. In Goodfellow M,

Mordarski M, Williams ST (ed), The biology of Actinomycetes. Academic

Press, London, United Kingdom.

33. Cross T, Goodfellow M. 1973. Taxonomy and classiﬁcation of the acti-

nomycetes. Soc Appl Bacteriol Symp Ser 2:11–112.

34. Dietz A, Mathews J. 1971. Classiﬁcation of Streptomyces spore surfaces

into ﬁve groups. Appl Microbiol 21:527–533.

35. Pridham TG, Hesseltine CW, Benedict RG. 1958. A guide for the

classiﬁcation of streptomycetes according to selected groups; placement

of strains in morphological sections. Appl Microbiol 6:52–79.

36. Dastager S, Dayanand LWJA, Tang SK, Tian XP, Zhi XY, Xu LH, Jiang

C. 2006. Separation, identiﬁcation and analysis of pigment (melanin)

production in Streptomyces. Afr J Biotechnol 5:1131–1134.

37. Manivasagan P, Venkatesan J, Sivakumar K, Kim SK. 2013. Marine

actinobacterial metabolites: current status and future perspectives. Mi-

crobiol Res 168:311–332. http://dx.doi.org/10.1016/j.micres.2013.02

.002.

38. Goodfellow M, Minnikin DE. 1985. Chemical methods in bacterial

systematics. Academic Press, London, United Kingdom.

39. O’Donnell AG. 1988. Recognition of novel actinomycetes, p 69–88. In

Goodfellow MM, Williams ST, Mordarski M (ed), Actinomycetes in bio-

technology. Academic Press, London, United Kingdom.

40. Goodfellow M, O’Donnell AG. 1989. Search and discovery of industri-

ally-signiﬁcant actinomycetes, p 343–383. In Baumberg S, Hunter IS,

Rhodes PM (ed), Microbial products: new approach. Cambridge Uni-

versity Press, Cambridge, United Kingdom.

41. Williams ST, Goodfellow M, Alderson G. 1989. Genus Streptomyces

Waksman and Henrici 1943, 339AL, p 2452–2492. In Williams ST,

Sharpe ME, Holt JG (ed), Bergey’s manual of systematic bacteriology, 1st

ed, vol 4. Williams & Wilkins, Baltimore, MD.

Barka et al.

26 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

42. Berd D. 1973. Laboratory identiﬁcation of clinically important aerobic

actinomycetes. J Appl Microbiol 25:665–681.

43. Willey JM, Sherwood LM, Woolverton CJ. 2010. Prescott’s microbiol-

ogy, 7th ed. McGraw-Hill, New York, NY.

44. Lechevalier MP, Lechevalier HA. 1980. The chemotaxonomy of actino-

mycetes, p 225–292. In Dietz A, Thayer DW (ed), Actinomycetes taxon-

omy, vol A6. Virginia Society of Industrial Microbiology, Arlington, VA.

45. Bouizgarne B, Ait Ben Aoumar A. 2014. Diversity of plant associated

Actinobacteria, p 41–100. In Maheshwari DK (ed), Bacterial diversity in

sustainable agriculture. Springer International, Heidelberg, Germany.

46. Kroppenstedt R. 1985. Fatty acid and menaquinone analysis of actino-

mycetes and related organisms, p 173–199. Chemical methods in bacte-

rial systematics. SAB Technical Series 20, Academic Press, London,

United Kingdom.

47. Suzuki K, Goodfellow M, O’Donnell AG. 1993. Cell envelopes and

classiﬁcation, p 195–250. In Goodfellow M, O’Donnell AG (ed), Hand-

book of new bacterial systematics. Academic Press, London, United

Kingdom.

48. Collins MD, Goodfellow M, Minnikin DE, Alderson G. 1985.

Menaquinone composition of mycolic acid-containing actinomycetes

and some sporoactinomycetes. J Appl Bacteriol 58:77–86. http://dx.doi

.org/10.1111/j.1365-2672.1985.tb01431.x.

49. Collins MD. 1994. Isoprenoid quinones, p 265–309. In Goodfellow M,

O’Donnell AG (ed), Chemical methods in prokaryotic systematics. Wi-

ley, Chichester, United Kingdom.

50. Collins MD, Smida J, Dorsch M, Stackebrandt E. 1988. Tsukamurella

gen. nov., harboring Corynebacterium paurometabolum and Rhodococcus

aurantiacus. Int J Syst Bacteriol 38:385–391. http://dx.doi.org/10.1099

/00207713-38-4-385.

51. Kroppenstedt RM, Stackebrandt E, Goodfellow M. 1990. Taxonomic

revision of the actinomycete genera Actinomadura and Microtetraspora.

Syst Appl Microbiol 13:148–160. http://dx.doi.org/10.1016/S0723

-2020(11)80162-1.

52. Yamada Y, Aoki K, Tahara Y. 1982. The structure of hexa-hydrogenated

isoprenoid sidechain menaquinone with nine isoprene units isolated

from Actinomadura madurae. J Gen Appl Microbiol 28:321–329. http:

//dx.doi.org/10.2323/jgam.28.321.

53. Goodfellow M. 1992. The family Nocardiaceae, p 1188–1212. In Balows

A, Truper HG, Dworkin M, Harder W, Scheifer K-H (ed), The pro-

karyotes. Springer, New York, NY.

54. Tindall BJ, Kampfer P, Euzeby JP, Oren A. 2006. Valid publication of

names of prokaryotes according to the rules of nomenclature: past his-

tory and current practice. Int J Syst Evol Microbiol 56:2715–2720. http:

//dx.doi.org/10.1099/ijs.0.64780-0.

55. Goodfellow M. 1989. The genus Rhodococcus Zopf 1891, p 2362–2371. In

Williams ST, Sharpe ME, Holt JG (ed), Bergey’s manual of systematic

bacteriology, 1st ed, vol 4. Williams & Wilkins, Baltimore, MD.

56. Lechevalier MP. 1977. Lipids in bacterial taxonomy: a taxonomist’s

view. Crit Rev Microbiol 5:109–210. http://dx.doi.org/10.3109

/10408417709102311.

57. Lechevalier MP, De Bievre C, Lechevalier HA. 1977. Chemotaxonomy

of aerobic actinomycetes: phospholipid composition. Biochem Syst Ecol

5:249–260. http://dx.doi.org/10.1016/0305-1978(77)90021-7.

58. Lechevalier MP, Stern AE, Lechevalier HA. 1981. Phospholipids in the

taxonomy of actinomycetes, p 111–116. In Schaal KP, Pulverer G (ed),

Actinomycetes. Gustav Fischer Verlag, Stuttgart, Germany.

59. Yokota A, Tamura T. 1994. Transfer of Nocardioides fastidiosa Collins

and Stackebrandt 1989 to the genus Aeromicrobium as Aeromicrobium

fastidiosum comb. nov. Int J Syst Bacteriol 44:608 –611. http://dx.doi.org

/10.1099/00207713-44-4-608.

60. Rainey FA, Klatte S, Kroppenstedt RM, Stackebrandt E. 1995. Dietzia,

a new genus including Dietzia maris comb. nov., formerly Rhodococcus

maris. Int J Syst Bacteriol 45:32–36. http://dx.doi.org/10.1099/00207713

-45-1-32.

61. Lechevalier MP, Lechevalier H. 1970. Chemical composition as a crite-

rion in the classiﬁcation of aerobic actinomycetes. Int J Syst Bacteriol

20:435–443. http://dx.doi.org/10.1099/00207713-20-4-435.

62. Asano K, Masunaga I, Kawamoto I. 1989. Catellatospora matsumo-

toense sp. nov. and C. tsunoense sp. nov., actinomycetes found in wood-

land soils. Int J Syst Bacteriol 39:309–313. http://dx.doi.org/10.1099

/00207713-39-3-309.

63. Maltsev II, Kalinovskii AI, Zgurskaya HI, Evtushenko LI. 1992.

Tyvelose in Agromyces cell walls. Syst Appl Microbiol 15:187–189. http:

//dx.doi.org/10.1016/S0723-2020(11)80090-1.

64. Ichikawa N, Oguchi A, Ikeda H, Ishikawa J, Kitani S, Watanabe Y,

Nakamura S, Katano Y, Kishi E, Sasagawa M, Ankai A, Fukui S,

Hashimoto Y, Kamata S, Otoguro M, Tanikawa S, Nihira T, Horin-

ouchi S, Ohnishi Y, Hayakawa M, Kuzuyama T, Arisawa A, Nomoto

F, Miura H, Takahashi Y, Fujita N. 2010. Genome sequence of Kita-

satospora setae NBRC 14216T: an evolutionary snapshot of the family

Streptomycetaceae. DNA Res 17:393–406. http://dx.doi.org/10.1093

/dnares/dsq026.

65. Kim BJ, Kim CJ, Chun J, Koh YH, Lee SH, Hyun JW, Cha CY, Kook

YH. 2004. Phylogenetic analysis of the genera Streptomyces and Kitasato-

spora based on partial RNA polymerase beta-subunit gene (rpoB) se-

quences. Int J Syst Evol Microbiol 54:593–598. http://dx.doi.org/10.1099

/ijs.0.02941-0.

66. Euzéby JP. 1997. List of bacterial names with standing in nomenclature:

a folder available on the Internet. Int J Syst Bacteriol 47:590–592. http:

//dx.doi.org/10.1099/00207713-47-2-590.

67. Raoult D, La Scola B, Lecocq P, Lepidi H, Fournier PE. 2001. Culture

and immunological detection of Tropheryma whippelii from the duode-

num of a patient with Whipple disease. JAMA 285:1039 –1043. http://dx

.doi.org/10.1001/jama.285.8.1039.

68. Raoult D, Lepidi H, Harle JR. 2001. Tropheryma whipplei circulating in

blood monocytes. N Engl J Med 345:548. http://dx.doi.org/10.1056

/NEJM200108163450716.

69. Bentley SD, Maiwald M, Murphy LD, Pallen MJ, Yeats CA, Dover LG,

Norbertczak HT, Besra GS, Quail MA, Harris DE, von Herbay A,

Goble A, Rutter S, Squares R, Squares S, Barrell BG, Parkhill J,

Relman DA. 2003. Sequencing and analysis of the genome of the Whip-

ple’s disease bacterium Tropheryma whipplei. Lancet 361:637–644. http:

//dx.doi.org/10.1016/S0140-6736(03)12597-4.

70. Raoult D, Ogata H, Audic S, Robert C, Suhre K, Drancourt M,

Claverie JM. 2003. Tropheryma whipplei Twist: a human pathogenic

Actinobacteria with a reduced genome. Genome Res 13:1800 –1809. http:

//dx.doi.org/10.1101/gr.1474603.

71. Desnues B, Al Moussawi K, Fenollar F. 2010. New insights into Whip-

ple’s disease and Tropheryma whipplei infections. Microbes Infect 12:

1102–1110. http://dx.doi.org/10.1016/j.micinf.2010.08.001.

72. Ingham E. 1999. The immunology of Propionibacterium acnes and acne.

Curr Opin Infect Dis 12:191–197. http://dx.doi.org/10.1097/00001432

-199906000-00006.

73. Csukas Z, Banizs B, Rozgonyi F. 2004. Studies on the cytotoxic effects

of Propionibacterium acnes strains isolated from cornea. Microb Pathog

36:171–174. http://dx.doi.org/10.1016/j.micpath.2003.09.002.

74. Jakab E, Zbinden R, Gubler J, Ruef C, Von Graevenitz A, Krause M.

1996. Severe infections caused by Propionibacterium acnes: an underes-

timated pathogen in late postoperative infections. Yale J Biol Med 69:

477–482.

75. Campisano A, Ometto L, Compant S, Pancher M, Antonielli L, Yousaf

S, Varotto C, Anfora G, Pertot I, Sessitsch A, Rota-Stabelli O. 2014.

Interkingdom transfer of the acne-causing agent, Propionibacterium ac-

nes, from human to grapevine. Mol Biol Evol 31:1059–1065. http://dx

.doi.org/10.1093/molbev/msu075.

76. Hirsch AM, Valdés M. 2009. Micromonospora: an important microbe

for biomedicine and potentially for biocontrol and biofuels. Soil Biol

Biochem 42:536–542. http://dx.doi.org/10.1016/j.soilbio.2009.11.023.

77. Genilloud O. 2012. Genus I. Micromonospora, p 1039–1057. In Good-

fellow M, Kämpfer P, Busse H-J, Trujillo ME, Suzuki K-I, Ludwig W,

Whitman WB (ed), Bergey’s manual of systematic bacteriology: the Ac-

tinobacteria, 2nd ed, vol 5. Springer-Verlag, New York, NY.

78. Hoskisson PA, Hobbs G, Sharples GP. 2000. Response of Micromono-

spora echinospora (NCIMB 12744) spores to heat treatment with evi-

dence of a heat activation phenomenon. Lett Appl Microbiol 30:114–

117. http://dx.doi.org/10.1046/j.1472-765x.2000.00680.x.

79. Trujillo ME, Bacigalupe R, Pujic P, Igarashi Y, Benito P, Riesco R,

Medigue C, Normand P. 2014. Genome features of the endophytic

actinobacterium Micromonospora lupini strain Lupac 08: on the process

of adaptation to an endophytic life style? PLoS One 9:e108522. http://dx

.doi.org/10.1371/journal.pone.0108522.

80. Berdy J. 2005. Bioactive microbial metabolites. J Antibiot 58:1–26. http:

//dx.doi.org/10.1038/ja.2005.1.

81. Das S, Ward LR, Burke C. 2008. Prospects of using marine actinobac-

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 27Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

teria as probiotics in aquaculture. Appl Microbiol Biotechnol 81:419–

429. http://dx.doi.org/10.1007/s00253-008-1731-8.

82. Jensen PR, Mafnas C. 2006. Biogeography of the marine actinomycete

Salinispora. Environ Microbiol 8:1881–1888. http://dx.doi.org/10.1111/j

.1462-2920.2006.01093.x.

83. Maldonado LA, Stach JE, Pathom-aree W, Ward AC, Bull AT, Good-

fellow M. 2005. Diversity of cultivable actinobacteria in geographically

widespread marine sediments. Antonie Van Leeuwenhoek 87:11–18.

http://dx.doi.org/10.1007/s10482-004-6525-0.

84. Fenical W, Jensen PR, Palladino MA, Lam KS, Lloyd GK, Potts BC.

2009. Discovery and development of the anticancer agent salinospora-

mide A (NPI-0052). Bioorg Med Chem 17:2175–2180. http://dx.doi.org

/10.1016/j.bmc.2008.10.075.

85. Jensen PR, Gontang E, Mafnas C, Mincer TJ, Fenical W. 2005. Cul-

turable marine actinomycete diversity from tropical Paciﬁc Ocean sedi-

ments. Environ Microbiol 7:1039–1048. http://dx.doi.org/10.1111/j

.1462-2920.2005.00785.x.

86. Bose U, Hewavitharana AK, Vidgen ME, Ng YK, Shaw PN, Fuerst JA,

Hodson MP. 2014. Discovering the recondite secondary metabolome

spectrum of Salinispora species: a study of inter-species diversity. PLoS

One 9:e91488. http://dx.doi.org/10.1371/journal.pone.0091488.

87. Jensen PR, Williams PG, Oh DC, Zeigler L, Fenical W. 2007. Species-

speciﬁc secondary metabolite production in marine actinomycetes of the

genus Salinispora. Appl Environ Microbiol 73:1146–1152. http://dx.doi

.org/10.1128/AEM.01891-06.

88. Waksman SA. 1961. The Actinomycetes, classiﬁcation, identiﬁcation and

description of genera and species, vol 2. Williams & Wilkins Company,

Baltimore, MD.

89. Waksman SA. 1967. The actinomycetes: a summary of current knowl-

edge. Roland Press Company, New York, NY.

90. Embley T, Stackebrandt E. 1994. The molecular phylogency and sys-

tematics of the actinomycetes. Annu Rev Microbiol 48:257–289. http:

//dx.doi.org/10.1146/annurev.mi.48.100194.001353.

91. Chatterjee D, Hunter W, McNeil M, Brennan PJ. 1992. Lipoarabino-

mannan: multiglycosylated form of the mycobacterial mannosylphos-

phatidylinositols. J Biol Chem 267:6228–6233.

92. Daffe M, Brennan PJ, McNeil M. 1990. Predominant structural features

of the cell wall arabinogalactan of Mycobacterium tuberculosis as revealed

through characterization of oligoglycosyl alditol fragments by gas chro-

matography/mass spectrometry and by

H and

C NMR analyses. J Biol

Chem 265:6734–6743.

93. Pitulle C, Dorsch M, Kazda J, Wolters J, Stackebrandt E. 1992.

Phylogeny of rapidly growing members of the genus Mycobacterium. Int

J Syst Bacteriol 42:337–343. http://dx.doi.org/10.1099/00207713-42-3

-337.

94. Rogall T, Wolters J, Flohr T, Bottger EC. 1990. Towards a phylogeny

and deﬁnition of species at the molecular level within the genus Myco-

bacterium. Int J Syst Bacteriol 40:323–330. http://dx.doi.org/10.1099

/00207713-40-4-323.

95. Stahl DA, Urbance JW. 1990. The division between fast- and slow-

growing species corresponds to natural relationships among the Myco-

bacteria. J Bacteriol 172:116–124.

96. Falkinham JO, III. 1996. Epidemiology of infection by nontuberculous

mycobacteria. Clin Microbiol Rev 9:177–215.

97. Collins CH. 2000. The bovine tubercle Bacillus. Br J Biomed Sci 57:

234–240.

98. Jacobson RR, Krahenbuhl JL. 1999. Leprosy. Lancet 353:655–660. http:

//dx.doi.org/10.1016/S0140-6736(98)06322-3.

99. Hayman J. 1991. Postulated epidemiology of Mycobacterium ulcerans

infection. Int J Epidemiol 20:1093–1098. http://dx.doi.org/10.1093/ije

/20.4.1093.

100. van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. 1999.

Mycobacterium ulcerans infection. Lancet 354:1013–1018. http://dx.doi

.org/10.1016/S0140-6736(99)01156-3.

101. Aronson JD. 1926. Spontaneous tuberculosis in salt water ﬁsh. J Infect

Dis 39:315–320. http://dx.doi.org/10.1093/infdis/39.4.315.

102. Norden A, Linell F. 1951. A new type of pathogenic Mycobacterium.

Nature 168:826. http://dx.doi.org/10.1038/168826a0.

103. Patel SS, Tavana ML, Boger MS, Win SS, Rimawi BH. 2014. Necro-

tizing soft tissue infection occurring after exposure to Mycobacterium

marinum. Case Rep Infect Dis 2014:702613. http://dx.doi.org/10.1155

/2014/702613.

104. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ, Jr. 2006.

Clinical and laboratory features of the Nocardia spp. based on current

molecular taxonomy. Clin Microbiol Rev 19:259–282. http://dx.doi.org

/10.1128/CMR.19.2.259-282.2006.

105. Abreu C, Rocha-Pereira N, Sarmento A, Magro F. 2015. Nocardia

infections among immunomodulated inﬂammatory bowel disease pa-

tients: a review. World J Gastroenterol 21:6491–6498. http://dx.doi.org

/10.3748/wjg.v21.i21.6491.

106. Simpson RS, Read RC. 2014. Nocardiosis and actinomycosis. Medicine

42:23–25. http://dx.doi.org/10.1016/j.mpmed.2013.10.012.

107. Yorke RF, Rouah E. 2003. Nocardiosis with brain abscess due to an

unusual species, Nocardia transvalensis. Arch Pathol Lab Med 127:

224–226.

108. Coco WM, Levinson WE, Crist MJ, Hektor HJ, Darzins A, Pienkos PT,

Squires CH, Monticello DJ. 2001. DNA shufﬂing method for generating

highly recombined genes and evolved enzymes. Nat Biotechnol 19:354–

359. http://dx.doi.org/10.1038/86744.

109. Shigemori H, Komaki H, Yazawa K, Mikami Y, Nemoto A, Tanaka Y,

Sasaki T, In Y, Ishida T, Kobayashi J. 1998. Brasilicardin A. A novel

tricyclic metabolite with potent immunosuppressive activity from acti-

nomycete Nocardia brasiliensis. J Org Chem 63:6900–6904.

110. Schlaberg R, Huard RC, Della-Latta P. 2008. Nocardia cyriacigeorgica,

an emerging pathogen in the United States. J Clin Microbiol 46:265–273.

http://dx.doi.org/10.1128/JCM.00937-07.

111. Sorrell TC, Mitchell DH, Iredell JR, Chen SC-A. 2009. Nocardia spe-

cies, p 3199–3207. In Mandell GL, Bennett JE, Dolin R (ed), Principles

and practice of infectious diseases, 7th ed. Churchill Livingstone, Phila-

delphia, PA.

112. Mandell G, Douglas R, Bennett J, Dolin R (ed). 2005. Principles and

practice of infectious diseases, 6th ed. Elsevier/Churchill Livingstone,

New York, NY.

113. Wiesmayr S, Stelzmueller I, Tabarelli W, Bargehr D, Graziadei I,

Freund M, Ladurner R, Steurer W, Geltner C, Mark W, Margreiter R,

Bonatti H. 2005. Nocardiosis following solid organ transplantation: a

single-centre experience. Transpl Int 18:1048 –1053. http://dx.doi.org/10

.1111/j.1432-2277.2005.00177.x.

114. Matulionyte R, Rohner P, Uckay I, Lew D, Garbino J. 2004. Secular

trends of nocardia infection over 15 years in a tertiary care hospital. J Clin

Pathol 57:807–812. http://dx.doi.org/10.1136/jcp.2004.016923.

115. Greene CE. 2006. Actinomycosis and nocardiosis. Elsevier, Philadel-

phia, PA.

116. Barksdale L. 1970. Corynebacterium diphtheriae and its relatives. Bac-

teriol Rev 34:378–422.

117. Collins MD, Cummins CS. 1986. Genus Corynebacterium. Williams &

Wilkins, Baltimore, MD.

118. Leuchtenberger W, Huthmacher K, Drauz K. 2005. Biotechnological

production of amino acids and derivatives: current status and prospects.

Appl Microbiol Biotechnol 69:1–8. http://dx.doi.org/10.1007/s00253

-005-0155-y.

119. Domingo MC, Fournier E, Masse C, Charest H, Bernard K, Cote JC,

Tremblay C. 2015. Draft genome sequences of two toxigenic Corynebac-

terium ulcerans strains. Genome Announc 3(3):e00699-15. http://dx.doi

.org/10.1128/genomeA.00699-15.

120. Ruckert C, Albersmeier A, Winkler A, Tauch A. 2015. Complete

genome sequence of Corynebacterium kutscheri DSM 20755, a coryne-

bacterial type strain with remarkably low G⫹C content of chromosomal

DNA. Genome Announce 3(3):e00571-15. http://dx.doi.org/10.1128

/genomeA.00571-15.

121. Fernandez-Natal MI, Soriano F, Ariza-Miguel J, Marrodan-Ciordia T,

Acedo A, Hernandez M, Tauch A, Rodriguez-Lazaro D. 2015. Draft

genome sequences of Corynebacterium kroppenstedtii CNM633/14 and

CNM632/14, multidrug-resistant and antibiotic-sensitive isolates from

nodules of granulomatous mastitis patients. Genome Announc 3(3):

e00525-15. http://dx.doi.org/10.1128/genomeA.00525-15.

122. Fernandez-Natal MI, Soriano F, Acedo A, Hernandez M, Tauch A,

Rodriguez-Lazaro D. 2015. Draft genome sequences of the two unre-

lated macrolide-resistant Corynebacterium argentoratense strains CNM

463/05 and CNM 601/08, isolated from patients in the University Hos-

pital of Leon, Spain. Genome Announc 3(4):e00765-15. http://dx.doi

.org/10.1128/genomeA.00765-15.

123. Donovan C, Heyer A, Pfeifer E, Polen T, Wittmann A, Kramer R,

Frunzke J, Bramkamp M. 2015. A prophage-encoded actin-like protein

required for efﬁcient viral DNA replication in bacteria. Nucleic Acids Res

43:5002–5016. http://dx.doi.org/10.1093/nar/gkv374.

Barka et al.

28 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

124. Hadﬁeld TL, McEvoy P, Polotsky Y, Tzinserling VA, Yakovlev AA.

2000. The pathology of diphtheria. J Infect Dis 181:S116 –S120. http://dx

.doi.org/10.1086/315551.

125. Holmes RK. 2000. Biology and molecular epidemiology of diphtheria

toxin and the tox gene. J Infect Dis 181(Suppl 1):S156 –S167. http://dx

.doi.org/10.1086/315554.

126. Mattos-Guaraldi AL, Sampaio JL, Santos CS, Pimenta FP, Pereira GA,

Pacheco LG, Miyoshi A, Azevedo V, Moreira LO, Gutierrez FL, Costa

JL, Costa-Filho R, Damasco PV, Camello TC, Hirata R, Jr. 2008. First

detection of Corynebacterium ulcerans producing a diphtheria-like toxin

in a case of human with pulmonary infection in the Rio de Janeiro met-

ropolitan area, Brazil. Mem Inst Oswaldo Cruz 103:396–400. http://dx

.doi.org/10.1590/S0074-02762008000400014.

127. Hatanaka A, Tsunoda A, Okamoto M, Ooe K, Nakamura A, Miyako-

shi M, Komiya T, Takahashi M. 2003. Corynebacterium ulcerans diph-

theria in Japan. Emerg Infect Dis 9:752–753. http://dx.doi.org/10.3201

/eid0906.020645.

128. Dessau RB, Brandt-Christensen M, Jensen OJ, Tonnesen P. 1995.

Pulmonary nodules due to Corynebacterium ulcerans. Eur Respir J

8:651–653.

129. Sing A, Bierschenk S, Heesemann J. 2005. Classical diphtheria caused

by Corynebacterium ulcerans in Germany: amino acid sequence differ-

ences between diphtheria toxins from Corynebacterium diphtheriae and

C. ulcerans. Clin Infect Dis 40:325–326. http://dx.doi.org/10.1086

/426687.

130. Jackman PJH, Pitcher DG, Pelczynska S, Borman P. 1987. Classiﬁca-

tion of Corynebacteria associated with endocarditis (group JK) as Coryne-

bacterium jeikeium sp. nov. Syst Appl Microbiol 9:83–90. http://dx.doi

.org/10.1016/S0723-2020(87)80060-7.

131. Funke G, von Graevenitz A, Clarridge JE, III, Bernard KA. 1997.

Clinical microbiology of coryneform bacteria. Clin Microbiol Rev 10:

125–159.

132. Tsukamura M. 1971. Proposal of a new genus, Gordona, for slightly

acid-fast organisms occurring in sputa of patients with pulmonary dis-

ease and in soil. J Gen Microbiol 68:15–26. http://dx.doi.org/10.1099

/00221287-68-1-15.

133. Hefferan M. 1904. A comparative and experimental study of bacilli pro-

ducing red pigment. Zentralbl Bakteriol Parasitenkd Abt II 73:74–96.

134. Stackebrandt E, Sproer C, Rainey FA, Burghardt J, Pauker O, Hippe

H. 1997. Phylogenetic analysis of the genus Desulfotomaculum: evidence

for the misclassiﬁcation of Desulfotomaculum guttoideum and descrip-

tion of Desulfotomaculum orientis as Desulfosporosinus orientis gen. nov.,

comb. nov. Int J Syst Bacteriol 47:1134–1139. http://dx.doi.org/10.1099

/00207713-47-4-1134.

135. Bell KS, Philp JC, Aw DW, Christoﬁ N. 1998. The genus Rhodococcus.

J Appl Microbiol 85:195–210. http://dx.doi.org/10.1046/j.1365-2672

.1998.00525.x.

136. Prescott JF. 1991. Rhodococcus equi: an animal and human pathogen.

Clin Microbiol Rev 4:20–34.

137. Goodfellow M, Cross T. 1984. Classiﬁcation, p 7–164. In Goodfellow M,

Mordarski M, Williams ST (ed), The biology of the actinomycetes. Aca-

demic Press, London, United Kingdom.

138. Goodfellow M, Lechevalier MP. 1989. Genus Nocardia, p 235–236. In

Williams ST, Sharpe ME, Holt JG (ed), Bergey’s manual of systematic

bacteriology, vol 4. Williams & Wilkins, Baltimore, MD.

139. Larkin MJ, Kulakov LA, Allen CC. 2005. Biodegradation and Rhodo-

coccus: masters of catabolic versatility. Curr Opin Biotechnol 16:282–

290. http://dx.doi.org/10.1016/j.copbio.2005.04.007.

140. Jones AL, Goodfellow M. 2012. Genus IV. Rhodococcus (Zopf 1891)

emend. Goodfellow, Alderson and Chun 1998a, p 437– 463. In Whitman

WB, Goodfellow M, Kämpfer P, Busse HJ, Trujillo ME, Ludwig W (ed),

Bergey’s manual of systematic bacteriology, vol 5. The Actinobacteria,

part A. Springer, New York, NY.

141. Goodfellow M, Sangal V, Jones AL, Sutcliffe IC. 2015. Charting stormy

waters: a commentary on the nomenclature of the equine pathogen var-

iously named Prescottella equi,Rhodococcus equi and Rhodococcus hoagii.

Equine Vet J 47:508–509. http://dx.doi.org/10.1111/evj.12399.

142. Evtushenko LI, Dorofeeva LV, Subbotin SA, Cole JR, Tiedje JM. 2000.

Leifsonia poae gen. nov., sp. nov., isolated from nematode galls on Poa

annua, and reclassiﬁcation of “Corynebacterium aquaticum” Leifson

1962 as Leifsonia aquatica (ex Leifson 1962) gen. nov., nom. rev., comb.

nov. and Clavibacter xyli Davis et al. 1984 with two subspecies as Leifsonia

xyli (Davis et al. 1984 gen. nov., comb. nov.). Int J Syst Evol Microbiol

50:371–380. http://dx.doi.org/10.1099/00207713-50-1-371.

143. Dastager SG, Lee JC, Ju YJ, Park DJ, Kim CJ. 2008. Leifsonia bigeu-

mensis sp. nov., isolated from soil on Bigeum Island, Korea. Int J Syst Evol

Microbiol 58:1935–1938. http://dx.doi.org/10.1099/ijs.0.65572-0.

144. Dastager SG, Lee JC, Ju YJ, Park DJ, Kim CJ. 2009. Leifsonia kribbensis

sp. nov., isolated from soil. Int J Syst Evol Microbiol 59:18 –21. http://dx

.doi.org/10.1099/ijs.0.001925-0.

145. Hao DC, Ge GB, Yang L. 2008. Bacterial diversity of Taxus rhizo-

sphere: culture-independent and culture-dependent approaches.

FEMS Microbiol Lett 284:204–212. http://dx.doi.org/10.1111/j.1574

-6968.2008.01201.x.

146. Janssen PH, Yates PS, Grinton BE, Taylor PM, Sait M. 2002. Improved

culturability of soil bacteria and isolation in pure culture of novel mem-

bers of the divisions Acidobacteria,Actinobacteria,Proteobacteria, and

Verrucomicrobia. Appl Environ Microbiol 68:2391–2396. http://dx.doi

.org/10.1128/AEM.68.5.2391-2396.2002.

147. Sutcliffe IC, Hutchings MI. 2007. Putative lipoproteins identiﬁed by

bioinformatic genome analysis of Leifsonia xyli ssp. xyli, the causative

agent of sugarcane ratoon stunting disease. Mol Plant Pathol 8:121–128.

http://dx.doi.org/10.1111/j.1364-3703.2006.00377.x.

148. Tissier H. 1900. Recherches sur la ﬂore intestinale normale et

pathologique du nourrisson (état normale et pathologique). G. Carre et

C. Naud, Paris, France.

149. Orla-Jensen S. 1924. La classiﬁcation des bactéries lactiques. Lait 4:468–

474. (In French.)

150. Lievin V, Peiffer I, Hudault S, Rochat F, Brassart D, Neeser JR, Servin

AL. 2000. Biﬁdobacterium strains from resident infant human gastroin-

testinal microﬂora exert antimicrobial activity. Gut 47:646–652. http:

//dx.doi.org/10.1136/gut.47.5.646.

151. Ouwehand AC, Salminen S, Isolauri E. 2002. Probiotics: an overview of

beneﬁcial effects. Antonie Van Leeuwenhoek 82:279–289. http://dx.doi

.org/10.1023/A:1020620607611.

152. Bevilacqua L, Ovidi M, Di Mattia E, Trovatelli LD, Canganella F. 2003.

Screening of Biﬁdobacterium strains isolated from human faeces for an-

tagonistic activities against potentially bacterial pathogens. Microbiol

Res 158:179–185. http://dx.doi.org/10.1078/0944-5013-00192.

153. Cheikhyoussef A, Pogori N, Chen H, Tian F, Chen W, Tang J, Zhang

H. 2009. Antimicrobial activity and partial characterization of bacterio-

cin-like inhibitory substances (BLIS) produced by Biﬁdobacterium infan-

tis BCRC 14602. Food Control 20:553–559. http://dx.doi.org/10.1016/j

.foodcont.2008.08.003.

154. Collado MC, Gonzalez A, Gonzalez R, Hernandez M, Ferrus MA, Sanz

Y. 2005. Antimicrobial peptides are among the antagonistic metabolites

produced by Biﬁdobacterium against Helicobacter pylori. Int J Antimicrob

Agents 25:385–391. http://dx.doi.org/10.1016/j.ijantimicag.2005.01.017.

155. Cheikhyoussef A, Pogori N, Chen H, Zhao J, Tang J, Chen W, Zhang

H. 2009. Comparison of three different methods for the isolation of

bacteriocin-like inhibitory substances from Biﬁdobacterium infantis

BCRC 14602. J Rapid Methods Automat Microbiol 17:182–194. http:

//dx.doi.org/10.1111/j.1745-4581.2009.00167.x.

156. Cheikhyoussef A, Cheikhyoussef N, Chen HZJ, Tang J, Zhang H. 2010.

Biﬁdin. I. A new bacteriocin produced by Biﬁdobacterium infantis BCRC

14602: puriﬁcation and partial amino acid sequence. Food Control 21:

746–753. http://dx.doi.org/10.1016/j.food.cont.2009.11.003.

157. von Ah U. 2006. Identiﬁcation of Biﬁdobacterium thermophilum RBL67

isolated from baby faeces and partial puriﬁcation of its bacteriocin. Swiss

Federal Institute of Technology, Zurich, Switzerland.

158. Harper J, Davis G. 1982. Cell wall analysis of Gardnerella vaginalis

(Haemophilus vaginalis). Int J Syst Bacteriol 32:48–50. http://dx.doi.org

/10.1099/00207713-32-1-48.

159. Greenwood J, Pickett M. 1980. Transfer of Haemophilus vaginalis Gard-

ner and Dukes to a new genus, Gardnerella:G. vaginalis (Gardner and

Dukes) comb nov. Int J Syst Bacteriol 30:170–178. http://dx.doi.org/10

.1099/00207713-30-1-170.

160. Kim TK, Thomas SM, Ho M, Sharma S, Reich CI, Frank JA, Yeater

KM, Biggs DR, Nakamura N, Stumpf R. 2009. Heterogeneity of vaginal

microbial communities within individuals. J Clin Microbiol 47:1181–

1189. http://dx.doi.org/10.1128/JCM.00854-08.

161. Menard JP, Mazouni C, Salem-Cherif I, Fenollar F, Raoult D, Boubli

L, Gamerre M, Bretelle F. 2010. High vaginal concentrations of Atopo-

bium vaginae and Gardnerella vaginalis in women undergoing preterm

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 29Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

labor. Obstet Gynecol 115:134–140. http://dx.doi.org/10.1097/AOG

.0b013e3181c391d7.

162. Lamont RF, Sobel JD, Akins RA, Hassan SS, Chaiworapongsa T,

Kusanovic JP, Romero R. 2011. The vaginal microbiome: new informa-

tion about genital tract ﬂora using molecular based techniques. BJOG

118:533–549. http://dx.doi.org/10.1111/j.1471-0528.2010.02840.x.

163. Miyadoh S. 1997. Atlas of actinomycetes. Asakura Publishing Co, To-

kyo, Japan.

164. Aderem A. 2005. Systems biology: its practice and challenges. Cell 121:

511–513. http://dx.doi.org/10.1016/j.cell.2005.04.020.

165. Hopwood DA. 2007. Streptomyces in nature and medicine: the antibiotic

makers. Oxford University Press, New York, NY.

166. Benson DR, Silvester WB. 1993. Biology of Frankia strains, actinomy-

cete symbionts of actinorhizal plants. Microbiol Rev 57:293–319.

167. Perrine-Walker F, Gherbi H, Imanishi L, Hocher V, Ghodhbane-

Gtari F, Lavenus J, Benabdoun FM, Nambiar-Veeti M, Svistoonoff

S, Laplaze L. 2011. Symbiotic signaling in actinorhizal symbioses.

Curr Protein Peptide Sci 12:156–164. http://dx.doi.org/10.2174

/138920311795684896.

168. Pawlowski K, Demchenko KN. 2012. The diversity of actinorhizal sym-

biosis. Protoplasma 249:967–979. http://dx.doi.org/10.1007/s00709-012

-0388-4.

169. Gtari M, Ghodhbane-Gtari F, Nouioui I, Beauchemin N, Tisa LS.

2012. Phylogenetic perspectives of nitrogen-ﬁxing actinobacteria. Arch

Microbiol 194:3–11. http://dx.doi.org/10.1007/s00203-011-0733-6.

170. Zhang Z, Wang Y, Ruan J. 1998. Reclassiﬁcation of Thermomonospora

and Microtetraspora. Int J Syst Bacteriol 48:411–422. http://dx.doi.org

/10.1099/00207713-48-2-411.

171. Kukolya J, Nagy I, Laday M, Toth E, Oravecz O, Marialigeti K,

Hornok L. 2002. Thermobiﬁda cellulolytica sp. nov., a novel lignocellu-

lose-decomposing actinomycete. Int J Syst Evol Microbiol 52:1193–

1199. http://dx.doi.org/10.1099/00207713-52-4-1193.

172. Yang LL, Tang SK, Zhang YQ, Zhi XY, Wang D, Xu LH, Li WJ. 2008.

Thermobiﬁda halotolerans sp. nov., isolated from a salt mine sample, and

emended description of the genus Thermobiﬁda. Int J Syst Evol Microbiol

58:1821–1825. http://dx.doi.org/10.1099/ijs.0.65732-0.

173. Chater KF, Biro S, Lee KJ, Palmer T, Schrempf H. 2010. The complex

extracellular biology of Streptomyces. FEMS Microbiol Rev 34:171–198.

http://dx.doi.org/10.1111/j.1574-6976.2009.00206.x.

174. Chater KF. 1972. A morphological and genetic mapping study of white

colony mutants of Streptomyces coelicolor. J Gen Microbiol 72:9 –28. http:

//dx.doi.org/10.1099/00221287-72-1-9.

175. Donachie WD. 1993. The cell cycle of Escherichia coli. Annu Rev Mi-

crobiol 47:199–230. http://dx.doi.org/10.1146/annurev.mi.47.100193

.001215.

176. Wildermuth H, Hopwood DA. 1970. Septation during sporulation in

Streptomyces coelicolor. J Gen Microbiol 60:51–59. http://dx.doi.org/10

.1099/00221287-60-1-51.

177. Claessen D, Rozen DE, Kuipers OP, Sogaard-Andersen L, van Wezel

GP. 2014. Bacterial solutions to multicellularity: a tale of bioﬁlms, ﬁla-

ments and fruiting bodies. Nat Rev Microbiol 12:115–124. http://dx.doi

.org/10.1038/nrmicro3178.

178. Elliot MA, Buttner MJ, Nodwell JR. 2008. Multicellular development in

Streptomyces, p 419–438. In Whitworth DE (ed), Myxobacteria: multi-

cellularity and differentiation. ASM Press, Washington, DC.

179. Bibb MJ. 2005. Regulation of secondary metabolism in streptomycetes.

Curr Opin Microbiol 8:208–215. http://dx.doi.org/10.1016/j.mib.2005

.02.016.

180. van Wezel GP, McDowall KJ. 2011. The regulation of the secondary

metabolism of Streptomyces: new links and experimental advances. Nat

Prod Rep 28:1311–1333. http://dx.doi.org/10.1039/c1np00003a.

181. Méndez C, Braña AF, Manzanal MB, Hardisson C. 1985. Role of

substrate mycelium in colony development in Streptomyces. Can J Mi-

crobiol 31:446–450. http://dx.doi.org/10.1139/m85-083.

182. Miguélez EM, Hardisson C, Manzanal MB. 1999. Hyphal death during

colony development in Streptomyces antibioticus: morphological evi-

dence for the existence of a process of cell deletion in a multicellular

prokaryote. J Cell Biol 145:515–525. http://dx.doi.org/10.1083/jcb.145.3

.515.

183. Wildermuth H. 1970. Development and organization of the aerial my-

celium in Streptomyces coelicolor. J Gen Microbiol 60:43–50. http://dx.doi

.org/10.1099/00221287-60-1-43.

184. Fernández M, Sánchez J. 2002. Nuclease activities and cell death pro-

cesses associated with the development of surface cultures of Strepto-

myce antibioticus. Microbiology 148:405–412. http://dx.doi.org/10

.1099/00221287-148-2-405.

185. Kim IS, Kang SG, Lee KJ. 1995. Physiological importance of trypsin like

protease during morphological differentiation of Streptomyces spp. J Mi-

crobiol 33:315–321.

186. Rigali S, Nothaft H, Noens EE, Schlicht M, Colson S, Muller M, Joris

B, Koerten HK, Hopwood DA, Titgemeyer F, van Wezel GP. 2006. The

sugar phosphotransferase system of Streptomyces coelicolor is regulated

by the GntR-family regulator DasR and links N-acetylglucosamine me-

tabolism to the control of development. Mol Microbiol 61:1237–1251.

http://dx.doi.org/10.1111/j.1365-2958.2006.05319.x.

187. Rigali S, Titgemeyer F, Barends S, Mulder S, Thomae AW, Hopwood

DA, van Wezel GP. 2008. Feast or famine: the global regulator DasR

links nutrient stress to antibiotic production by Streptomyces. EMBO Rep

9:670–675. http://dx.doi.org/10.1038/embor.2008.83.

188. Chater KF. 2011. Differentiation in Streptomyces: the properties and

programming of diverse cell-types, p 43– 86. In Dyson P (ed), Streptomy-

ces: molecular biology and biotechnology. Caister Academic Press, Nor-

folk, United Kingdom.

189. Manteca A, Ye J, Sanchez J, Jensen ON. 2011. Phosphoproteome

analysis of Streptomyces development reveals extensive protein phos-

phorylation accompanying bacterial differentiation. J Proteome Res 10:

5481–5492. http://dx.doi.org/10.1021/pr200762y.

190. Merrick MJ. 1976. A morphological and genetic mapping study of bald

colony mutants of Streptomyces coelicolor. J Gen Microbiol 96:299–315.

http://dx.doi.org/10.1099/00221287-96-2-299.

191. Hopwood DA, Wildermuth H, Palmer HM. 1970. Mutants of Strepto-

myces coelicolor defective in sporulation. J Gen Microbiol 61:397–408.

http://dx.doi.org/10.1099/00221287-61-3-397.

192. Champness WC. 1988. New loci required for Streptomyces coelicolor

morphological and physiological differentiation. J Bacteriol 170:1168–

1174.

193. Gehring AM, Nodwell JR, Beverley SM, Losick R. 2000. Genomewide

insertional mutagenesis in Streptomyces coelicolor reveals additional

genes involved in morphological differentiation. Proc Natl Acad Sci

USA97:9642–9647. http://dx.doi.org/10.1073/pnas.170059797.

194. Hopwood DA. 1999. Forty years of genetics with Streptomyces: from in

vivo through in vitro to in silico. Microbiology 145:2183–2202. http://dx

.doi.org/10.1099/00221287-145-9-2183.

195. Ryding NJ, Bibb MJ, Molle V, Findlay KC, Chater KF, Buttner MJ.

1999. New sporulation loci in Streptomyces coelicolor A3(2). J Bacteriol

181:5419–5425.

196. Ma H, Kendall K. 1994. Cloning and analysis of a gene cluster from

Streptomyces coelicolor that causes accelerated aerial mycelium formation

in Streptomyces lividans. J Bacteriol 176:3800–3811.

197. Kawamoto S, Ensign JC. 1995. Isolation of mutants of Streptomyces

griseus that sporulate in nutrient rich media: cloning of DNA fragments

that suppress the mutations. Actinomycetologica 9:124–135. http://dx

.doi.org/10.3209/saj.9_124.

198. Pope MK, Green BD, Westpheling J. 1996. The bld mutants of Strep-

tomyces coelicolor are defective in the regulation of carbon utilization,

morphogenesis and cell– cell signalling. Mol Microbiol 19:747–756. http:

//dx.doi.org/10.1046/j.1365-2958.1996.414933.x.

199. Seo JW, Ohnishi Y, Hirata A, Horinouchi S. 2002. ATP-binding cas-

sette transport system involved in regulation of morphological differen-

tiation in response to glucose in Streptomyces griseus. J Bacteriol 184:91–

103. http://dx.doi.org/10.1128/JB.184.1.91-103.2002.

200. den Hengst CD, Tran NT, Bibb MJ, Chandra G, Leskiw BK, Buttner

MJ. 2010. Genes essential for morphological development and antibiotic

production in Streptomyces coelicolor are targets of BldD during vegeta-

tive growth. Mol Microbiol 78:361–379. http://dx.doi.org/10.1111/j

.1365-2958.2010.07338.x.

201. Elliot MA, Bibb MJ, Buttner MJ, Leskiw BK. 2001. BldD is a direct

regulator of key developmental genes in Streptomyces coelicolor A3(2).

Mol Microbiol 40:257–269. http://dx.doi.org/10.1046/j.1365-2958.2001

.02387.x.

202. Elliot MA, Locke TR, Galibois CM, Leskiw BK. 2003. BldD from

Streptomyces coelicolor is a non-essential global regulator that binds its

own promoter as a dimer. FEMS Microbiol Lett 225:35– 40. http://dx.doi

.org/10.1016/S0378-1097(03)00474-9.

203. Bibb MJ, Molle V, Buttner MJ. 2000. sigma(BldN), an extracytoplasmic

function RNA polymerase sigma factor required for aerial mycelium for-

Barka et al.

30 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

mation in Streptomyces coelicolor A3(2). J Bacteriol 182:4606 –4616. http:

//dx.doi.org/10.1128/JB.182.16.4606-4616.2000.

204. Chater KF, Bruton CJ, Plaskitt KA, Buttner MJ, Mendez C, Helmann

JD. 1989. The developmental fate of S. coelicolor hyphae depends upon a

gene product homologous with the motility sigma factor of B. subtilis.

Cell 59:133–143. http://dx.doi.org/10.1016/0092-8674(89)90876-3.

205. Méndez C, Chater KF. 1987. Cloning of whiG, a gene critical for spo-

rulation of Streptomyces coelicolor A3(2). J Bacteriol 169:5715–5720.

206. Persson J, Chater KF, Flärdh K. 2013. Molecular and cytological anal-

ysis of the expression of Streptomyces sporulation regulatory gene whiH.

FEMS Microbiol Lett 341:96–105. http://dx.doi.org/10.1111/1574-6968

.12099.

207. Ryding NJ, Kelemen GH, Whatling CA, Flärdh K, Buttner MJ, Chater

KF. 1998. A developmentally regulated gene encoding a repressor-like

protein is essential for sporulation in Streptomyces coelicolor A3(2).

Mol Microbiol 29:343–357. http://dx.doi.org/10.1046/j.1365-2958.1998

.00939.x.

208. Lawlor EJ, Baylis HA, Chater KF. 1987. Pleiotropic morphological and

antibiotic deﬁciencies result from mutations in a gene encoding a tRNA-

like product in Streptomyces coelicolor A3(2). Genes Dev 1:1305–1310.

http://dx.doi.org/10.1101/gad.1.10.1305.

209. Leskiw BK, Mah R, Lawlor EJ, Chater KF. 1993. Accumulation of

bldA-speciﬁed tRNA is temporally regulated in Streptomyces coelicolor

A3(2). J Bacteriol 175:1995–2005.

210. Hesketh A, Bucca G, Laing E, Flett F, Hotchkiss G, Smith CP, Chater

KF. 2007. New pleiotropic effects of eliminating a rare tRNA from Strep-

tomyces coelicolor, revealed by combined proteomic and transcriptomic

analysis of liquid cultures. BMC Genomics 8:261. http://dx.doi.org/10

.1186/1471-2164-8-261.

211. Kim DW, Chater K, Lee KJ, Hesketh A. 2005. Changes in the extracel-

lular proteome caused by the absence of the bldA gene product, a devel-

opmentally signiﬁcant tRNA, reveal a new target for the pleiotropic reg-

ulator AdpA in Streptomyces coelicolor. J Bacteriol 187:2957–2966. http:

//dx.doi.org/10.1128/JB.187.9.2957-2966.2005.

212. Guyet A, Benaroudj N, Proux C, Gominet M, Coppee JY, Mazodier P.

2014. Identiﬁed members of the Streptomyces lividans AdpA regulon in-

volved in differentiation and secondary metabolism. BMC Microbiol

14:81. http://dx.doi.org/10.1186/1471-2180-14-81.

213. Higo A, Hara H, Horinouchi S, Ohnishi Y. 2012. Genome-wide dis-

tribution of AdpA, a global regulator for secondary metabolism and

morphological differentiation in Streptomyces, revealed the extent and

complexity of the AdpA regulatory network. DNA Res 19:259 –273. http:

//dx.doi.org/10.1093/dnares/dss010.

214. Ohnishi Y, Yamazaki H, Kato JY, Tomono A, Horinouchi S. 2005.

AdpA, a central transcriptional regulator in the A-factor regulatory cas-

cade that leads to morphological development and secondary metabo-

lism in Streptomyces griseus. Biosci Biotechnol Biochem 69:431–439.

http://dx.doi.org/10.1271/bbb.69.431.

215. Yamazaki H, Tomono A, Ohnishi Y, Horinouchi S. 2004. DNA-

binding speciﬁcity of AdpA, a transcriptional activator in the A-factor

regulatory cascade in Streptomyces griseus. Mol Microbiol 53:555–572.

http://dx.doi.org/10.1111/j.1365-2958.2004.04153.x.

216. Horinouchi S. 2002. A microbial hormone, A-factor, as a master switch

for morphological differentiation and secondary metabolism in Strepto-

myces griseus. Front Biosci 7:d2045–d2057. http://dx.doi.org/10.2741

/horinouc.

217. Horinouchi S, Beppu T. 1994. A-factor as a microbial hormone that

controls cellular differentiation and secondary metabolism in Streptomy-

ces griseus. Mol Microbiol 12:859–864. http://dx.doi.org/10.1111/j.1365

-2958.1994.tb01073.x.

218. Khoklov AS, Tovarova II, Borisova N, Pliner SA, Schevchenko LA,

Kornitskaya NS, Ivkina NS, Rapoport IA. 1967. A-faktor, obespecchi-

vaiushchii biosintez streptomitsina mutantnym shtammom Actinomy-

ces streptomycini. Dokl Akad Nauk SSSR 177:232–235. (In Russian.)

219. Ohnishi Y, Kameyama S, Onaka H, Horinouchi S. 1999. The A-fac-

tor regulatory cascade leading to streptomycin biosynthesis in Strep-

tomyces griseus: identiﬁcation of a target gene of the A-factor receptor.

Mol Microbiol 34:102–111. http://dx.doi.org/10.1046/j.1365-2958

.1999.01579.x.

220. Takano E, Chakraburtty R, Nihira T, Yamada Y, Bibb MJ. 2001. A

complex role for the gamma-butyrolactone SCB1 in regulating antibiotic

production in Streptomyces coelicolor A3(2). Mol Microbiol 41:1015–

1028. http://dx.doi.org/10.1046/j.1365-2958.2001.02562.x.

221. Nguyen KT, Tenor J, Stettler H, Nguyen LT, Nguyen LD, Thompson

CJ. 2003. Colonial differentiation in Streptomyces coelicolor depends on

translation of a speciﬁc codon within the adpA gene. J Bacteriol 185:

7291–7296. http://dx.doi.org/10.1128/JB.185.24.7291-7296.2003.

222. Takano E, Tao M, Long F, Bibb MJ, Wang L, Li W, Buttner MJ,

Deng ZX, Chater KF. 2003. A rare leucine codon in adpA is impli-

cated in the morphological defect of bldA mutants of Streptomyces

coelicolor. Mol Microbiol 50:475– 486. http://dx.doi.org/10.1046/j

.1365-2958.2003.03728.x.

223. Higo A, Horinouchi S, Ohnishi Y. 2011. Strict regulation of morpho-

logical differentiation and secondary metabolism by a positive feedback

loop between two global regulators AdpA and BldA in Streptomyces gri-

seus. Mol Microbiol 81:1607–1622. http://dx.doi.org/10.1111/j.1365

-2958.2011.07795.x.

224. Tschowri N, Schumacher MA, Schlimpert S, Chinnam NB, Findlay

KC, Brennan RG, Buttner MJ. 2014. Tetrameric c-di-GMP mediates

effective transcription factor dimerization to control Streptomyces devel-

opment. Cell 158:1136–1147. http://dx.doi.org/10.1016/j.cell.2014.07

.022.

225. Tenconi E, Urem M, Swiatek-Polatynska MA, Titgemeyer F, Muller

YA, van Wezel GP, Rigali S. 2015. Multiple allosteric effectors control

the afﬁnity of DasR for its target sites. Biochem Biophys Res Commun

464:324–329. http://dx.doi.org/10.1016/j.bbrc.2015.06.152.

226. Chater KF. 2001. Regulation of sporulation in Streptomyces coelicolor

A3(2): a checkpoint multiplex? Curr Opin Microbiol 4:667–673. http:

//dx.doi.org/10.1016/S1369-5274(01)00267-3.

227. Kelemen GH, Buttner MJ. 1998. Initiation of aerial mycelium formation

in Streptomyces. Curr Opin Microbiol 1:656–662. http://dx.doi.org/10

.1016/S1369-5274(98)80111-2.

228. Nodwell JR, McGovern K, Losick R. 1996. An oligopeptide permease

responsible for the import of an extracellular signal governing aerial my-

celium formation in Streptomyces coelicolor. Mol Microbiol 22:881–893.

http://dx.doi.org/10.1046/j.1365-2958.1996.01540.x.

229. Nodwell JR, Yang M, Kuo D, Losick R. 1999. Extracellular comple-

mentation and the identiﬁcation of additional genes involved in aerial

mycelium formation in Streptomyces coelicolor. Genetics 151:569–584.

230. Willey J, Santamaria R, Guijarro J, Geistlich M, Losick R. 1991.

Extracellular complementation of a developmental mutation implicates

a small sporulation protein in aerial mycelium formation by S. coelicolor.

Cell 65:641–650. http://dx.doi.org/10.1016/0092-8674(91)90096-H.

231. Willey J, Schwedock J, Losick R. 1993. Multiple extracellular signals

govern the production of a morphogenetic protein involved in aerial

mycelium formation by Streptomyces coelicolor. Genes Dev 7:895–903.

http://dx.doi.org/10.1101/gad.7.5.895.

232. Kwakman JH, Postma PW. 1994. Glucose kinase has a regulatory role in

carbon catabolite repression in Streptomyces coelicolor. J Bacteriol 176:

2694–2698.

233. Sanchez S, Chavez A, Forero A, Garcia-Huante Y, Romero A, Sanchez

M, Rocha D, Sanchez B, Avalos M, Guzman-Trampe S, Rodriguez-

Sanoja R, Langley E, Ruiz B. 2010. Carbon source regulation of antibi-

otic production. J Antibiot 63:442–459. http://dx.doi.org/10.1038/ja

.2010.78.

234. Angell S, Lewis CG, Buttner MJ, Bibb MJ. 1994. Glucose repression in

Streptomyces coelicolor A3(2): a likely regulatory role for glucose kinase.

Mol Gen Genet 244:135–143.

235. van Wezel GP, Konig M, Mahr K, Nothaft H, Thomae AW, Bibb M,

Titgemeyer F. 2007. A new piece of an old jigsaw: glucose kinase is

activated posttranslationally in a glucose transport-dependent manner in

Streptomyces coelicolor A3(2). J Mol Microbiol Biotechnol 12:67–74. http:

//dx.doi.org/10.1159/000096461.

236. van Wezel GP, McKenzie NL, Nodwell JR. 2009. Applying the genetics

of secondary metabolism in model actinomycetes to the discovery of new

antibiotics. Methods Enzymol 458:117–141. http://dx.doi.org/10.1016

/S0076-6879(09)04805-8.

237. Pope MK, Green B, Westpheling J. 1998. The bldB gene encodes a small

protein required for morphogenesis, antibiotic production, and catabo-

lite control in Streptomyces coelicolor. J Bacteriol 180:1556–1562.

238. Gubbens J, Janus M, Florea BI, Overkleeft HS, van Wezel GP. 2012.

Identiﬁcation of glucose kinase dependent and independent pathways

for carbon control of primary metabolism, development and antibiotic

production in Streptomyces coelicolor by quantitative proteomics. Mol

Microbiol 86:1490–1507. http://dx.doi.org/10.1111/mmi.12072.

239. Nothaft H, Dresel D, Willimek A, Mahr K, Niederweis M, Titgemeyer

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 31Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

F. 2003. The phosphotransferase system of Streptomyces coelicolor is bi-

ased for N-acetylglucosamine metabolism. J Bacteriol 185:7019–7023.

http://dx.doi.org/10.1128/JB.185.23.7019-7023.2003.

240. Parche S, Nothaft H, Kamionka A, Titgemeyer F. 2000. Sugar

uptake and utilisation in Streptomyces coelicolor: a PTS view to the

genome. Antonie Van Leeuwenhoek 78:243–251. http://dx.doi.org

/10.1023/A:1010274317363.

241. Colson S, van Wezel GP, Craig M, Noens EE, Nothaft H, Mommaas

AM, Titgemeyer F, Joris B, Rigali S. 2008. The chitobiose-binding

protein, DasA, acts as a link between chitin utilization and morphogen-

esis in Streptomyces coelicolor. Microbiology 154:373–382. http://dx.doi

.org/10.1099/mic.0.2007/011940-0.

242. Uguru GC, Stephens KE, Stead JA, Towle JE, Baumberg S, Mc-

Dowall KJ. 2005. Transcriptional activation of the pathway-speciﬁc

regulator of the actinorhodin biosynthetic genes in Streptomyces coe-

licolor. Mol Microbiol 58:131–150. http://dx.doi.org/10.1111/j.1365

-2958.2005.04817.x.

243. Keijser BJ, van Wezel GP, Canters GW, Kieser T, Vijgenboom E. 2000.

The ram-dependence of Streptomyces lividans differentiation is bypassed

by copper. J Mol Microbiol Biotechnol 2:565–574.

244. Lambert S, Traxler MF, Craig M, Maciejewska M, Ongena M, van

Wezel GP, Kolter R, Rigali S. 2014. Altered desferrioxamine-

mediated iron utilization is a common trait of bald mutants of Strep-

tomyces coelicolor. Metallomics 6:1390 –1399. http://dx.doi.org/10

.1039/C4MT00068D.

245. Nodwell JR, Losick R. 1998. Puriﬁcation of an extracellular signaling

molecule involved in production of aerial mycelium by Streptomyces coe-

licolor. J Bacteriol 180:1334–1337.

246. Viollier PH, Minas W, Dale GE, Folcher M, Thompson CJ. 2001. Role

of acid metabolism in Streptomyces coelicolor morphological differentia-

tion and antibiotic biosynthesis. J Bacteriol 183:3184–3192. http://dx

.doi.org/10.1128/JB.183.10.3184-3192.2001.

247. Claessen D, Rink R, de Jong W, Siebring J, de Vreugd P, Boersma FG,

Dijkhuizen L, Wösten HA. 2003. A novel class of secreted hydrophobic

proteins is involved in aerial hyphae formation in Streptomyces coelicolor

by forming amyloid-like ﬁbrils. Genes Dev 17:1714–1726. http://dx.doi

.org/10.1101/gad.264303.

248. Claessen D, Stokroos I, Deelstra HJ, Penninga NA, Bormann C, Salas

JA, Dijkhuizen L, Wosten HA. 2004. The formation of the rodlet layer

of streptomycetes is the result of the interplay between rodlins and chap-

lins. Mol Microbiol 53:433–443. http://dx.doi.org/10.1111/j.1365-2958

.2004.04143.x.

249. Elliot MA, Karoonuthaisiri N, Huang J, Bibb MJ, Cohen SN, Kao CM,

Buttner MJ. 2003. The chaplins: a family of hydrophobic cell-surface

proteins involved in aerial mycelium formation in Streptomyces coeli-

color. Genes Dev 17:1727–1740. http://dx.doi.org/10.1101/gad.264403.

250. Glauert AM, Hopwood DA. 1961. The ﬁne structure of Streptomyces

violaceoruber (S. coelicolor). III. The walls of the mycelium and spores. J

Biophys Biochem Cytol 10:505–516. http://dx.doi.org/10.1083/jcb.10.4

.505.

251. Wildermuth H, Wehrli E, Horne RW. 1971. The surface structure of

spores and aerial mycelium in Streptomyces coelicolor. J Ultrastruct Res

35:168–180. http://dx.doi.org/10.1016/S0022-5320(71)80149-1.

252. Claessen D, de Jong W, Dijkhuizen L, Wösten HA. 2006. Regulation of

Streptomyces development: reach for the sky! Trends Microbiol 14:313–

319. http://dx.doi.org/10.1016/j.tim.2006.05.008.

253. Wösten HA, Willey JM. 2000. Surface-active proteins enable microbial

aerial hyphae to grow into the air. Microbiology 146:767–773. http://dx

.doi.org/10.1099/00221287-146-4-767.

254. Wösten HA, van Wetter MA, Lugones LG, van der Mei HC,

Busscher HJ, Wessels JG. 1999. How a fungus escapes the water to

grow into the air. Curr Biol 9:85– 88. http://dx.doi.org/10.1016/S0960

-9822(99)80019-0.

255. Sawyer EB, Claessen D, Haas M, Hurgobin B, Gras SL. 2011. The

assembly of individual chaplin peptides from Streptomyces coelicolor into

functional amyloid ﬁbrils. PLoS One 6:e18839. http://dx.doi.org/10.1371

/journal.pone.0018839.

256. Chater KF, Chandra G. 2006. The evolution of development in Strepto-

myces analysed by genome comparisons. FEMS Microbiol Rev 30:651–

672. http://dx.doi.org/10.1111/j.1574-6976.2006.00033.x.

257. Capstick DS, Willey JM, Buttner MJ, Elliot MA. 2007. SapB and the

chaplins: connections between morphogenetic proteins in Streptomyces

coelicolor. Mol Microbiol 64:602–613. http://dx.doi.org/10.1111/j.1365

-2958.2007.05674.x.

258. Claessen D, Wösten HA, van Keulen G, Faber OG, Alves AM, Meijer

WG, Dijkhuizen L. 2002. Two novel homologous proteins of Strepto-

myces coelicolor and Streptomyces lividans are involved in the formation of

the rodlet layer and mediate attachment to a hydrophobic surface. Mol

Microbiol 44:1483–1492. http://dx.doi.org/10.1046/j.1365-2958.2002

.02980.x.

259. Willey JM, Gaskell AA. 2011. Morphogenetic signaling molecules of the

streptomycetes. Chem Rev 111:174–187. http://dx.doi.org/10.1021

/cr1000404.

260. Willey JM, Willems A, Kodani S, Nodwell JR. 2006. Morphogenetic

surfactants and their role in the formation of aerial hyphae in Streptomy-

ces coelicolor. Mol Microbiol 59:731–742. http://dx.doi.org/10.1111/j

.1365-2958.2005.05018.x.

261. Di Berardo C, Capstick DS, Bibb MJ, Findlay KC, Buttner MJ, Elliot

MA. 2008. Function and redundancy of the chaplin cell surface proteins

in aerial hypha formation, rodlet assembly, and viability in Streptomyces

coelicolor. J Bacteriol 190:5879–5889. http://dx.doi.org/10.1128/JB

.00685-08.

262. Capstick DS, Jomaa A, Hanke C, Ortega J, Elliot MA. 2011. Dual

amyloid domains promote differential functioning of the chaplin pro-

teins during Streptomyces aerial morphogenesis. Proc Natl Acad SciUSA

108:9821–9826. http://dx.doi.org/10.1073/pnas.1018715108.

263. Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson

NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman

A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A,

Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T,

Larke L, Murphy L, Oliver K, O’Neil S, Rabbinowitsch E, Rajandream

MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares

R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J, Barrell

BG, Parkhill J, Hopwood DA. 2002. Complete genome sequence of the

model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147.

http://dx.doi.org/10.1038/417141a.

264. Tillotson RD, Wosten HA, Richter M, Willey JM. 1998. A surface active

protein involved in aerial hyphae formation in the ﬁlamentous fungus

Schizophillum commune restores the capacity of a bald mutant of the

ﬁlamentous bacterium Streptomyces coelicolor to erect aerial structures.

Mol Microbiol 30:595–602. http://dx.doi.org/10.1046/j.1365-2958.1998

.01093.x.

265. Kodani S, Lodato MA, Durrant MC, Picart F, Willey JM. 2005. SapT,

a lanthionine-containing peptide involved in aerial hyphae formation in

the streptomycetes. Mol Microbiol 58:1368–1380. http://dx.doi.org/10

.1111/j.1365-2958.2005.04921.x.

266. Ueda K, Oinuma K, Ikeda G, Hosono K, Ohnishi Y, Horinouchi S,

Beppu T. 2002. AmfS, an extracellular peptidic morphogen in Strepto-

myces griseus. J Bacteriol 184:1488–1492. http://dx.doi.org/10.1128/JB

.184.5.1488-1492.2002.

267. Ueda K, Hsheh CW, Tosaki T, Shinkawa H, Beppu T, Horinouchi S.

1998. Characterization of an A-factor-responsive repressor for amfR es-

sential for onset of aerial mycelium formation in Streptomyces griseus.J

Bacteriol 180:5085–5093.

268. Keijser BJ, van Wezel GP, Canters GW, Vijgenboom E. 2002. Devel-

opmental regulation of the Streptomyces lividans ram genes: involvement

of RamR in regulation of the ramCSAB operon. J Bacteriol 184:4420–

4429. http://dx.doi.org/10.1128/JB.184.16.4420-4429.2002.

269. Nguyen KT, Willey JM, Nguyen LD, Nguyen LT, Viollier PH, Thomp-

son CJ. 2002. A central regulator of morphological differentiation in the

multicellular bacterium Streptomyces coelicolor. Mol Microbiol 46:1223–

1238. http://dx.doi.org/10.1046/j.1365-2958.2002.03255.x.

270. O’Connor TJ, Nodwell JR. 2005. Pivotal roles for the receiver domain in

the mechanism of action of the response regulator RamR of Streptomyces

coelicolor. J Mol Biol 351:1030–1047. http://dx.doi.org/10.1016/j.jmb

.2005.06.053.

271. Kodani S, Hudson ME, Durrant MC, Buttner MJ, Nodwell JR, Willey

JM. 2004. The SapB morphogen is a lantibiotic-like peptide derived from

the product of the developmental gene ramS in Streptomyces coelicolor.

Proc Natl Acad SciUSA101:11448–11453. http://dx.doi.org/10.1073

/pnas.0404220101.

272. Willey JM, van der Donk WA. 2007. Lantibiotics: peptides of diverse

structure and function. Annu Rev Microbiol 61:477–501. http://dx.doi

.org/10.1146/annurev.micro.61.080706.093501.

273. Gaskell AA, Giovinazzo JA, Fonte V, Willey JM. 2012. Multi-tier

Barka et al.

32 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

regulation of the streptomycete morphogenetic peptide SapB. Mol

Microbiol 84:501–515. http://dx.doi.org/10.1111/j.1365-2958.2012

.08041.x.

274. Kormanec J, Sevcikova B, Sprusansky O, Benada O, Kofronova O,

Novakova R, Rezuchova B, Potuckova L, Homerova D. 1998. The

Streptomyces aureofaciens homologue of the whiB gene is essential for

sporulation; its expression correlates with the developmental stage. Folia

Microbiol (Praha) 43:605– 612. http://dx.doi.org/10.1007/BF02816376.

275. Keijser BJ, Noens EE, Kraal B, Koerten HK, van Wezel GP. 2003. The

Streptomyces coelicolor ssgB gene is required for early stages of sporula-

tion. FEMS Microbiol Lett 225:59–67. http://dx.doi.org/10.1016/S0378

-1097(03)00481-6.

276. Jyothikumar V, Tilley EJ, Wali R, Herron PR. 2008. Time-lapse

microscopy of Streptomyces coelicolor growth and sporulation. Appl

Environ Microbiol 74:6774 –6781. http://dx.doi.org/10.1128/AEM

.01233-08.

277. Jakimowicz D, van Wezel GP. 2012. Cell division and DNA segre-

gation in Streptomyces: how to build a septum in the middle of nowhere?

Mol Microbiol 85:393–404. http://dx.doi.org/10.1111/j.1365-2958.2012

.08107.x.

278. McCormick JR. 2009. Cell division is dispensable but not irrelevant in

Streptomyces. Curr Opin Biotechnol 12:689–698. http://dx.doi.org/10

.1016/j.mib.2009.10.004.

279. Bi EF, Lutkenhaus J. 1991. FtsZ ring structure associated with divi-

sion in Escherichia coli. Nature 354:161–164. http://dx.doi.org/10

.1038/354161a0.

280. Lowe J, Amos LA. 1998. Crystal structure of the bacterial cell-division

protein FtsZ. Nature 391:203–206. http://dx.doi.org/10.1038/34472.

281. Lutkenhaus J, Addinall SG. 1997. Bacterial cell division and the Z ring.

Annu Rev Biochem 66:93–116. http://dx.doi.org/10.1146/annurev

.biochem.66.1.93.

282. Margolin W. 2005. FtsZ and the division of prokaryotic cells and organ-

elles. Nature Rev Mol Cell Biol 6:862–871. http://dx.doi.org/10.1038

/nrm1745.

283. Romberg L, Levin PA. 2003. Assembly dynamics of the bacterial cell

division protein FTSZ: poised at the edge of stability. Annu Rev Micro-

biol 57:125–154. http://dx.doi.org/10.1146/annurev.micro.57.012903

.074300.

284. Grantcharova N, Lustig U, Flärdh K. 2005. Dynamics of FtsZ assembly

during sporulation in Streptomyces coelicolor A3(2). J Bacteriol 187:3227–

3237. http://dx.doi.org/10.1128/JB.187.9.3227-3237.2005.

285. Schwedock J, Mccormick JR, Angert ER, Nodwell JR, Losick R. 1997.

Assembly of the cell division protein FtsZ into ladder like structures in

the aerial hyphae of Streptomyces coelicolor. Mol Microbiol 25:847–858.

http://dx.doi.org/10.1111/j.1365-2958.1997.mmi507.x.

286. Willemse J, van Wezel GP. 2009. Imaging of Streptomyces coelicolor

A3(2) with reduced autoﬂuorescence reveals a novel stage of FtsZ local-

ization. PLoS One 4:e4242. http://dx.doi.org/10.1371/journal.pone

.0004242.

287. Flärdh K, Leibovitz E, Buttner MJ, Chater KF. 2000. Generation of a

non-sporulating strain of Streptomyces coelicolor A3(2) by the manipula-

tion of a developmentally controlled ftsZ promoter. Mol Microbiol 38:

737–749. http://dx.doi.org/10.1046/j.1365-2958.2000.02177.x.

288. Willemse J, Mommaas AM, van Wezel GP. 2012. Constitutive expres-

sion of ftsZ overrides the whi developmental genes to initiate sporulation

of Streptomyces coelicolor. Antonie Van Leeuwenhoek 101:619–632.

http://dx.doi.org/10.1007/s10482-011-9678-7.

289. McCormick JR, Su EP, Driks A, Losick R. 1994. Growth and viability of

Streptomyces coelicolor mutant for the cell division gene ftsZ. Mol Micro-

biol 14:243–254. http://dx.doi.org/10.1111/j.1365-2958.1994.tb01285.x.

290. Bennett JA, Aimino RM, McCormick JR. 2007. Streptomyces coelicolor

genes ftsL and divIC play a role in cell division but are dispensable for

colony formation. J Bacteriol 189:8982–8992. http://dx.doi.org/10.1128

/JB.01303-07.

291. Bennett JA, Yarnall J, Cadwallader AB, Kuennen R, Bidey P, Stadel-

maier B, McCormick JR. 2009. Medium-dependent phenotypes of

Streptomyces coelicolor with mutations in ftsI or ftsW. J Bacteriol 191:661–

664. http://dx.doi.org/10.1128/JB.01048-08.

292. McCormick JR, Losick R. 1996. Cell division gene ftsQ is required for

efﬁcient sporulation but not growth and viability in Streptomyces coeli-

color A3(2). J Bacteriol 178:5295–5301.

293. Mistry BV, Del Sol R, Wright C, Findlay K, Dyson P. 2008. FtsW is a

dispensable cell division protein required for Z-ring stabilization during

sporulation septation in Streptomyces coelicolor. J Bacteriol 190:5555–

5566. http://dx.doi.org/10.1128/JB.00398-08.

294. Marston AL, Thomaides HB, Edwards DH, Sharpe ME, Errington J.

1998. Polar localization of the MinD protein of Bacillus subtilis and its

role in selection of the mid-cell division site. Genes Dev 12:3419–3430.

http://dx.doi.org/10.1101/gad.12.21.3419.

295. Raskin DM, de Boer PA. 1997. The MinE ring: an FtsZ-independent cell

structure required for selection of the correct division site in E. coli. Cell

91:685–694. http://dx.doi.org/10.1016/S0092-8674(00)80455-9.

296. Wu LJ, Errington J. 2012. Nucleoid occlusion and bacterial cell division.

Nat Rev Microbiol 10:8–12. http://dx.doi.org/10.1038/nmicro2671.

297. Begg K, Nikolaichik Y, Crossland N, Donachie WD. 1998. Roles of FtsA

and FtsZ in activation of division sites. J Bacteriol 180:881–884.

298. Hale CA, de Boer PA. 1997. Direct binding of FtsZ to ZipA, an

essential component of the septal ring structure that mediates cell

division in E. coli. Cell 88:175–185. http://dx.doi.org/10.1016/S0092

-8674(00)81838-3.

299. Jakimowicz D, Gust B, Zakrzewska-Czerwinska J, Chater KF. 2005.

Developmental-stage-speciﬁc assembly of ParB complexes in Streptomy-

ces coelicolor hyphae. J Bacteriol 187:3572–3580. http://dx.doi.org/10

.1128/JB.187.10.3572-3580.2005.

300. Jakimowicz D, Zydek P, Kois A, Zakrzewska-Czerwinska J, Chater KF.

2007. Alignment of multiple chromosomes along helical ParA scaffold-

ing in sporulating Streptomyces hyphae. Mol Microbiol 65:625– 641. http:

//dx.doi.org/10.1111/j.1365-2958.2007.05815.x.

301. Kim HJ, Calcutt MJ, Schmidt FJ, Chater KF. 2000. Partitioning of the

linear chromosome during sporulation of Streptomyces coelicolor A3(2)

involves an oriC-linked parAB locus. J Bacteriol 182:1313–1320. http:

//dx.doi.org/10.1128/JB.182.5.1313-1320.2000.

302. Ausmees N, Wahlstedt H, Bagchi S, Elliot MA, Buttner MJ, Flärdh K.

2007. SmeA, a small membrane protein with multiple functions in Strep-

tomyces sporulation including targeting of a SpoIIIE/FtsK-like protein to

cell division septa. Mol Microbiol 65:1458–1473. http://dx.doi.org/10

.1111/j.1365-2958.2007.05877.x.

303. Dedrick RM, Wildschutte H, McCormick JR. 2009. Genetic interac-

tions of smc,ftsK, and parB genes in Streptomyces coelicolor and their

developmental genome segregation phenotypes. J Bacteriol 191:320 –

332. http://dx.doi.org/10.1128/JB.00858-08.

304. Wang L, Vining LC. 2003. Control of growth, secondary metabolism

and sporulation in Streptomyces venezuelae ISP5230 by jadW(1), a mem-

ber of the afsA family of gamma-butyrolactone regulatory genes. Micro-

biology 149:1991–2004. http://dx.doi.org/10.1099/mic.0.26209-0.

305. Salerno P, Larsson J, Bucca G, Laing E, Smith CP, Flärdh K. 2009. One

of the two genes encoding nucleoid-associated HU proteins in Strepto-

myces coelicolor is developmentally regulated and speciﬁcally involved in

spore maturation. J Bacteriol 191:6489 –6500. http://dx.doi.org/10.1128

/JB.00709-09.

306. Swiercz JP, Nanji T, Gloyd M, Guarne A, Elliot MA. 2013. A novel

nucleoid-associated protein speciﬁc to the actinobacteria. Nucleic Acids

Res 41:4171–4184. http://dx.doi.org/10.1093/nar/gkt095.

307. Yang YH, Song E, Willemse J, Park SH, Kim WS, Kim EJ, Lee BR, Kim

JN, van Wezel GP, Kim BG. 2012. A novel function of Streptomyces

integration host factor (sIHF) in the control of antibiotic production and

sporulation in Streptomyces coelicolor. Antonie Van Leeuwenhoek 101:

479–492. http://dx.doi.org/10.1007/s10482-011-9657-z.

308. Kois A, Swiatek M, Jakimowicz D, Zakrzewska-Czerwinska J. 2009.

SMC protein-dependent chromosome condensation during aerial hy-

phal development in Streptomyces. J Bacteriol 191:310 –319. http://dx.doi

.org/10.1128/JB.00513-08.

309. Facey PD, Hitchings MD, Saavedra-Garcia P, Fernandez-Martinez

L, Dyson PJ, Del Sol R. 2009. Streptomyces coelicolor Dps-like pro-

teins: differential dual roles in response to stress during vegetative

growth and in nucleoid condensation during reproductive cell divi-

sion. Mol Microbiol 73:1186–1202. http://dx.doi.org/10.1111/j.1365

-2958.2009.06848.x.

310. Traag BA, van Wezel GP. 2008. The SsgA-like proteins in actinomyce-

tes: small proteins up to a big task. Antonie Van Leeuwenhoek 94:85–97.

http://dx.doi.org/10.1007/s10482-008-9225-3.

311. Xu Q, Traag BA, Willemse J, McMullan D, Miller MD, Elsliger MA,

Abdubek P, Astakhova T, Axelrod HL, Bakolitsa C, Carlton D, Chen

C, Chiu HJ, Chruszcz M, Clayton T, Das D, Deller MC, Duan L,

Ellrott K, Ernst D, Farr CL, Feuerhelm J, Grant JC, Grzechnik A,

Grzechnik SK, Han GW, Jaroszewski L, Jin KK, Klock HE, Knuth

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 33Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

MW, Kozbial P, Krishna SS, Kumar A, Marciano D, Minor W,

Mommaas AM, Morse AT, Nigoghossian E, Nopakun A, Okach L,

Oommachen S, Paulsen J, Puckett C, Reyes R, Rife CL, Sefcovic N,

Tien HJ, Trame CB, van den Bedem H, Wang S, Weekes D, Hodgson

KO, Wooley J, Deacon AM, Godzik A, Lesley SA, Wilson I, van Wezel

GP. 2009. Structural and functional characterizations of SsgB, a con-

served activator of developmental cell division in morphologically com-

plex actinomycetes. J Biol Chem 284:25268 –25279. http://dx.doi.org/10

.1074/jbc.M109.018564.

312. Kawamoto S, Watanabe H, Hesketh A, Ensign JC, Ochi K. 1997.

Expression analysis of the ssgA gene product, associated with sporulation

and cell division in Streptomyces griseus. Microbiology 143:1077–1086.

http://dx.doi.org/10.1099/00221287-143-4-1077.

313. van Wezel GP, Krabben P, Traag BA, Keijser BJ, Kerste R, Vijgen-

boom E, Heijnen JJ, Kraal B. 2006. Unlocking Streptomyces spp. for use

as sustainable industrial production platforms by morphological engi-

neering. Appl Environ Microbiol 72:5283–5288. http://dx.doi.org/10

.1128/AEM.00808-06.

314. Jiang H, Kendrick KE. 2000. Characterization of ssfR and ssgA, two genes

involved in sporulation of Streptomyces griseus. J Bacteriol 182:5521–

5529. http://dx.doi.org/10.1128/JB.182.19.5521-5529.2000.

315. van Wezel GP, J van der Meulen Kawamoto S, Luiten RG, Koerten

HK, Kraal B. 2000. ssgA is essential for sporulation of Streptomyces

coelicolor A3(2) and affects hyphal development by stimulating septum

formation. J Bacteriol 182:5653–5662. http://dx.doi.org/10.1128/JB.182

.20.5653-5662.2000.

316. Willemse J, Borst JW, de Waal E, Bisseling T, van Wezel GP. 2011.

Positive control of cell division: FtsZ is recruited by SsgB during sporu-

lation of Streptomyces. Genes Dev 25:89–99. http://dx.doi.org/10.1101

/gad.600211.

317. Del Sol R, Mullins JG, Grantcharova N, Flärdh K, Dyson P. 2006.

Inﬂuence of CrgA on assembly of the cell division protein FtsZ during

development of Streptomyces coelicolor. J Bacteriol 188:1540 –1550. http:

//dx.doi.org/10.1128/JB.188.4.1540-1550.2006.

318. Plocinski P, Ziolkiewicz M, Kiran M, Vadrevu SI, Nguyen HB, Hu-

gonnet J, Veckerle C, Arthur M, Dziadek J, Cross TA, Madiraju M,

Rajagopalan M. 2011. Characterization of CrgA, a new partner of the

Mycobacterium tuberculosis peptidoglycan polymerization complexes. J

Bacteriol 193:3246–3256. http://dx.doi.org/10.1128/JB.00188-11.

319. Celler K, Koning RI, Koster AJ, van Wezel GP. 2013. Multidimensional

view of the bacterial cytoskeleton. J Bacteriol 195:1627–1636. http://dx

.doi.org/10.1128/JB.02194-12.

320. Heichlinger A, Ammelburg M, Kleinschnitz EM, Latus A, Maldener I,

Flärdh K, Wohlleben W, Muth G. 2011. The MreB-like protein Mbl of

Streptomyces coelicolor A3(2) depends on MreB for proper localization

and contributes to spore wall synthesis. J Bacteriol 193:1533–1542. http:

//dx.doi.org/10.1128/JB.01100-10.

321. Mazza P, Noens EE, Schirner K, Grantcharova N, Mommaas AM,

Koerten HK, Muth G, Flärdh K, van Wezel GP, Wohlleben W. 2006.

MreB of Streptomyces coelicolor is not essential for vegetative growth but

is required for the integrity of aerial hyphae and spores. Mol Microbiol

60:838–852. http://dx.doi.org/10.1111/j.1365-2958.2006.05134.x.

322. Bagchi S, Tomenius H, Belova LM, Ausmees N. 2008. Intermediate

ﬁlament-like proteins in bacteria and a cytoskeletal function in Strepto-

myces. Mol Microbiol 70:1037–1050. http://dx.doi.org/10.1111/j.1365

-2958.2008.06473.x.

323. Holmes NA, Walshaw J, Leggett RM, Thibessard A, Dalton KA,

Gillespie MD, Hemmings AM, Gust B, Kelemen GH. 2013. Coiled-coil

protein Scy is a key component of a multiprotein assembly controlling

polarized growth in Streptomyces. Proc Natl Acad SciUSA110:E397–

E406. http://dx.doi.org/10.1073/pnas.1210657110.

324. Walshaw J, Gillespie MD, Kelemen GH. 2010. A novel coiled-coil

repeat variant in a class of bacterial cytoskeletal proteins. J Struct Biol

170:202–215. http://dx.doi.org/10.1016/j.jsb.2010.02.008.

325. Flärdh K. 2010. Cell polarity and the control of apical growth in Strep-

tomyces. Curr Opin Microbiol 13:758–765. http://dx.doi.org/10.1016/j

.mib.2010.10.002.

326. Flärdh K. 2003. Essential role of DivIVA in polar growth and morpho-

genesis in Streptomyces coelicolor A3(2). Mol Microbiol 49:1523–1536.

http://dx.doi.org/10.1046/j.1365-2958.2003.03660.x.

327. Ditkowski B, Holmes N, Rydzak J, Donczew M, Bezulska M, Ginda K,

Kedzierski P, Zakrzewska-Czerwinska J, Kelemen GH, Jakimowicz D.

2013. Dynamic interplay of ParA with the polarity protein, Scy, coordi-

nates the growth with chromosome segregation in Streptomyces coeli-

color. Open Biol 3:130006. http://dx.doi.org/10.1098/rsob.130006.

328. Baltz RH. 2005. Antibiotic discovery from actinomycetes: will a renais-

sance follow the decline and fall? SIM News 55:186–196.

329. Xu H, Chater KF, Deng Z, Tao M. 2008. A cellulose synthase-like

protein involved in hyphal tip growth and morphological differentiation

in Streptomyces. J Bacteriol 190:4971– 4978. http://dx.doi.org/10.1128/JB

.01849-07.

330. Noens EE, Mersinias V, Willemse J, Traag BA, Laing E, Chater KF,

Smith CP, Koerten HK, van Wezel GP. 2007. Loss of the controlled

localization of growth stage-speciﬁc cell-wall synthesis pleiotropically

affects developmental gene expression in an ssgA mutant of Streptomyces

coelicolor. Mol Microbiol 64:1244–1259. http://dx.doi.org/10.1111/j

.1365-2958.2007.05732.x.

331. Bennett JW. 1998. Mycotechnology: the role of fungi in biotechnology.

J Biotechnol 66:101–107. http://dx.doi.org/10.1016/S0168-1656(98)001

33-3.

332. Hopwood DA, Chater KF, Bibb MJ. 1995. Genetics of antibiotic pro-

duction in Streptomyces coelicolor A3(2), a model streptomycete. Bio-

technology 28:65–102.

333. Ilicˆ S, Konstantinovicˆ S, Todorovicˆ Z, Lazicˆ M, Veljkovicˆ V, JokovicˆN,

RadovanovicˆB.2007. Characterization and antimicrobial activity of the

bioactive metabolites in streptomycete isolates. Mikrobiologiia 76:480–

487. (In Russian.)

334. Rudd BA, Hopwood DA. 1979. Genetics of actinorhodin biosynthesis by

Streptomyces coelicolor A3(2). J Gen Microbiol 114:35–43. http://dx.doi

.org/10.1099/00221287-114-1-35.

335. Feitelson JS, Malpartida F, Hopwood DA. 1985. Genetic and biochem-

ical characterization of the red gene cluster of Streptomyces coelicolor

A3(2). J Gen Microbiol 131:2431–2441.

336. Hopwood DA, Wright HM. 1983. CDA is a new chromosomally-

determined antibiotic from Streptomyces coelicolor A3(2). J Gen Micro-

biol 129:3575–3579.

337. Wright LF, Hopwood DA. 1976. Identiﬁcation of the antibiotic deter-

mined by the SCP1 plasmid of Streptomyces coelicolor A3(2). J Gen Mi-

crobiol 95:96–106. http://dx.doi.org/10.1099/00221287-95-1-96.

338. Challis GL, Hopwood DA. 2003. Synergy and contingency as driving

forces for the evolution of multiple secondary metabolite production by

Streptomyces species. Proc Natl Acad Sci U S A 100(Suppl 2):S14555–

S14561. http://dx.doi.org/10.1073/pnas.1934677100.

339. Pawlik K, Kotowska M, Chater KF, Kuczek K, Takano E. 2007. A

cryptic type I polyketide synthase (cpk) gene cluster in Streptomyces coe-

licolor A3(2). Arch Microbiol 187:87–99. http://dx.doi.org/10.1007

/s00203-006-0176-7.

340. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T,

Sakaki Y, Hattori M, Omura S. 2003. Complete genome sequence and

comparative analysis of the industrial microorganism Streptomyces aver-

mitilis. Nat Biotechnol 21:526–531. http://dx.doi.org/10.1038/nbt820.

341. Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, Ikeda H,

Yamashita A, Hattori M, Horinouchi S. 2008. Genome sequence of

the streptomycin-producing microorganism Streptomyces griseus IFO

13350. J Bacteriol 190:4050–4060. http://dx.doi.org/10.1128/JB

.00204-08.

342. Oliynyk M, Samborskyy M, Lester JB, Mironenko T, Scott N, Dickens

S, Haydock SF, Leadlay PF. 2007. Complete genome sequence of the

erythromycin-producing bacterium Saccharopolyspora erythraea

NRRL23338. Nat Biotechnol 25:447–453. http://dx.doi.org/10.1038

/nbt1297.

343. Udwary DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W,

Jensen PR, Moore BS. 2007. Genome sequencing reveals complex sec-

ondary metabolome in the marine actinomycete Salinispora tropica. Proc

Natl Acad SciUSA104:10376–10381. http://dx.doi.org/10.1073/pnas

.0700962104.

344. Gross H. 2009. Genomic mining: a concept for the discovery of new

bioactive natural products. Curr Opin Drug Discov Dev 12:207–219.

345. Medema MH, Breitling R, Bovenberg R, Takano E. 2011. Exploiting

plug-and-play synthetic biology for drug discovery and production in

microorganisms. Nat Rev Microbiol 9:131–137. http://dx.doi.org/10

.1038/nrmicro2478.

346. Nett M, Ikeda H, Moore BS. 2009. Genomic basis for natural product

biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1362–1384.

http://dx.doi.org/10.1039/b817069j.

347. Zerikly M, Challis GL. 2009. Strategies for the discovery of new natural

Barka et al.

34 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

products by genome mining. Chembiochem 10:625–633. http://dx.doi

.org/10.1002/cbic.200800389.

348. Baltz RH. 2008. Renaissance in antibacterial discovery from actinomy-

cetes. Curr Opin Pharmacol 8:557–563. http://dx.doi.org/10.1016/j.coph

.2008.04.008.

349. Ochi K, Tanaka Y, Tojo S. 2014. Activating the expression of bacterial

cryptic genes by rpoB mutations in RNA polymerase or by rare earth

elements. J Ind Microbiol Biotechnol 41:403–414. http://dx.doi.org/10

.1007/s10295-013-1349-4.

350. Rutledge PJ, Challis GL. 2015. Discovery of microbial natural products

by activation of silent biosynthetic gene clusters. Nat Rev Microbiol 13:

509–523. http://dx.doi.org/10.1038/nrmicro3496.

351. Yoon V, Nodwell JR. 2014. Activating secondary metabolism with stress

and chemicals. J Ind Microbiol Biotechnol 41:415– 424. http://dx.doi.org

/10.1007/s10295-013-1387-y.

352. Zhu H, Sandiford SK, van Wezel GP. 2014. Triggers and cues that

activate antibiotic production by actinomycetes. J Ind Microbiol Bio-

technol 41:371–386. http://dx.doi.org/10.1007/s10295-013-1309-z.

353. Colson S, Stephan J, Hertrich T, Saito A, van Wezel GP, Titgemeyer

F, Rigali S. 2007. Conserved cis-acting elements upstream of genes com-

posing the chitinolytic system of streptomycetes are DasR-responsive

elements. J Mol Microbiol Biotechnol 12:60–66. http://dx.doi.org/10

.1159/000096460.

354. Delic I, Robbins P, Westpheling J. 1992. Direct repeat sequences are

implicated in the regulation of two Streptomyces chitinase promoters that

are subject to carbon catabolite control. Proc Natl Acad SciUSA89:

1885–1889. http://dx.doi.org/10.1073/pnas.89.5.1885.

355. Saito A, Fujii T, Miyashita K. 2003. Distribution and evolution of

chitinase genes in Streptomyces species: involvement of gene-duplication

and domain-deletion. Antonie Van Leeuwenhoek 84:7–15. http://dx.doi

.org/10.1023/A:1024463113606.

356. Nothaft H, Rigali S, Boomsma B, Swiatek M, McDowall KJ, van Wezel

GP, Titgemeyer F. 2010. The permease gene nagE2 is the key to N-

acetylglucosamine sensing and utilization in Streptomyces coelicolor and

is subject to multi-level control. Mol Microbiol 75:1133–1144. http://dx

.doi.org/10.1111/j.1365-2958.2009.07020.x.

357. Postma PW, Lengeler JW, Jacobson GR. 1993. Phosphoenolpyruvate:

carbohydrate phosphotransferase systems of bacteria. Microbiol Rev 57:

543–594.

358. Titgemeyer F, Walkenhorst J, Reizer J, Stuiver MH, Cui X, Saier MH,

Jr. 1995. Identiﬁcation and characterization of phosphoenolpyruvate:

fructose phosphotransferase systems in three Streptomyces species. Mi-

crobiology 141:51–58. http://dx.doi.org/10.1099/00221287-141-1-51.

359. Saito A, Shinya T, Miyamoto K, Yokoyama T, Kaku H, Minami E,

Shibuya N, Tsujibo H, Nagata Y, Ando A, Fujii T, Miyashita K. 2007.

The dasABC gene cluster, adjacent to dasR, encodes a novel ABC trans-

porter for the uptake of N,N=-diacetylchitobiose in Streptomyces coeli-

color A3(2). Appl Environ Microbiol 73:3000 –3008. http://dx.doi.org/10

.1128/AEM.02612-06.

360. Swiatek MA, Tenconi E, Rigali S, van Wezel GP. 2012. Functional

analysis of the N-acetylglucosamine metabolic genes of Streptomyces coe-

licolor and role in control of development and antibiotic production. J

Bacteriol 194:1136–1144. http://dx.doi.org/10.1128/JB.06370-11.

361. Nazari B, Kobayashi M, Saito A, Hassaninasab A, Miyashita K, Fujii T.

2013. Chitin-induced gene expression in secondary metabolic pathways

of Streptomyces coelicolor A3(2) grown in soil. Appl Environ Microbiol

79:707–713. http://dx.doi.org/10.1128/AEM.02217-12.

362. Craig M, Lambert S, Jourdan S, Tenconi E, Colson S, Maciejewska M,

Ongena M, Martin JF, van Wezel G, Rigali S. 2012. Unsuspected

control of siderophore production by N-acetylglucosamine in strepto-

mycetes. Environ Microbiol Rep 4:512–521. http://dx.doi.org/10.1111/j

.1758-2229.2012.00354.x.

363. S

´wia˛ tek-Połatyn´ ska MA, Bucca G, Laing E, Gubbens J, Titgemeyer F,

Smith CP, Rigali S, van Wezel GP. 2015. Genome-wide analysis of in

vivo binding of the master regulator DasR in Streptomyces coelicolor iden-

tiﬁes novel non-canonical targets. PLoS One 10:e0122479. http://dx.doi

.org/10.1371/journal.pone.0122479.

364. Gomez-Escribano JP, Song L, Fox DJ, Yeo V, Bibb MJ, Challis GL.

2012. Structure and biosynthesis of the unusual polyketide alkaloid coe-

limycin P1, a metabolic product of the cpk gene cluster of Streptomyces

coelicolor M145. Chem Sci 3:2716–2720. http://dx.doi.org/10.1039

/c2sc20410j.

365. Abrudan MI, Smakman F, Grimbergen AJ, Westhoff S, Miller EL, van

Wezel GP, Rozen DE. 2015. Socially mediated induction and suppres-

sion of antibiosis during bacterial coexistence. Proc Natl Acad SciUSA

112:11054–11059. http://dx.doi.org/10.1073/pnas.1504076112.

366. Davies J, Spiegelman GB, Yim G. 2006. The world of subinhibitory

antibiotic concentrations. Curr Opin Microbiol 9:445– 453. http://dx.doi

.org/10.1016/j.mib.2006.08.006.

367. Linares JF, Gustafsson I, Baquero F, Martinez JL. 2006. Antibiotics as

intermicrobial signaling agents instead of weapons. Proc Natl Acad Sci

USA103:19484–19489. http://dx.doi.org/10.1073/pnas.0608949103.

368. Romero D, Traxler MF, Lopez D, Kolter R. 2011. Antibiotics as

signal molecules. Chem Rev 111:5492–5505. http://dx.doi.org/10

.1021/cr2000509.

369. Hoffman LR, D’Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller

SI. 2005. Aminoglycoside antibiotics induce bacterial bioﬁlm formation.

Nature 436:1171–1175. http://dx.doi.org/10.1038/nature03912.

370. Stevens DL, Ma Y, Salmi DB, McIndoo E, Wallace RJ, Bryant AE.

2007. Impact of antibiotics on expression of virulence-associated exo-

toxin genes in methicillin-sensitive and methicillin-resistant Staphylo-

coccus aureus. J Infect Dis 195:202–211. http://dx.doi.org/10.1086

/510396.

371. Fajardo A, Martinez JL. 2008. Antibiotics as signals that trigger speciﬁc

bacterial responses. Curr Opin Microbiol 11:161–167. http://dx.doi.org

/10.1016/j.mib.2008.02.006.

372. Angell S, Bench BJ, Williams H, Watanabe CM. 2006. Pyocyanin

isolated from a marine microbial population: synergistic production be-

tween two distinct bacterial species and mode of action. Chem Biol 13:

1349–1359. http://dx.doi.org/10.1016/j.chembiol.2006.10.012.

373. Konig CC, Scherlach K, Schroeckh V, Horn F, Nietzsche S, Brakhage

AA, Hertweck C. 2013. Bacterium induces cryptic meroterpenoid path-

way in the pathogenic fungus Aspergillus fumigatus. Chembiochem 14:

938–942. http://dx.doi.org/10.1002/cbic.201300070.

374. Oh DC, Kauffman CA, Jensen PR, Fenical W. 2007. Induced produc-

tion of emericellamides A and B from the marine-derived fungus Emeri-

cella sp. in competing co-culture. J Nat Prod 70:515–520. http://dx.doi

.org/10.1021/np060381f.

375. Schroeckh V, Scherlach K, Nutzmann HW, Shelest E, Schmidt-Heck

W, Schuemann J, Martin K, Hertweck C, Brakhage AA. 2009. Intimate

bacterial-fungal interaction triggers biosynthesis of archetypal

polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A 106:14558–

14563. http://dx.doi.org/10.1073/pnas.0901870106.

376. Wu C, Zacchetti B, Ram AF, van Wezel GP, Claessen D, Hae Choi Y.

2015. Expanding the chemical space for natural products by Aspergillus-

Streptomyces co-cultivation and biotransformation. Sci Rep 5:10868.

http://dx.doi.org/10.1038/srep10868.

377. Haseltine WA, Block R. 1973. Synthesis of guanosine tetra- and pent-

aphosphate requires the presence of a codon-speciﬁc, uncharged transfer

ribonucleic acid in the acceptor site of ribosomes. Proc Natl Acad Sci

USA70:1564–1568. http://dx.doi.org/10.1073/pnas.70.5.1564.

378. Potrykus K, Cashel M. 2008. (p) ppGpp: still magical? Annu Rev Mi-

crobiol 62:35–51. http://dx.doi.org/10.1146/annurev.micro.62.081307

.162903.

379. Ochi K. 1990. A relaxed (rel) mutant of Streptomyces coelicolor A3(2)

with a missing ribosomal protein lacks the ability to accumulate ppGpp,

A-factor and prodigiosin. J Gen Microbiol 136:2405–2412. http://dx.doi

.org/10.1099/00221287-136-12-2405.

380. Chakraburtty R, Bibb M. 1997. The ppGpp synthetase gene (relA)of

Streptomyces coelicolor A3(2) plays a conditional role in antibiotic pro-

duction and morphological differentiation. J Bacteriol 179:5854–5861.

381. Hesketh A, Chen WJ, Ryding J, Chang S, Bibb M. 2007. The global role

of ppGpp synthesis in morphological differentiation and antibiotic pro-

duction in Streptomyces coelicolor A3(2). Genome Biol 8:R161. http://dx

.doi.org/10.1186/gb-2007-8-8-r161.

382. Battesti A, Bouveret E. 2006. Acyl carrier protein/SpoT interaction, the

switch linking SpoT-dependent stress response to fatty acid metabolism.

Mol Microbiol 62:1048–1063. http://dx.doi.org/10.1111/j.1365-2958

.2006.05442.x.

383. Martin SM, Bushell ME. 1996. Effect of hyphal micromorphology on

bioreactor performance of antibiotic-producing Saccharopolyspora

erythraea cultures. Microbiology 142:1783–1788. http://dx.doi.org/10

.1099/13500872-142-7-1783.

384. Yin P, Wang YH, Zhang SL, Chu J, Zhuang YP, Wang ML, Zhou J.

2008. Isolation of soluble proteins from an industrial strain Streptomyces

avermitilis in complex culture medium for two-dimensional gel electro-

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 35Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

phoresis. J Microbiol Methods 73:105–110. http://dx.doi.org/10.1016/j

.mimet.2008.02.012.

385. Bewick MW, Williams ST, Veltkamp C. 1976. Growth and ultrastruc-

ture of Streptomyces venezuelae during chloramphenicol production. Mi-

crobios 16:191–199.

386. Glazebrook MA, Doull JL, Stuttard C, Vining LC. 1990. Sporulation of

Streptomyces venezuelae in submerged cultures. J Gen Microbiol 136:

581–588. http://dx.doi.org/10.1099/00221287-136-3-581.

387. van Dissel D, Claessen D, Roth M, van Wezel GP. 2015. A novel locus

for mycelial aggregation forms a gateway to improved Streptomyces cell

factories. Microb Cell Fact 14:44. http://dx.doi.org/10.1186/s12934-015

-0224-6.

388. Roth M, Noack D, Geuther R. 1985. Maintenance of the recombinant

plasmid pIJ2 in chemostat cultures of Streptomyces lividans 66 (pIJ2). J Basic

Microbiol 25:265–271. http://dx.doi.org/10.1002/jobm.3620250407.

389. Liu G, Xing M, Han Q. 2005. A population-based morphologically

structured model for hyphal growth and product formation in strepto-

mycin fermentation. World J Microbiol Biotechnol 21:1329 –1338. http:

//dx.doi.org/10.1007/s11274-005-3648-z.

390. Meyerhoff J, Tiller V, Bellgardt KH. 1995. Two mathematical models

for the development of a single microbial pellet. Bioprocess Eng 12:305–

313. http://dx.doi.org/10.1007/BF00369507.

391. Tough AJ, Prosser JI. 1996. Experimental veriﬁcation of a mathematical

model for pelleted growth of Streptomyces coelicolor A3(2) in submerged

batch culture. Microbiology 142:639 –648. http://dx.doi.org/10.1099

/13500872-142-3-639.

392. Celler K, Picioreanu C, van Loosdrecht MC, van Wezel GP. 2012.

Structured morphological modeling as a framework for rational strain

design of Streptomyces species. Antonie Van Leeuwenhoek 102:409–423.

http://dx.doi.org/10.1007/s10482-012-9760-9.

393. Nieminen L, Webb S, Smith MC, Hoskisson PA. 2013. A ﬂexible

mathematical model platform for studying branching networks: experi-

mentally validated using the model actinomycete, Streptomyces coelicolor.

PLoS One 8:e54316. http://dx.doi.org/10.1371/journal.pone.0054316.

394. Willemse J, Ruban-Osmialowska B, Widdick D, Celler K, Hutchings

MI, van Wezel GP, Palmer T. 2012. Dynamic localization of Tat protein

transport machinery components in Streptomyces coelicolor. J Bacteriol

194:6272–6281. http://dx.doi.org/10.1128/JB.01425-12.

395. Liu G, Chater KF, Chandra G, Niu G, Tan H. 2013. Molecular regu-

lation of antibiotic biosynthesis in streptomyces. Microbiol Mol Biol Rev

77:112–143. http://dx.doi.org/10.1128/MMBR.00054-12.

396. Olmos E, Mehmood N, Haj Husein L, Goergen JL, Fick M, Delaunay

S. 2013. Effects of bioreactor hydrodynamics on the physiology of Strep-

tomyces. Bioproc Biosyst Eng 36:259–272. http://dx.doi.org/10.1007

/s00449-012-0794-1.

397. Petkovic H, Cullum J, Hranueli D, Hunter IS, Peric-Concha N, Pigac

J, Thamchaipenet A, Vujaklija D, Long PF. 2006. Genetics of Strepto-

myces rimosus, the oxytetracycline producer. Microbiol Mol Biol Rev

70:704–728. http://dx.doi.org/10.1128/MMBR.00004-06.

398. Vanek Z, Janecek J. 1997. The physiology and biosynthesis of secondary

metabolites. Acta Biol Hung 48:339–358.

399. Wietzorrek A, Bibb M. 1997. A novel family of proteins that regulates

antibiotic production in streptomycetes appears to contain an OmpR-

like DNA-binding fold. Mol Microbiol 25:1181–1184. http://dx.doi.org

/10.1046/j.1365-2958.1997.5421903.x.

400. Gramajo HC, Takano E, Bibb MJ. 1993. Stationary-phase production of

the antibiotic actinorhodin in Streptomyces coelicolor A3(2) is transcrip-

tionally regulated. Mol Microbiol 7:837–845. http://dx.doi.org/10.1111

/j.1365-2958.1993.tb01174.x.

401. Takano E, Gramajo HC, Strauch E, Andres N, White J, Bibb MJ. 1992.

Transcriptional regulation of the redD transcriptional activator gene ac-

counts for growth-phase-dependent production of the antibiotic unde-

cylprodigiosin in Streptomyces coelicolor A3(2). Mol Microbiol 6:2797–

2804. http://dx.doi.org/10.1111/j.1365-2958.1992.tb01459.x.

402. Tomono A, Tsai Y, Yamazaki H, Ohnishi Y, Horinouchi S. 2005.

Transcriptional control by A-factor of strR, the pathway-speciﬁc tran-

scriptional activator for streptomycin biosynthesis in Streptomyces gri-

seus. J Bacteriol 187:5595–5604. http://dx.doi.org/10.1128/JB.187.16

.5595-5604.2005.

403. Claesen J, Bibb M. 2010. Genome mining and genetic analysis of cype-

mycin biosynthesis reveal an unusual class of posttranslationally modi-

ﬁed peptides. Proc Natl Acad SciUSA107:16297–16302. http://dx.doi

.org/10.1073/pnas.1008608107.

404. Flinspach K, Westrich L, Kaysser L, Siebenberg S, Gomez-Escribano

JP, Bibb M, Gust B, Heide L. 2010. Heterologous expression of the

biosynthetic gene clusters of coumermycin A(1), clorobiocin and ca-

prazamycins in genetically modiﬁed Streptomyces coelicolor strains.

Biopolymers 93:823–832. http://dx.doi.org/10.1002/bip.21493.

405. Gverzdys TA. 2011. The development of protocols to engineer and

screen Streptomyces in high throughput to test for the activation of cryp-

tic clusters by the heterologous expression of pleiotropic regulators. M.S.

dissertation. McMaster University, Hamilton, Ontario, Canada.

406. Komatsu M, Komatsu K, Koiwai H, Yamada Y, Kozone I, Izumikawa

M, Hashimoto J, Takagi M, Omura S, Shin-ya K, Cane DE, Ikeda H.

2013. Engineered Streptomyces avermitilis host for heterologous expres-

sion of biosynthetic gene cluster for secondary metabolites. ACS Synth

Biol 2:384–396. http://dx.doi.org/10.1021/sb3001003.

407. Komatsu M, Uchiyama T, Omura S, Cane DE, Ikeda H. 2010. Ge-

nome-minimized Streptomyces host for the heterologous expression of

secondary metabolism. Proc Natl Acad SciUSA107:2646 –2651. http:

//dx.doi.org/10.1073/pnas.0914833107.

408. Medema MH, Breitling R, Takano E. 2011. Synthetic biology in Strep-

tomyces bacteria. Methods Enzymol 497:485–502. http://dx.doi.org/10

.1016/B978-0-12-385075-1.00021-4.

409. Waksman SA, Woodruff HB. 1940. Bacteriostatic and bactericidal sub-

stances produced by a soil actinomyces. Proc Soc Exp Biol Med 45:609.

http://dx.doi.org/10.3181/00379727-45-11768.

410. Waksman SA, Woodruff HB. 1942. Selective antibiotic action of various

substances of microbial origin. J Bacteriol 44:373–384.

411. Schatz A, Waksman SA. 1944. Effect of streptomycin and other antibi-

otic substances upon Mycobacterium tuberculosis and related organisms.

Proc Soc Exp Biol Med 57:244 –248. http://dx.doi.org/10.3181/00379727

-57-14769.

412. Baltz RH. 2007. Antimicrobials from actinomycetes: back to the future.

Microbe 2:125–131.

413. Busscher GF, Rutjes FP, van Delft FL. 2005. 2-Deoxystreptamine:

central scaffold of aminoglycoside antibiotics. Chem Rev 105:775–791.

http://dx.doi.org/10.1021/cr0404085.

414. Park SR, Park JW, Ban YH, Sohng JK, Yoon YJ. 2013. 2-Deoxys-

treptamine-containing aminoglycoside antibiotics: recent advances in

the characterization and manipulation of their biosynthetic pathways.

Nat Prod Rep 30:11–20. http://dx.doi.org/10.1039/C2NP20092A.

415. Vakulenko SB, Mobashery S. 2003. Versatility of aminoglycosides and

prospects for their future. Clin Microbiol Rev 16:430 –450. http://dx.doi

.org/10.1128/CMR.16.3.430-450.2003.

416. Kharel MK, Pahari P, Shepherd MD, Tibrewal N, Nybo SE, Shaaban

KA, Rohr J. 2012. Angucyclines: biosynthesis, mode-of-action, new nat-

ural products, and synthesis. Nat Prod Rep 29:264–325. http://dx.doi

.org/10.1039/C1NP00068C.

417. Kang Q, Shen Y, Bai L. 2012. Biosynthesis of 3,5-AHBA-derived natu-

ral products. Nat Prod Rep 29:243–263. http://dx.doi.org/10.1039/C2NP00

019A.

418. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. 2004. Anthra-

cyclines: molecular advances and pharmacologic developments in anti-

tumor activity and cardiotoxicity. Pharmacol Rev 56:185–229. http://dx

.doi.org/10.1124/pr.56.2.6.

419. Nitiss JL. 2009. Targeting DNA topoisomerase II in cancer chemother-

apy. Nat Rev Cancer 9:338–350. http://dx.doi.org/10.1038/nrc2607.

420. Liras P. 1999. Biosynthesis and molecular genetics of cephamycins.

Cephamycins produced by actinomycetes. Antonie Van Leeuwenhoek

75:109–124.

421. Jensen SE, Paradkar AS. 1999. Biosynthesis and molecular genetics of

clavulanic acid. Antonie Van Leeuwenhoek 75:125–133. http://dx.doi

.org/10.1023/A:1001755724055.

422. Saudagar PS, Survase SA, Singhal RS. 2008. Clavulanic acid: a review.

Biotechnol Adv 26:335–351. http://dx.doi.org/10.1016/j.biotechadv

.2008.03.002.

423. Vining LC, Stuttard C. 1994. Chloramphenicol, genetics and biochem-

istry of antibiotic production. Butterworth-Heinemann, Boston, MA.

424. Kominek L. 1975. Cycloheximide production by Streptomyces griseus:

control mechanisms of cycloheximide biosynthesis. Antimicrob Agents

Chem 7:856–860. http://dx.doi.org/10.1128/AAC.7.6.856.

425. Butler MS, Hansford KA, Blaskovich MA, Halai R, Cooper MA. 2014.

Glycopeptide antibiotics: back to the future. J Antibiot 67:631– 644. http:

//dx.doi.org/10.1038/ja.2014.111.

426. Van Bambeke F. 2006. Glycopeptides and glycodepsipeptides in clin-

Barka et al.

36 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

ical development: a comparative review of their antibacterial spec-

trum, pharmacokinetics and clinical efﬁcacy. Curr Opin Investig

Drugs 7:740–749.

427. Baltz RH. 2010. Genomics and the ancient origins of the daptomycin

biosynthetic gene cluster. J Antibiot 63:506–511. http://dx.doi.org/10

.1038/ja.2010.82.

428. Gaynor M, Mankin AS. 2003. Macrolide antibiotics: binding site, mech-

anism of action, resistance. Curr Top Med Chem 3:949–961. http://dx

.doi.org/10.2174/1568026033452159.

429. Poehlsgaard J, Douthwaite S. 2003. Macrolide antibiotic interaction

and resistance on the bacterial ribosome. Curr Opin Investig Drugs

4:140–148.

430. Mulinos MG. 1955. Cycloserine: an antibiotic paradox. Antibiot Annu

3:131–135.

431. Johnston NJ, Mukhtar TA, Wright GD. 2002. Streptogramin antibiot-

ics: mode of action and resistance. Curr Drug Targets 3:335–344. http:

//dx.doi.org/10.2174/1389450023347678.

432. Okami Y, Hotta K. 1988. Search and discovery of new antibiotics, p

33–67. In Goodfellow M, Williams ST, Mordarski M (ed), Actinomyce-

tes in biotechnology. Academic Press, San Diego, CA.

433. Behal V. 2000. Bioactive products from Streptomyces. Adv Appl Micro-

biol 47:113–157. http://dx.doi.org/10.1016/S0065-2164(00)47003-6.

434. Jizba J, Sedmera P, Zima J, Beran M, Blumauerová M, Kandybin N,

Samoukina G. 1991. Macrotetrolide antibiotics produced by Streptomy-

ces globisporus. Folia Microbiol (Praha) 36:437– 443. http://dx.doi.org/10

.1007/BF02884062.

435. Oishi H, Sugawa T, Okutomi T, Suzuki K, Hayashi T. 1970. Insecti-

cidal activity of macrotetrolide antibiotics. J Antibiot 23:105–106. http:

//dx.doi.org/10.7164/antibiotics.23.105.

436. Sagawa T, Hirano S, Takahashi H, Tanaka N, Oishi H. 1972. Tetran-

actin, a new miticidal antibiotic. 3. Miticidal and other biological prop-

erties. J Econ Entomol 65:372–375.

437. Sakamoto K, Asano T, Mizuochi K, Sasaki K, Hasegawa K. 1978.

Makrotetrolid-Antibiotikum zur Bekämpfung der Geﬂügelkokzidiose.

Chem Abstr 89:152 732r. German patent DE 28 02 455 C2.

438. Nippon Kayaku Co Ltd, Chugai Pharm Co Ltd. 1981. Polynactins as

anthelmintics. Chem Abstr 95:108 866n. Japan patent Kokai Tokkyo

Koho 8157.714.

439. Shichi H, Tanouchi Y, Kamada Y. June 1989. Immunosuppressive

agent. Chem Abstr 112:91 787g. US patent 4,843,092.

440. Ando K, Oishi H, Hirano S, Okutomi T, Suzuki K. 1971. Tetranactin,

a new miticidal antibiotic. I. Isolation, characterization and properties of

tetranactin. J Antibiot 24:347–352.

441. Ando K, Murakami Y, Nawata Y. 1971. Tetranactin, a new miticidal

antibiotic. II. Structure of tetranactin. J Antibiot 24:418–422.

442. Misato T. 1982. Present status and future prospects of agricultural anti-

biotics. J Pestic Sci 7:301–305. http://dx.doi.org/10.1584/jpestics.7.301.

443. Omura S, Crump A. 2014. Ivermectin: panacea for resource-poor com-

munities? Trends Parasitol 30:445–455. http://dx.doi.org/10.1016/j.pt

.2014.07.005.

444. Harada S, Kishi T. 1978. Isolation and characterization of mildiomycin,

a new nucleoside antibiotic. J Antibiot 31:519–524. http://dx.doi.org/10

.7164/antibiotics.31.519.

445. Feduchi E, Cosin M, Carrasco L. 1985. Mildiomycin: a nucleoside

antibiotic that inhibits protein synthesis. J Antibiot 38:415–419. http:

//dx.doi.org/10.7164/antibiotics.38.415.

446. Dharmaraj S. 2010. Marine Streptomyces as a novel source of bioactive

substances. World J Microbiol Biotechnol 26:2123–2139. http://dx.doi

.org/10.1007/s11274-010-0415-6.

447. Arora SK. 1985. Molecular structure of heliomycin, an inhibitor of RNA

synthesis. J Antibiot 38:113–115. http://dx.doi.org/10.7164/antibiotics

.38.113.

448. Barac T, Taghavi S, Borremans B, Provoost A, Oeyen L, Colpaert JV,

Vangronsveld J, van der Lelie D. 2004. Engineered endophytic bacteria

improve phytoremediation of water-soluble, volatile, organic pollutants.

Nat Biotechnol 22:583–588. http://dx.doi.org/10.1038/nbt960.

449. Wu MC, Law B, Wilkinson B, Mickleﬁeld J. 2012. Bioengineering

natural product biosynthetic pathways for therapeutic applications. Curr

Opin Biotechnol 23:931–940. http://dx.doi.org/10.1016/j.copbio.2012

.03.008.

450. Watve MG, Tickoo R, Jog MM, Bhole BD. 2001. How many antibiotics

are produced by the genus? Arch Microbiol 176:386–390. http://dx.doi

.org/10.1007/s002030100345.

451. Baltz RH. 2006. Marcel Faber Roundtable: is our antibiotic pipeline

unproductive because of starvation, constipation or lack of inspiration? J

Ind Microbiol Biotechnol 33:507–513. http://dx.doi.org/10.1007/s10295

-005-0077-9.

452. Umezawa H, Okami Y, Hashimoto T, Suhara Y, Hamada M, Takeuchi

T. 1965. A new antibiotic, kasugsmycin. J Antibiot 18:101–103.

453. Isono K, Nagatsu J, Kawashima Y, Suzuki S. 1965. Studies on polyox-

ins, antifungal antibiotics. Part I. Isolation and characterization of

polyoxins A and B. Agric Biol Chem (Tokyo) 29:848–854. http://dx.doi

.org/10.1080/00021369.1965.10858475.

454. Endo A, Misato T. 1969. Polyoxin D, a competitive inhibitor of UDP-

N-acetylglucosamine: chitin N-acetylglucosaminyltransferase in Neuro-

spora crassa. Biochem Biophys Res Commun 37:718–722. http://dx.doi

.org/10.1016/0006-291X(69)90870-5.

455. British Crop Protection Council. 1994. The pesticide manual, 10th ed.

British Crop Protection Council, Alton, United Kingdom.

456. Kameda Y. 1987. Validoxylamines as trehalase inhibitors. J Antibiot

40:563–565. http://dx.doi.org/10.7164/antibiotics.40.563.

457. Elbein AD, Pan YT, Pastuszak I, Carroll D. 2003. New insights on

trehalose: a multifunctional molecule. Glycobiology 13:17R–27R. http:

//dx.doi.org/10.1093/glycob/cwg047.

458. Moran NA. 2006. Symbiosis. Curr Biol 16:R866 –R871. http://dx.doi.org

/10.1016/j.cub.2006.09.019.

459. Seipke RF, Barke J, Ruiz-Gonzalez MX, Orivel J, Yu DW, Hutchings

MI. 2012. Fungus-growing Allomerus ants are associated with antibiotic-

producing actinobacteria. Antonie Van Leeuwenhoek 101:443–447.

http://dx.doi.org/10.1007/s10482-011-9621-y.

460. Seipke RF, Kaltenpoth M, Hutchings MI. 2012. Streptomyces as symbi-

onts: an emerging and widespread theme? FEMS Microbiol Rev 36:862–

876. http://dx.doi.org/10.1111/j.1574-6976.2011.00313.x.

461. Leung TLF, Poulin R. 2008. Parasitism, commensalism, and mutualism:

exploring the many shades of symbioses. Life Environ 58:107–115.

462. Brauman A, Dore J, Eggleton P, Bignell D, Breznak JA, Kane MD.

2001. Molecular phylogenetic proﬁling of prokaryotic communities in

guts of termites with different feeding habits. FEMS Microbiol Ecol 35:

27–36. http://dx.doi.org/10.1111/j.1574-6941.2001.tb00785.x.

463. Breznak JA. 1982. Intestinal microbiota of termites and other xylopha-

gous insects. Annu Rev Microbiol 36:323–343. http://dx.doi.org/10.1146

/annurev.mi.36.100182.001543.

464. Hongoh Y. 2011. Toward the functional analysis of uncultivable, sym-

biotic microorganisms in the termite gut. Cell Mol Life Sci 68:1311–1325.

http://dx.doi.org/10.1007/s00018-011-0648-z.

465. Dejean A, Solano PJ, Ayroles J, Corbara B, Orivel J. 2005. Insect

behaviour: arboreal ants build traps to capture prey. Nature 434:973.

http://dx.doi.org/10.1038/434973a.

466. Schultz TR, Brady SG. 2008. Major evolutionary transitions in ant

agriculture. Proc Natl Acad SciUSA105:5435–5440. http://dx.doi.org

/10.1073/pnas.0711024105.

467. Currie CR, Bot Anm, Boomsma JJ. 2003. Experimental evidence of a

tripartite mutualism: bacteria protect ant fungal gardens from special-

ized parasites. Oikos 101:91–102. http://dx.doi.org/10.1034/j.1600-0706

.2003.12036.x.

468. Currie CR, Mueller UG, Malloch D. 1999. The agricultural pathology of

ant fungus gardens. Proc Natl Acad SciUSA96:7998–8002. http://dx

.doi.org/10.1073/pnas.96.14.7998.

469. Currie CR, Wong B, Stuart AE, Schultz TR, Rehner SA, Mueller UG,

Sung GH, Spatafora JW, Straus NA. 2003. Ancient tripartite coevolu-

tion in the attine ant-microbe symbiosis. Science 299:386 –388. http://dx

.doi.org/10.1126/science.1078155.

470. Oh DC, Poulsen M, Currie CR, Clardy J. 2009. Dentigerumycin: a

bacterial mediator of an ant-fungus symbiosis. Nat Chem Biol 5:391–

393. http://dx.doi.org/10.1038/nchembio.159.

471. Currie CR. 2001. Prevalence and impact of a virulent parasite on a

tripartite mutualism. Oecologia 128:99–106. http://dx.doi.org/10.1007

/s004420100630.

472. Barke J, Seipkel RF, Gruschow S, Heavens D, Drou N, Bibb MJ, Goss

RJ, Yu DW, Hutchings MI. 2010. A mixed community of actinomycetes

produce multiple antibiotics for the fungus farming ant Acromyrmex

octospinosus. BMC Biol 8:109. http://dx.doi.org/10.1186/1741-7007-8

-109.

473. Mueller UG, Dash D, Rabeling C, Rodrigues A. 2008. Coevolution

between attine ants and actinomycete bacteria: a reevaluation. Evolution

62:2894–2912. http://dx.doi.org/10.1111/j.1558-5646.2008.00501.x.

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 37Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

474. Currie CR, Scott JA, Summerbell RC, Malloch D. 1999. Fungus-

growing ants use antibiotic producing bacteria to control garden para-

sites. Nature 398:701–704. http://dx.doi.org/10.1038/19519.

475. Morales-Jimenez J, Vera-Ponce de Leon A, Garcia-Dominguez A,

Martinez-Romero E, Zuniga G, Hernandez-Rodriguez C. 2013. Nitro-

gen-ﬁxing and uricolytic bacteria associated with the gut of Dendroctonus

rhizophagus and Dendroctonus valens (Curculionidae: Scolytinae). Mi-

crob Ecol 66:200–210. http://dx.doi.org/10.1007/s00248-013-0206-3.

476. Hulcr J, Adams AS, Raffa K, Hofstetter RW, Klepzig KD, Currie CR.

2011. Presence and diversity of Streptomyces in Dendroctonus and sym-

patric bark beetle galleries across North America. Microb Ecol 61:759–

768. http://dx.doi.org/10.1007/s00248-010-9797-0.

477. Vasanthakumar A, Handelsman J, Schloss PD, Bauer LS, Raffa KF.

2008. Gut microbiota of an invasive subcortical beetle, Agrilus planipen-

nis Fairmaire, across various life stages. Environ Entomol 37:1344–1353.

http://dx.doi.org/10.1093/ee/37.5.1344.

478. Miltner EC, Bermudez LE. 2000. Mycobacterium avium grown in Acan-

thamoeba castellanii is protected from the effects of antimicrobials. An-

timicrob Agents Chemother 44:1990–1994. http://dx.doi.org/10.1128

/AAC.44.7.1990-1994.2000.

479. van Ingen J, Boeree MJ, van Soolingen D, Iseman MD, Heifets LB,

Daley CL. 2012. Are phylogenetic position, virulence, drug suscepti-

bility and in vivo response to treatment in mycobacteria interrelated?

Infect Genet Evol 12:832–837. http://dx.doi.org/10.1016/j.meegid

.2011.10.006.

480. Greub G, Raoult D. 2004. Microorganisms resistant to free-living amoe-

bae. Clin Microbiol Rev 17:413– 433. http://dx.doi.org/10.1128/CMR.17

.2.413-433.2004.

481. Amissah NA, Gryseels S, Tobias NJ, Ravadgar B, Suzuki M, Vande-

lannoote K, Durnez L, Leirs H, Stinear TP, Portaels F, Ablordey A,

Eddyani M. 2014. Investigating the role of free-living amoebae as a

reservoir for Mycobacterium ulcerans. PLoS Negl Trop Dis 8:e3148. http:

//dx.doi.org/10.1371/journal.pntd.0003148.

482. Gryseels S, Amissah D, Durnez L, Vandelannoote K, Leirs H, De

Jonckheere J, Silva MT, Portaels F, Ablordey A, Eddyani M. 2012.

Amoebae as potential environmental hosts for Mycobacterium ulcerans

and other mycobacteria, but doubtful actors in Buruli ulcer epidemiol-

ogy. PLoS Negl Trop Dis 6:e1764. http://dx.doi.org/10.1371/journal

.pntd.0001764.

483. Kennedy GM, Morisaki JH, Champion PA. 2012. Conserved mecha-

nisms of Mycobacterium marinum pathogenesis within the environmen-

tal amoeba Acanthamoeba castellanii. Appl Environ Microbiol 78:2049–

2052. http://dx.doi.org/10.1128/AEM.06965-11.

484. Crielaard W, Zaura E, Schuller AA, Huse SM, Montijn RC, Keijser BJ.

2011. Exploring the oral microbiota of children at various developmental

stages of their dentition in the relation to their oral health. BMC Med

Genomics 4:22. http://dx.doi.org/10.1186/1755-8794-4-22.

485. Zaura E, Keijser BJ, Huse SM, Crielaard W. 2009. Deﬁning the healthy

“core microbiome” of oral microbial communities. BMC Microbiol

9:259. http://dx.doi.org/10.1186/1471-2180-9-259.

486. Andersson AF, Lindberg M, Jakobsson H, Backhed F, Nyren P, Eng-

strand L. 2008. Comparative analysis of human gut microbiota by bar-

coded pyrosequencing. PLoS One 3:e2836. http://dx.doi.org/10.1371

/journal.pone.0002836.

487. Pei Z, Bini EJ, Yang L, Zhou M, Francois F, Blaser MJ. 2004. Bacterial

biota in the human distal esophagus. Proc Natl Acad SciUSA101:4250–

4255. http://dx.doi.org/10.1073/pnas.0306398101.

488. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R.

2009. Bacterial community variation in human body habitats across

space and time. Science 326:1694–1697. http://dx.doi.org/10.1126

/science.1177486.

489. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F,

Soriguer F, Queipo-Ortuno MI. 2013. Gut microbiota in children with

type 1 diabetes differs from that in healthy children: a case-control study.

BMC Med 11:46. http://dx.doi.org/10.1186/1741-7015-11-46.

490. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent

M, Gill SR, Nelson KE, Relman DA. 2005. Diversity of the human

intestinal microbial ﬂora. Science 308:1635–1638. http://dx.doi.org/10

.1126/science.1110591.

491. Turroni F, Marchesi JR, Foroni E, Gueimonde M, Shanahan F, Mar-

golles A, van Sinderen D, Ventura M. 2009. Microbiomic analysis of the

biﬁdobacterial population in the human distal gut. ISME J 3:745–751.

http://dx.doi.org/10.1038/ismej.2009.19.

492. Inness V, McCartney A, Khoo C, Gross K, Gibson G. 2007. Molecular

characterisation of the gut microﬂora of healthy and inﬂammatory bowel

disease cats using ﬂuorescence in situ hybridisation with special reference

to Desulfovibrio spp. J Anim Physiol Anim Nutr 91:48–53. http://dx.doi

.org/10.1111/j.1439-0396.2006.00640.x.

493. Jia J, Frantz N, Khoo C, Gibson GR, Rastall RA, McCartney AL. 2010.

Investigation of the faecal microbiota associated with canine chronic

diarrhoea. FEMS Microbiol Ecol 71:304–312. http://dx.doi.org/10.1111

/j.1574-6941.2009.00812.x.

494. McNeil MM, Brown JM. 1994. The medically important aerobic acti-

nomycetes: epidemiology and microbiology. Clin Microbiol Rev 7:357–

417.

495. Tsukamura M. 1982. Numerical analysis of the taxonomy of Nocardiae

and Rhodococci. Microbiol Immunol 26:1101–1119. http://dx.doi.org/10

.1111/j.1348-0421.1982.tb00260.x.

496. Kapadia M, Rolston KV, Han XY. 2007. Invasive Streptomyces infec-

tions: six cases and literature review. Am J Clin Pathol 127:619–624.

http://dx.doi.org/10.1309/QJEBXP0BCGR54L15.

497. Kirby R, Sangal V, Tucker NP, Zakrzewska-Czerwinska J, Wierzbicka

K, Herron PR, Chu CJ, Chandra G, Fahal AH, Goodfellow M, Hosk-

isson PA. 2012. Draft genome sequence of the human pathogen Strep-

tomyces somaliensis, a signiﬁcant cause of actinomycetoma. J Bacteriol

194:3544–3545. http://dx.doi.org/10.1128/JB.00534-12.

498. Quintana ET, Wierzbicka K, Mackiewicz P, Osman A, Fahal AH,

Hamid ME, Zakrzewska-Czerwinska J, Maldonado LA, Goodfellow M.

2008. Streptomyces sudanensis sp. nov., a new pathogen isolated from

patients with actinomycetoma. Antonie Van Leeuwenhoek 93:305–313.

http://dx.doi.org/10.1007/s10482-007-9205-z.

499. Dunne EF, Burman WJ, Wilson ML. 1998. Streptomyces pneumonia in

a patient with human immunodeﬁciency virus infection: case report and

review of the literature on invasive Streptomyces infections. Clin Infect

Dis 27:93–96. http://dx.doi.org/10.1086/514612.

500. Datta P, Arora S, Jain R, Chander J, van de Sande W. 2012. Secondary

peritonitis caused by Streptomyces viridis. J Clin Microbiol 50:1813–1814.

http://dx.doi.org/10.1128/JCM.06045-11.

501. Gugnani A, Unaogu I, Emeruwa C. 1993. Pulmonary infection due to

Streptomyces griseus. J Commun Disord 25:38–40.

502. Kofteridis DP, Maraki S, Scoulica E, Tsioutis C, Maltezakis G, Gikas

A. 2007. Streptomyces pneumonia in an immunocompetent patient: a

case report and literature review. Diagn Microbiol Infect Dis 59:459–

462. http://dx.doi.org/10.1016/j.diagmicrobio.2007.06.009.

503. Bulgarelli D, Schlaeppi K, Spaepen S, Ver Loren van Themaat E,

Schulze-Lefert P. 2013. Structure and functions of the bacterial micro-

biota of plants. Annu Rev Plant Biol 64:807–838. http://dx.doi.org/10

.1146/annurev-arplant-050312-120106.

504. Bignell DR, Seipke RF, Huguet-Tapia JC, Chambers AH, Parry RJ,

Loria R. 2010. Streptomyces scabies 87-22 contains a coronafacic acid-like

biosynthetic cluster that contributes to plant-microbe interactions. Mol

Plant Microbe Interact 23:161–175. http://dx.doi.org/10.1094/MPMI-23

-2-0161.

505. Loria R, Kers J, Joshi M. 2006. Evolution of plant pathogenicity in

Streptomyces. Annu Rev Phytopathol 44:469–487. http://dx.doi.org/10

.1146/annurev.phyto.44.032905.091147.

506. Faucher E, Savard T, Bealieu C. 1992. Characterization of actinomyce-

tes isolated from common scab lesions on potato tubers. Can J Plant

Pathol 14:197–202. http://dx.doi.org/10.1080/07060669209500874.

507. Kreuze JF, Suomalainen S, Paulin L, Valkonen JP. 1999. Phyloge-

netic analysis of 16S rRNA genes and PCR analysis of the nec1 gene

from Streptomyces spp. causing common scab, pitted scab, and netted

scab in Finland. Phytopathology 89:462–469. http://dx.doi.org/10

.1094/PHYTO.1999.89.6.462.

508. Wanner LA. 2006. A survey of genetic variation in Streptomyces isolates

causing potato common scab in the United States. Phytopathology 96:

1363–1371. http://dx.doi.org/10.1094/PHYTO-96-1363.

509. Loria R, Bukhalid A, Fry B, King RR. 1997. Plant pathogenicity in the

genus Streptomyces. Plant Dis 81:836–846. http://dx.doi.org/10.1094

/PDIS.1997.81.8.836.

510. Lambert DH, Loria R. 1989. Streptomyces scabies sp. nov., nom. rev. Int

J Syst Bacteriol 39:387–392. http://dx.doi.org/10.1099/00207713-39-4

-387.

511. Harrison MD. 1962. Potato russet scab, its cause and factors affecting its

development. Am J Potato Res 39:368–387. http://dx.doi.org/10.1007

/BF02861618.

Barka et al.

38 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

512. Scholte K, Labruyere RE. 1985. Netted scab: a new name for an old

disease in Europe. Potato Res 28:443–448. http://dx.doi.org/10.1007

/BF02357520.

513. Blanchette RA, Sutherland JB, Crawford DL. 1981. Actinomycetes in

discolored wood of living silver maple. Can J Bot 59:1–7. http://dx.doi

.org/10.1139/b81-001.

514. Wallis G. 1983. Actinomycte and actinomycete-like vessel oclusions of

sugar maple, Acer sacharum. M.S. dissertation. SUNY College of Envi-

ronmental Science and Forestry, Syracuse, NY.

515. Sutherland JB, Blanchette RA, Crawford DL, Pometto AL. 1979.

Breakdown of Douglas ﬁr phloem by a lignocellulose-degrading

Streptomyces. Curr Microbiol 2:123–126. http://dx.doi.org/10.1007

/BF02603069.

516. Tilford PE. 1936. Fasciation of sweet peas caused by Phytomonas fascians

n. sp. J Agric Res 53:383–394.

517. Goethals K, Vereecke D, Jaziri M, Van Montagu M, Holsters M. 2001.

Leafy gall formation by Rhodococcus fascians. Annu Rev Phytopathol 39:

27–52. http://dx.doi.org/10.1146/annurev.phyto.39.1.27.

518. Vereecke D, Burssens S, Simon-Mateo C, Inze D, Van Montagu M,

Goethals K, Jaziri M. 2000. The Rhodococcus fascians-plant interaction:

morphological traits and biotechnological applications. Planta 210:241–

251. http://dx.doi.org/10.1007/PL00008131.

519. Stes E, Francis I, Pertry I, Dolzblasz A, Depuydt S, Vereecke D. 2013.

The leafy gall syndrome induced by Rhodococcus fascians. FEMS Micro-

biol Lett 342:187–194. http://dx.doi.org/10.1111/1574-6968.12119.

520. de O Manes CL, Beeckman T, Ritsema T, Van Montagu M, Goethals

K, Holsters M. 2004. Phenotypic alterations in Arabidopsis thaliana

plants caused by Rhodococcus fascians infection. J Plant Res 117:139–145.

http://dx.doi.org/10.1007/s10265-003-0138-y.

521. Vandeputte O, Oden S, Mol A, Vereecke D, Goethals K, El Jaziri M,

Prinsen E. 2005. Biosynthesis of auxin by the gram-positive phytopatho-

gen Rhodococcus fascians is controlled by compounds speciﬁc to infected

plant tissues. Appl Environ Microbiol 71:1169–1177. http://dx.doi.org

/10.1128/AEM.71.3.1169-1177.2005.

522. Flügel M, Becker A, Gartemann K-H, Eichenlaub R. 2012. Analysis of

the interaction of Clavibacter michiganensis subsp. michiganensis with its

host plant tomato by genome-wide expression proﬁling. J Biotechnol

160:42–54. http://dx.doi.org/10.1016/j.biotec.2012.01.023.

523. Eichenlaub R, Gartemann K-H. 2011. The Clavibacter michiganensis

subspecies: molecular investigation of Gram-positive bacterial plant

pathogens. Annu Rev Phytopathol 49:445–464. http://dx.doi.org/10

.1146/annurev-phyto-072910-095258.

524. Monteiro-Vitorello CB, Camargo LE, Van Sluys MA, Kitajima JP,

Trufﬁ D, do Amaral AM, Harakava R, de Oliveira JC, Wood D, de

Oliveira MC, Miyaki C, Takita MA, da Silva AC, Furlan LR, Carraro

DM, Camarotte G, Almeida NF, Jr, Carrer H, Coutinho LL, El-Dorry

HA, Ferro MI, Gagliardi PR, Giglioti E, Goldman MH, Goldman GH,

Kimura ET, Ferro ES, Kuramae EE, Lemos EG, Lemos MV, Mauro

SM, Machado MA, Marino CL, Menck CF, Nunes LR, Oliveira RC,

Pereira GG, Siqueira W, de Souza AA, Tsai SM, Zanca AS, Simpson

AJ, Brumbley SM, Setubal JC. 2004. The genome sequence of the gram-

positive sugarcane pathogen Leifsonia xyli subsp. xyli. Mol Plant Microbe

Interact 17:827–836. http://dx.doi.org/10.1094/MPMI.2004.17.8.827.

525. Dreier J, Meletzus D, Eichenlaub R. 1997. Characterization of the

plasmid encoded virulence region pat-1 of phytopathogenic Clavibacter

michiganensis subsp. michiganensis. Mol Plant Microbe Interact 10:195–

206. http://dx.doi.org/10.1094/MPMI.1997.10.2.195.

526. Laine MJ, Haapalainen M, Wahlroos T, Kankare K, Nissinen R,

Kassuwi S, Metzler MC. 2000. The cellulase encoded by the native

plasmid of Clavibacter michiganensis ssp. sepedonicus plays a role in vir-

ulence and contains an expansin-like domain. Physiol Mol Plant P 57:

221–233. http://dx.doi.org/10.1006/pmpp.2000.0301.

527. Harth G, Horwitz MA. 1997. Expression and efﬁcient export of enzy-

matically active Mycobacterium tuberculosis glutamine synthetase in My-

cobacterium smegmatis and evidence that the information for export is

contained within the protein. J Biol Chem 272:22728–22735. http://dx

.doi.org/10.1074/jbc.272.36.22728.

528. King RR, Calhoun LA. 2009. The thaxtomin phytotoxins: sources, syn-

thesis, biosynthesis, biotransformation and biological activity. Phyto-

chemistry 70:833–841. http://dx.doi.org/10.1016/j.phytochem.2009.04

.013.

529. Duval I, Brochu V, Simard M, Beaulieu C, Beaudoin N. 2005. Thax-

tomin A induces programmed cell death in Arabidopsis thaliana suspen-

sion-cultured cells. Planta 222:820–831. http://dx.doi.org/10.1007

/s00425-005-0016-z.

530. Errakhi R, Meimoun P, Lehner A, Vidal G, Briand J, Corbineau F,

Rona J-P, Bouteau F. 2008. Anion channel activity is necessary to induce

ethylene synthesis and programmed cell death in response to oxalic acid.

J Exp Bot 59:3121–3129. http://dx.doi.org/10.1093/jxb/ern166.

531. Fry BA, Loria R. 2002. Thaxtomin A: evidence for a plant cell wall target.

Physiol Mol Plant Pathol 60:1–8. http://dx.doi.org/10.1006/pmpp.2001

.0371.

532. Scheible WR, Fry B, Kochevenko A, Schindelasch D, Zimmerli L,

Somerville S, Loria R, Somerville CR. 2003. An Arabidopsis mutant

resistant to thaxtomin A, a cellulose synthesis inhibitor from Streptomy-

ces species. Plant Cell 15:1781–1794. http://dx.doi.org/10.1105/tpc

.013342.

533. Tegg RS, Melian L, Wilson CR, Shabala S. 2005. Plant cell growth and

ion ﬂux responses to the streptomycete phytotoxin thaxtomin A: calcium

and hydrogen ﬂux patterns revealed by the non-invasive MIFE tech-

nique. Plant Cell Physiol 46:638–648. http://dx.doi.org/10.1093/pcp

/pci069.

534. Kinkel LL, Bowers JH, Shimizu K, Neeno-Eckwall EC, Schottel JL.

1998. Quantitative relationships among thaxtomin A production, potato

scab severity, and fatty acid composition in Streptomyces. Can J Micro-

biol 44:768–776.

535. Goyer C, Vachon J, Beaulieu C. 1998. Pathogenicity of Streptomyces

scabies mutants altered in thaxtomin A production. Phytopathology 88:

442–445. http://dx.doi.org/10.1094/PHYTO.1998.88.5.442.

536. Healy FG, Wach M, Krasnoff SB, Gibson DM, Loria R. 2000. The txtAB

genes of the plant pathogen Streptomyces acidiscabies encode a peptide

synthetase required for phytotoxin thaxtomin A production and patho-

genicity. Mol Microbiol 38:794–804. http://dx.doi.org/10.1046/j.1365

-2958.2000.02170.x.

537. King RR, Lawrence CH, Clark MC, Calhoun LA. 1989. Isolation and

characterization of phytotoxins associated with Streptomyces scabies.J

Chem Soc Chem Commun 13:849–850.

538. Lawrence CH, Clark MC, King RR. 1990. Induction of common scab

symptoms in aseptically cultured potato tubers by the vivotoxin, thaxto-

min. Phytopathology 80:606–608. http://dx.doi.org/10.1094/Phyto-80

-606.

539. Raymer G, Willard JM, Schottel JL. 1990. Cloning, sequencing, and

regulation of expression of an extracellular esterase gene from the plant

pathogen Streptomyces scabies. J Bacteriol 172:7020–7026.

540. Li Y, Darley CP, Ongaro V, Fleming A, Schipper O, Baldauf SL,

McQueen-Mason SJ. 2002. Plant expansins are a complex multigene

family with an ancient evolutionary origin. Plant Physiol 128:854–864.

http://dx.doi.org/10.1104/pp.010658.

541. Stavrinides J, McCann HC, Guttman DS. 2008. Host-pathogen inter-

play and the evolution of bacterial effectors. Cell Microbiol 10:285–292.

http://dx.doi.org/10.1111/j.1462-5822.2007.01078.x.

542. Gribbon EM, Shoesmith J, Cunliffe W, Holland K. 1994. The

microaerophily and photosensitivity of Propionibacterium acnes.J

Appl Bacteriol 77:583–590. http://dx.doi.org/10.1111/j.1365-2672

.1994.tb04405.x.

543. Westerhof W, Relyveld GN, Kingswijk MM, de Man P, Menke HE.

2004. Propionibacterium acnes and the pathogenesis of progressive mac-

ular hypomelanosis. Arch Dermatol 140:210–214. http://dx.doi.org/10

.1001/archderm.140.2.210.

544. Kinashi H, Someno K, Sakaguchi K. 1984. Isolation and characteriza-

tion of concanamycins A, B and C. J Antibiot 37:1333–1343. http://dx

.doi.org/10.7164/antibiotics.37.1333.

545. Haydock SF, Appleyard AN, Mironenko T, Lester J, Scott N, Leadlay

PF. 2005. Organization of the biosynthetic gene cluster for the macrolide

concanamycin A in Streptomyces neyagawaensis ATCC 27449. Microbi-

ology 151:3161–3169. http://dx.doi.org/10.1099/mic.0.28194-0.

546. Seki-Asano M, Okazaki T, Yamagishi M, Sakai N, Hanada K, Mizoue

K. 1994. Isolation and characterization of new 18-membered macrolides

FD-891 and FD-892. J Antibiot 47:1226 –1233. http://dx.doi.org/10.7164

/antibiotics.47.1226.

547. Natsume M, Ryu R, Abe H. 1996. Production of phytotoxins, conca-

namycins A and B by Streptomyces spp. Ann Phytopathol Soc Jpn 62:411–

413. http://dx.doi.org/10.3186/jjphytopath.62.411.

548. Natsume M, Yamada A, Tashiro N, Abe H. 1998. Differential produc-

tion of the phytotoxins thaxtomin A and concanamycins A and B by

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 39Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

potato common scab-causing Streptomyces spp. Ann Phytopathol Soc

Jpn 64:202–204. http://dx.doi.org/10.3186/jjphytopath.64.202.

549. Natsume M, Komiya M, Koyanagi F, Tashiro N, Kawaide H, Abe H.

2005. Phytotoxin produced by Streptomyces sp. causing potato russet

scab in Japan. J Gen Plant Pathol 71:364–369. http://dx.doi.org/10.1007

/s10327-005-0211-6.

550. Natsume M, Taki M, Tashiro N, Abe H. 2001. Phytotoxin production

and aerial mycelium formation by Streptomyces scabies and S. acidiscabies

in vitro. J Gen Plant Pathol 67:299–302. http://dx.doi.org/10.1007

/PL00013035.

551. Fenton A, Stephens P, Crowley J, O’Callaghan M, O’Gara F. 1992.

Exploitation of gene(s) involved in 2,4-diacetylphloroglucinol biosyn-

thesis to confer a new biocontrol capability to a Pseudomonas strain. Appl

Environ Microbiol 58:3873–3878.

552. Glick BR. 1995. The enhancement of plant growth by free-living bacte-

ria. Can J Microbiol 41:109–117. http://dx.doi.org/10.1139/m95-015.

553. Gomes R, Semedo L, Soares R, Alviano C, Linhares L, Coelho R. 2000.

Chitinolytic activity of actinomycetes from a cerrado soil and their po-

tential in biocontrol. Lett Appl Microbiol 30:146–150. http://dx.doi.org

/10.1046/j.1472-765x.2000.00687.x.

554. Kim BS, Moon SS, Hwang BK. 2000. Structure elucidation and anti-

fungal activity of an anthracycline antibiotic, daunomycin, isolated from

Actinomadura roseola. J Agric Food Chem 48:1875–1881. http://dx.doi

.org/10.1021/jf990402u.

555. Ouhdouch Y, Barakate M, Finace C. 2001. Actinomycetes from Ma-

roccan habitats: screening for antifungal activites. Eur J Soil Biol 37:69–

74. http://dx.doi.org/10.1016/S1164-5563(01)01069-X.

556. El-Tarabily KA, Sivasithamparam K. 2006. Non-streptomycete actino-

mycetes as biocontrol agents of soil-borne fungal plant pathogens and as

plant growth promoters. Soil Biol Biochem 38:1505–1520. http://dx.doi

.org/10.1016/j.soilbio.2005.12.017.

557. Cohen MF, Mazzola M. 2006. Resident bacteria, nitric oxide emission

and particle size modulate the effect of Brassica napus seed meal on dis-

ease incited by Rhizoctonia solani and Pythium spp. Plant Soil 286:75– 86.

http://dx.doi.org/10.1007/s11104-006-9027-1.

558. Doumbou CL, Salove MKH, Crawford DL, Beaulieu C. 2001. Ac-

tinomycetes, promising tools to control plant diseases and to promote

plant growth. Phytoprotection 82:85–102. http://dx.doi.org/10.7202

/706219ar.

559. Mahmoudi E, Tabatabaei BES, Venturi V. 2011. Virulence attenuation

of Pectobacterium carotovorum using N-acyl-homoserine lactone degrad-

ing bacteria isolated from potato rhizosphere. Plant Pathol J 27:242–248.

http://dx.doi.org/10.5423/PPJ.2011.27.3.242.

560. Cao L, Qiu Z, You J, Tan H, Zhou S. 2005. Isolation and characteriza-

tion of endophytic streptomycete antagonists of Fusarium wilt pathogen

from surface-sterilized banana roots. FEMS Microbiol Lett 247:147–152.

http://dx.doi.org/10.1016/j.femsle.2005.05.006.

561. Getha K, Vikineswary S, Wong W, Seki T, Ward A, Goodfellow M.

2005. Evaluation of Streptomyces sp. strain g10 for suppression of Fusar-

ium wilt and rhizosphere colonization in pot-grown banana plantlets. J

Ind Microbiol Biotechnol 32:24–32. http://dx.doi.org/10.1007/s10295

-004-0199-5.

562. Errakhi R, Bouteau F, Lebrihi A, Barakate M. 2007. Evidences of

biological control capacities of Streptomyces spp. against Sclerotium rolfsii

responsible for damping-off disease in sugar beet (Beta vulgaris L.).

World J Microbiol Biotechnol 23:1503–1509. http://dx.doi.org/10.1007

/s11274-007-9394-7.

563. Jain PK, Jain P. 2007. Isolation, characterization and antifungal activity

of Streptomyces sampsonii GS 1322. Indian J Exp Biol 45:203–206.

564. Trejo-Estrada S, Paszczynski A, Crawford D. 1998. Antibiotics and

enzymes produced by the biocontrol agent Streptomyces violaceusnuger

YCED-9. J Ind Microbiol Biotechnol 21:81–90. http://dx.doi.org/10

.1038/sj.jim.2900549.

565. Xiao K, Samac DA, Kinkel LL. 2002. Biological control of Phytophthora

root rots on alfalfa and soybean with Streptomyces. Biol Control 23:285–

295. http://dx.doi.org/10.1006/bcon.2001.1015.

566. Taechowisan T, Perberdy JF, Lumyong S. 2003. Isolation of endo-

phytic actinomycetes from selected plants and their antifungal activ-

ity. World J Microbiol Biotechnol 19:381–385. http://dx.doi.org/10

.1023/A:1023901107182.

567. Miyashita K, Fujii T, Sawada Y. 1991. Molecular cloning and charac-

terization of chitinase genes from Streptomyces lividans 66. J Gen Micro-

biol 137:2065–2072. http://dx.doi.org/10.1099/00221287-137-9-2065.

568. Abd-Allah EF. 2001. Streptomyces plicatus as a model biocontrol

agent. Folia Microbiol (Praha) 46:309–314. http://dx.doi.org/10.1007

/BF02815619.

569. Joo G-J. 2005. Production of an anti-fungal substance for biological

control of Phytophthora capsici causing phytophthora blight in red-

peppers by Streptomyces halstedii. Biotechnol Lett 27:201–205. http://dx

.doi.org/10.1007/s10529-004-7879-0.

570. Mahadevan B, Crawford DL. 1997. Properties of the chitinase of the anti-

fungal biocontrol agent Streptomyces lydicus WYEC108. Enzyme Microb

Technol 20:489 –493. http://dx.doi.org/10.1016/S0141-0229(96)00175-5.

571. Barakate M, Ouhdouch Y, Oufdou K, Beaulieu C. 2002. Characteriza-

tion of rhizospheric soil strepomycetes from moroccan habitat and their

antimicrobial activities. World J Microbiol Biotechnol 18:49–54. http:

//dx.doi.org/10.1023/A:1013966407890.

572. Emmert EA, Handelsman J. 1999. Biocontrol of plant disease: a (Gram-)

positive perspective. FEMS Microbiol Lett 171:1–9. http://dx.doi.org/10

.1111/j.1574-6968.1999.tb13405.x.

573. Millard WA. 1923. Common scab of potatoes. Ann Appl Biol 10:70–88.

http://dx.doi.org/10.1111/j.1744-7348.1923.tb05654.x.

574. Sanford GB. 1926. Some factors affecting the pathogenicity of Actino-

myces scabies. Phytopathology 16:525–547.

575. Millard WA, Taylor CB. 1927. Antagonism of micro-organisms as the

controlling factor in the inhibition of scab by green-manuring. Ann Appl

Biol 14:202–216. http://dx.doi.org/10.1111/j.1744-7348.1927.tb07076.x.

576. Kloepper JW. 1996. Host speciﬁcity in microbe-microbe interactions.

Bioscience 46:406–409.

577. Gardner JM, Chandler JL, Feldman AW. 1984. Growth promotion and

inhibition by antibiotic-producing ﬂuorescent pseudomonads on citrus

roots. Plant Soil 77:103–113. http://dx.doi.org/10.1007/BF02182816.

578. O’Neill GA, Radley RA, Chanaway CP. 1992. Variable effects of

emergence-promoting rhizobacteria on conifer seed growth under

nursery conditions. Biol Fertil Soils 13:45–49. http://dx.doi.org/10

.1007/BF00337237.

579. Giri S, Pati B. 2004. A comparative study on phyllosphere nitrogen

ﬁxation by newly isolated Corynebacterium sp. & Flavobacterium sp. and

their potentialities as biofertilizer. Acta Microbiol Immunol Hung 51:

47–56. http://dx.doi.org/10.1556/AMicr.51.2004.1-2.3.

580. Mahendra S, Alvarez-Cohen L. 2005. Pseudonocardia dioxanivoran sp.

nov., a novel actinomycete that grows on 1,4-dioxane. Int J Syst Evol

Microbiol 55:593–598. http://dx.doi.org/10.1099/ijs.0.63085-0.

581. Aldesuquy HS, Mansour FA, Abo-Hamed SA. 1998. Effect of the

culture ﬁltrates of Streptomyces on growth and productivity of wheat

plants. Folia Microbiol (Praha) 43:465–470. http://dx.doi.org/10

.1007/BF02820792.

582. Alexander M. 1977. Introduction to soil microbiology. Krieger Publish-

ing Company, Malabar, FL.

583. Merriman PR, Price RD, Kollmorgen JF, Piggott T, Ridge EH. 1974.

Effect of seed inoculation with Bacillus subtilis and Streptomyces griseus

on the growth of cereals and carrots. Aust J Agric Res 25:219 –226. http:

//dx.doi.org/10.1071/AR9740219.

584. El-Abyad M, El-Sayed M, El-Shanshoury A, El-Sabbagh SM. 1993.

Towards the biological control of fungal and bacterial diseases of tomato

using antagonistic Streptomyces spp. Plant Soil 149:185–195. http://dx

.doi.org/10.1007/BF00016608.

585. Kaltenpoth M. 2009. Actinobacteria as mutualists: general healthcare for

insects? Trends Microbiol 17:529–535. http://dx.doi.org/10.1016/j.tim

.2009.09.006.

586. Kucho K, Hay AE, Normand P. 2010. The determinants of the acti-

norhizal symbiosis. Microbes Environ 25:241–252. http://dx.doi.org/10

.1264/jsme2.ME10143.

587. Trujillo ME, Alonso-Vega P, Rodriguez R, Carro L, Cerda E, Alonso P,

Martinez-Molina E. 2010. The genus Micromonospora is widespread in

legume root nodules: the example of Lupinus angustifolius. ISME J

4:1265–1281. http://dx.doi.org/10.1038/ismej.2010.55.

588. Buckley DH, Huangyutitham V, Hsu SF, Nelson TA. 2007. Stable

isotope probing with 15N2 reveals novel noncultivated diazotrophs in

soil. Appl Environ Microbiol 73:3196–3204. http://dx.doi.org/10.1128

/AEM.02610-06.

589. Gtari M, Brusetti L, Hassen A, Mora D, Daffonchio D, Boudabous A.

2007. Genetic diversity among Elaeagnus compatible Frankia strains and

sympatric-related nitrogen-ﬁxing actinobacteria revealed by nifH se-

quence analysis. Soil Biol Biochem 39:372–377. http://dx.doi.org/10

.1016/j.soilbio.2006.07.005.

Barka et al.

40 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

590. Valdes M, Perez NO, Estrada-de Los Santos P, Caballero-Mellado J,

Pena-Cabriales JJ, Normand P, Hirsch AM. 2005. Non-Frankia acti-

nomycetes isolated from surface-sterilized roots of Casuarina equisetifo-

lia ﬁx nitrogen. Appl Environ Microbiol 71:460–466. http://dx.doi.org

/10.1128/AEM.71.1.460-466.2005.

591. Zakhia F, Jeder H, Willems A, Gillis M, Dreyfus B, de Lajudie P. 2006.

Diverse bacteria associated with root nodules of spontaneous legumes in

Tunisia and ﬁrst report for nifH-like gene within the genera Microbacte-

rium and Starkeya. Microb Ecol 51:375–393. http://dx.doi.org/10.1007

/s00248-006-9025-0.

592. Roy S, Khasa DP, Greer CW. 2007. Combining alders, frankiae, and

mycorrhizae for the revegetation and remediation of contaminated eco-

systems. Can J Bot 85:237–251. http://dx.doi.org/10.1139/B07-017.

593. Sardi P, Saracchi M, Quaroni S, Petrolini B, Borgonovi GE, Merli S.

1992. Isolation of endophytic Streptomyces strains from surface-sterilized

roots. Appl Environ Microbiol 58:2691–2693.

594. Coombs JT, Michelsen P, Franco CMM. 2004. Evaluation of endo-

phytic actinobacteria as antagonists of Gaeumannomyces graminis var.

tritici in wheat. Biol Control 29:359–366. http://dx.doi.org/10.1016/j

.biocontrol.2003.08.001.

595. Overvoorde P, Fukaki H, Beeckman T. 2010. Auxin control of root

development. Cold Spring Harb Perspect Biol 2:a001537. http://dx.doi

.org/10.1101/cshperspect.a001537.

596. Tokala RK, Strap JL, Jung CM, Crawford DL, Salove MH, Deobald LA,

Bailey JF, Morra MJ. 2002. Novel plant-microbe rhizosphere interac-

tion involving Streptomyces lydicus WYEC108 and the pea plant (Pisum

sativum). Appl Environ Microbiol 68:2161–2171. http://dx.doi.org/10

.1128/AEM.68.5.2161-2171.2002.

597. Couillerot O, Loqman S, Toribio A, Hubert J, Gandner L, Nuzillard

JM, Ouhdouch Y, Clement C, Barka EA, Renault JH. 2014. Puriﬁcation

of antibiotics from the biocontrol agent Streptomyces anulatus S37 by

centrifugal partition chromatography. J Chromatogr B 944:30–34. http:

//dx.doi.org/10.1016/j.jchromb.2013.11.008.

598. Berg G, Marten P, Minkwitz A, Bruckner S. 2001. Efﬁcient biological

control of fungal plant diseases by Streptomyces sp. DSMZ 12424. J Plant

Dis Prot 108:1–10.

599. El-Tarabily KA, Soliman MH, Nassar AH, Al-Hassani HA, Sivas-

ithamparam K, McKenna F, Hardy GES. 2000. Biological control of

Sclerotinia minor using a chitinolytic bacterium and actinomycetes.

Plant Pathol 49:573–583. http://dx.doi.org/10.1046/j.1365-3059.2000

.00494.x.

600. Quecine MC, Araujo WL, Marcon J, Gai CS, Azevedo JL, Pizzirani-

Kleiner AA. 2008. Chitinolytic activity of endophytic Streptomyces and

potential for biocontrol. Lett Appl Microbiol 47:486–491. http://dx.doi

.org/10.1111/j.1472-765X.2008.02428.x.

601. Verma VC, Singh SK, Prakash S. 2011. Bio-control and plant growth

promotion potential of siderophore producing endophytic Streptomyces

from Azadirachta indica A Juss. J Basic Microbiol 51:550–556. http://dx

.doi.org/10.1002/jobm.201000155.

602. Murray RGE, Brenner DJ, Holt JG, Krieg NR, Mulder JW, Pfenning N,

Sneath PH, Stoley JT, Williams ST (ed). 1989. Bergey’s manual of

systematic bacteriology, vol 4. Williams & Wilkins, Baltimore, MD.

603. Bister B, Bischoff D, Strobele M, Riedlinger J, Reicke A, Wolter F, Bull

AT, Zahner H, Fiedler HP, Sussmuth RD. 2004. Abyssomicin C: a

polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor

of the p-aminobenzoic acid/tetrahydrofolate biosynthesis pathway. An-

gew Chem Int Ed Engl 43:2574–2576. http://dx.doi.org/10.1002/anie

.200353160.

604. Heinemann B, Kaplan MA, Muir RD, Hooper IR. 1953. Amphomycin,

a new antibiotic. Antibiot Chemother 3:1239–1242.

605. Grein A, Merli S, Spalla C. 1980. New anthracycline glycosides from

Micromonospora. I. Description of the producing strain. J Antibiot 33:

1462–1467.

606. Barbe V, Bouzon M, Mangenot S, Badet B, Poulain J, Segurens B,

Vallenet D, Marliere P, Weissenbach J. 2011. Complete genome se-

quence of Streptomyces cattleya NRRL 8057, a producer of antibiotics

and ﬂuorometabolites. J Bacteriol 193:5055–5056. http://dx.doi.org/10

.1128/JB.05583-11.

607. Yang HJ, Huang XZ, Zhang ZL, Wang CX, Zhou J, Huang K, Zhou

JM, Zheng W. 2014. Two novel amphomycin analogues from Strepto-

myces canus strain FIM-0916. Nat Prod Res 28:861– 867. http://dx.doi

.org/10.1080/14786419.2014.886210.

608. Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R,

Kong YL, Monaghan RL, Olson G, Putter I, Tunac JB, Wallick H,

Stapley EO, Oiwa R, Omura S. 1979. Avermectins, new family of potent

anthelmintic agents: producing organism and fermentation. Antimicrob

Agents Chemother 15:361–367. http://dx.doi.org/10.1128/AAC.15.3

.361.

609. Omura S, Imamura N, Oiwa R, Kuga H, Iwata R, Masuma R, Iwai Y.

1986. Clostomicins. New antibiotics produced by Micromonospora echi-

nospora subsp. armeniaca subsp. nov. I. Production, isolation, and

physico-chemical and biological properties. J Antibiot 39:1407–1412.

610. Pendela M, Dragovic S, Bockx L, Hoogmartens J, Van Schepdael A,

Adams E. 2008. Development of a liquid chromatographic method for

the determination of related substances and assay of D-cycloserine. J

Pharm Biomed Anal 47:807–811. http://dx.doi.org/10.1016/j.jpba.2008

.03.012.

611. Mchenney MA, Hosted TJ, Dehoff BS, Rosteck PR, Jr, Baltz RH. 1998.

Molecular cloning and physical mapping of the daptomycin gene cluster

from Streptomyces roseosporus. J Bacteriol 180:143–151.

612. Mc Guire JM, Bunch RL, Anderson RC, Boaz HE, Flynn EH, Powell

HM, Smith JW. 1952. Ilotycin, a new antibiotic. Antibiot Chemother

(Northﬁeld) 2:281–283.

613. Weinstein MJ, Luedemann GM, Oden EM, Wagman GH, Rosselet JP,

Marquez JA, Coniglio CT, Charney W, Herzog HL, Black J. 1963.

Gentamicin, a new antibiotic complex from Micromonospora. J Med

Chem 6:463–464. http://dx.doi.org/10.1021/jm00340a034.

614. Gonzalez A, Jimenez A, Vazquez D, Davies J, Schindler D. 1978.

Studies on the mode of action of hygromycin B, an inhibitor of translo-

cation in eukaryotes. Biochim Biophys Acta 521:459–469.

615. Umezawa H, Ueda M, Maeda K, Yagishita K, Kondo S, Okami Y,

Utahara R, Osato Y, Nitta K, Takeuchi T. 1957. Production and

isolation of a new antibiotic: kanamycin. J Antibiot 10:181–188.

616. Hata T, Koga F, Kanamori H. 1953. Studies on leucomycin. II. Bacte-

riological properties of Streptomyces kitasatoensis. J Antibiot 6:109–112.

617. Mason DJ, Lewis C. 1964. Biological activity of the lincomycin-related

antibiotics. Antimicrob Agents Chemother 10:7–12.

618. Kwon HC, Kauffman CA, Jensen PR, Fenical W. 2006. Marinomycins

A-D, antitumor-antibiotics of a new structure class from a marine acti-

nomycete of the recently discovered genus “Marinispora.” J Am Chem

Soc 128:1622–1632.

619. Dulmage HT. 1951. The production of neomycin by Stretomyces fradiae

3535. Ph.D. thesis. Rutgers University, New Brunswick, NJ.

620. Kominek LA. 1972. Biosynthesis of novobiocin by Streptomyces niveus.

Antimicrob Agents Chemother 1:123–134. http://dx.doi.org/10.1128

/AAC.1.2.123.

621. Williams DH, Rajananda V, Williamson MP, Bojesen G. 1980. The

vancomycin and ristocetin group of antibiotics, p 119–158. In Sammes

PG (ed), Topics in antibiotic chemistry, vol 5. Ellis Horwood, Chichester,

United Kingdom.

622. Rhodes PM. 1984. The production of oxytetracycline in chemostat

culture. Biotechnol Bioeng 26:382–385. http://dx.doi.org/10.1002/bit

.260260415.

623. Blanc V, Lagneaux D, Didier P, Gil P, Lacroix P, Crouzet J. 1995.

Cloning and analysis of structural genes from Streptomyces pristinaespi-

ralis encoding enzymes involved in the conversion of pristinamycin IIB

to pristinamycin IIA (PIIA): PIIA synthase and NADH:riboﬂavin 5=-

phosphate oxidoreductase. J Bacteriol 177:5206–5214.

624. Pamboukian CR, Facciotti MC. 2004. Production of antitumoral

retamycin during fed-batch fermentations of Streptomyces olindensis.

Appl Biochem Biotechnol 112:111–122. http://dx.doi.org/10.1385

/ABAB:112:2:111.

625. Margalith P, Beretta G. 1960. Rifomycin. XI. Taxonomic study on

Streptomyces mediterranei nov. sp. Mycopathol Mycol Applic 13:321–

330.

626. Pinnert-Sindico S. 1954. Une nouvelle espèce de Streptomyces produc-

trice d’antibiotiques: Streptomyces ambofaciens n. sp. Ann Inst Pasteur

87:702–707. (In French.).

627. Yanagimoto M. 1983. Novel actions of inducer in staphylomycin pro-

duction by Streptomyces virginiae. J Ferment Technol 61:443–448.

628. Thompson RQ, Hughes MS. 1963. Stendomycin: a new antifungal an-

tibiotic. J Antibiot 16:187–194.

629. Li XB, Qiao B, Yuan YJ. 2006. Differential analysis of secondary me-

tabolites by LC-MS following strain improvement of Streptomyces lydicus

AS 4.2501. Biotechnol Appl Biochem 45:107–118. http://dx.doi.org/10

.1042/BA20060042.

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 41Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

630. Darken MA, Berenson H, Shirk RJ, Sjolander NO. 1960. Production of

tetracycline by Streptomyces aureofaciens in synthetic media. Appl Micro-

biol 8:46–51.

631. Romero F, Espliego F, Perez Baz J, Garcia de Quesada T, Gravalos D,

de la Calle F, Fernandez-Puentes JL. 1997. Thiocoraline, a new depsi-

peptide with antitumor activity produced by a marine Micromonospora.

I. Taxonomy, fermentation, isolation, and biological activities. J Antibiot

50:734–737.

632. Brigham RB, Pittenger RC. 1956. Streptomyces orientalis, n. sp., the

source of vancomycin. Antibiot Chemother (Northﬁeld) 6:642–647.

633. Linke HA, Mechlinski W, Schaffner CP. 1974. Production of ampho-

tericin B-

CbyStreptomyces nodosus fermentation, and preparation of

the amphotericin B-

C-methyl-ester. J Antibiot 27:155–160. http://dx

.doi.org/10.7164/antibiotics.27.155.

634. Takeuchi S, Hirayama K, Ueda K, Sakai H, Yonehara H. 1958. Blas-

ticidin S, a new antibiotic. J Antibiot 11:1–5.

635. Acker RF, Lechevalier H. 1954. Some nutritional requirements of Strep-

tomyces griseus 3570 for growth and candicidin production. Appl Micro-

biol 2:152–157.

636. Hohmann C, Schneider K, Bruntner C, Irran E, Nicholson G, Bull AT,

Jones AL, Brown R, Stach JE, Goodfellow M, Beil W, Kramer M,

Imhoff JF, Sussmuth RD, Fiedler HP. 2009. Caboxamycin, a new

antibiotic of the benzoxazole family produced by the deep-sea strain

Streptomyces sp. NTK 937. J Antibiot 62:99–104. http://dx.doi.org/10

.1038/ja.2008.24.

637. Matsuoka M, Yagishita K, Umezawa H. 1953. Studies on the interme-

diate metabolism of chloramphenicol production. II. On the carbohy-

drate metabolism of Streptomyces venezuelae. Jpn J Med Sci Biol 6:161–

169.

638. Shih HD, Liu YC, Hsu FL, Mulabagal V, Dodda R, Huang JW. 2003.

Fungichromin: a substance from Streptomyces padanus with inhibitory

effects on Rhizoctonia solani. J Agric Food Chem 51:95–99. http://dx.doi

.org/10.1021/jf025879b.

639. Doull JL, Ayer SW, Singh AK, Thibault P. 1993. Production of a novel

polyketide antibiotic, jadomycin B, by Streptomyces venezuelae following

heat shock. J Antibiot 46:869 –871. http://dx.doi.org/10.7164/antibiotics

.46.869.

640. Hayashi Ki, Nozaki H. 1999. Kitamycins, new antimycin antibiotics

produced by Streptomyces sp. J Antibiot 52:325–328. http://dx.doi.org/10

.7164/antibiotics.52.325.

641. Struyk AP, Hoette I, Drost G, Waisvisz JM, van Eek T, Hoogerheide

JC. 1958. Pimaricin, a new antifungal antibiotic, p 878 –885. In Welch H,

Marti-Ibanez F (ed), Antibiotics annual 1957-1958. Medical Encylope-

dia, Inc., New York, NY.

642. Bormann C, Huhn W, Zahner H, Rathmann R, Hahn H, Konig WA.

1985. Metabolic products of microorganisms. 228. New nikkomycins

produced by mutants of Streptomyces tendae. J Antibiot 38:9–16.

643. Smith RM, Peterson WH, McCoy E. 1954. Oligomycin, a new antifun-

gal antibiotic. Antibiot Chemother (Northﬁeld) 4:962–970.

644. Hwang BK, Lim SW, Kim BS, Lee J Y, Moon SS. 2001. Isolation and in

vivo and in vitro antifungal activity of phenylacetic acid and sodium

phenylacetate from Streptomyces humidus. Appl Environ Microbiol 67:

3739–3745. http://dx.doi.org/10.1128/AEM.67.8.3739-3745.2001.

645. Zhang YL, Li S, Jiang DH, Kong LC, Zhang PH, Xu JD. 2013.

Antifungal activities of metabolites produced by a termite-associated

Streptomyces canus BYB02. J Agric Food Chem 61:1521–1524. http://dx

.doi.org/10.1021/jf305210u.

646. Hoshino Y, Mukai A, Yazawa K, Uno J, Ando A, Mikami Y, Fukai T,

Ishikawa J, Yamaguchi K. 2004. Transvalencin A, a thiazolidine zinc

complex antibiotic produced by a clinical isolate of Nocardia transvalen-

sis. II. Structure elucidation. J Antibiot 57:803– 807. http://dx.doi.org/10

.7164/antibiotics.57.803.

647. Iwasa T, Yamamoto H, Shibata M. 1970. Studies on validamycins, new

antibiotics. I. Streptomyces hygroscopicus var. limoneus nov. var., valida-

mycin-producing organism. J Antibiot 23:595–602.

648. Schmitzer PR, Graupner PR, Chapin EL, Fields SC, Gilbert JR, Gray

JA, Peacock CL, Gerwick BC. 2000. Ribofuranosyl triazolone: a natural

product herbicide with activity on adenylosuccinate synthetase following

phosphorylation. J Nat Prod 63:777–781. http://dx.doi.org/10.1021

/np990590i.

649. Omura S, Iwai Y, Takahashi Y, Sadakane N, Nakagawa A, Oiwa H,

Hasegawa Y, Ikai T. 1979. Herbimycin, a new antibiotic produced by a

strain of Streptomyces. J Antibiot 32:255–261. http://dx.doi.org/10.7164

/antibiotics.32.255.

650. Omura S, Crump A. 2004. The life and times of ivermectin: a success

story. Nat Rev Microbiol 2:984–989. http://dx.doi.org/10.1038

/nrmicro1048.

651. Box SJ, Cole M, Yeoman GH. 1973. Prasinons A and B: potent insecti-

cides from Streptomyces prasinus. Appl Microbiol 26:699–704.

652. Waldron C, Matsushima P, Rosteck PR, Jr, Broughton MC, Turner

J, Madduri K, Crawford KP, Merlo DJ, Baltz RH. 2001. Cloning and

analysis of the spinosad biosynthetic gene cluster of Saccharopolyspora spi-

nosa. Chem Biol 8:487–499. http://dx.doi.org/10.1016/S1074-5521(01)

00029-1.

653. Cerdeno AM, Bibb MJ, Challis GL. 2001. Analysis of the prodiginine

biosynthesis gene cluster of Streptomyces coelicolor A3(2): new mecha-

nisms for chain initiation and termination in modular multien-

zymes. Chem Biol 8:817–829. http://dx.doi.org/10.1016/S1074-5521

(01)00054-0.

654. Tomita F, Tamaoki T, Morimoto M, Fujimoto K. 1981. Trioxacarcins,

novel antitumor antibiotics. I. Producing organism, fermentation and

biological activities. J Antibiot 34:1519–1524.

655. Farmer PB, Suhadolnik RJ. 1972. Nucleoside antibiotics. Biosynthesis

of arabinofuranosyladenine by Streptomyces antibioticus. Biochemistry

11:911–916.

656. Aoyagi T, Yagisawa M, Kumagai M, Hamada M, Okami Y. 1971. An

enzyme inhibitor, panosialin, produced by Streptomyces. I. Biologi-

cal activity, isolation and characterization of panosialin. J Antibiot

24:860–869.

657. Igarashi Y, Trujillo ME, Martinez-Molina E, Yanase S, Miyanaga S,

Obata T, Sakurai H, Saiki I, Fujita T, Furumai T. 2007. Antitumor

anthraquinones from an endophytic actinomycete Micromonospora lu-

pini sp. nov. Bioorg Med Chem Lett 17:3702–3705. http://dx.doi.org/10

.1016/j.bmcl.2007.04.039.

658. Nemoto A, Hoshino Y, Yazawa K, Ando A, Mikami Y, Komaki H,

Tanaka Y, Grafe U. 2002. Asterobactin, a new siderophore group anti-

biotic from Nocardia asteroides. J Antibiot 55:593–597. http://dx.doi.org

/10.7164/antibiotics.55.593.

659. Vino S, Lokesh KR. 2008. Borrelidin: a promising anticancer agent from

Streptomyces species. Adv Biotech 6:22–26.

660. Charan RD, Schlingmann G, Janso J, Bernan V, Feng X, Carter GT.

2004. Diazepinomicin, a new antimicrobial alkaloid from a marine Mi-

cromonospora sp. J Nat Prod 67:1431–1433. http://dx.doi.org/10.1021

/np040042r.

661. Malet-Cascon L, Romero F, Espliego-Vazquez F, Gravalos D, Fernan-

dez-Puentes JL. 2003. IB-00208, a new cytotoxic polycyclic xanthone

produced by a marine-derived Actinomadura. I. Isolation of the strain,

taxonomy and biological activites. J Antibiot 56:219–225. http://dx.doi

.org/10.7164/antibiotics.56.219.

662. Kanoh K, Matsuo Y, Adachi K, Imagawa H, Nishizawa M, Shizuri Y.

2005. Mechercharmycins A and B, cytotoxic substances from marine-

derived Thermoactinomyces sp. YM3-251. J Antibiot 58:289–292. http:

//dx.doi.org/10.1038/ja.2005.36.

663. Williams PG, Buchanan GO, Feling RH, Kauffman CA, Jensen PR,

Fenical W. 2005. New cytotoxic salinosporamides from the marine Ac-

tinomycete Salinispora tropica. J Org Chem 70:6196 –6203. http://dx.doi

.org/10.1021/jo050511⫹.

664. Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla

C. 1969. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibi-

otic from S. peucetius var. caesius. Biotechnol Bioeng 11:1101–1110. http:

//dx.doi.org/10.1002/bit.260110607.

665. White RJ, Stroshane RM. 1984. Daunorubicin and adriamycin: prop-

erties, biosynthesis, and fermentation, p 569 –594. In Vandamme EJ (ed),

Biotechnology of industrial antibiotics, vol 22. Marcel Dekker, Inc., New

York, NY.

666. Perez Baz J, Canedo LM, Fernandez Puentes JL, Silva Elipe MV. 1997.

Thiocoraline, a novel depsipeptide with antitumor activity produced by a

marine Micromonospora. II. Physico-chemical properties and structure

determination. J Antibiot 50:738–741.

667. de Reijke TM, de Boer EC, Schamhart DH, Kurth KH. 1997. Immu-

nostimulation in the urinary bladder by local application of Nocardia

rubra cell wall skeleton preparation (Rubratin) for superﬁcial bladder

cancer immunotherapy: a phase I/II study. Urol Res 25:117–120. http:

//dx.doi.org/10.1007/BF01037926.

668. Blomgren H, Strender LE, Edsmyr F. 1980. Bestatin treatment and the

Barka et al.

42 mmbr.asm.org March 2016 Volume 80 Number 1Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

peripheral lymphocyte population in cancer patients. Recent Res Cancer

75:133–138. http://dx.doi.org/10.1007/978-3-642-81491-4_21.

669. Iwami M, Nakayama O, Terano H, Kohsaka M, Aoki H, Imanaka H.

1987. A new immunomodulator, FR-900494: taxonomy, fermentation,

isolation, and physico-chemical and biological characteristics. J Antibiot

40:612–622. http://dx.doi.org/10.7164/antibiotics.40.612.

670. Komaki H, Nemoto A, Tanaka Y, Takagi H, Yazawa K, Mikami Y,

Shigemori H, Kobayashi J, Ando A, Nagata Y. 1999. Brasilicardin A, a

new terpenoid antibiotic from pathogenic Nocardia brasiliensis: fermen-

tation, isolation and biological activity. J Antibiot 52:13–19. http://dx.doi

.org/10.7164/antibiotics.52.13.

671. Uyeda M, Mizukami M, Yokomizo K, Suzuki K. 2001. Pentalenolac-

tone I and hygromycin A, immunosuppressants produced by Streptomy-

ces ﬁlipinensis and Streptomyces hygroscopicus. Biosci Biotechnol

Biochem 65:1252–1254. http://dx.doi.org/10.1271/bbb.65.1252.

672. DeJong P. 1972. L-Asparaginase production by Streptomyces griseus.

Appl Microbiol 23:1163–1164.

673. Balagurunatha R, Radhakrishnon M, Somasumdarom ST. 2010. L-

Glutaminase producing Actinomycetes from marine sediments-selective

isolation, semiquantitative assay and characterization of potential strain.

Aust J Basic Appl Sci 4:698–705.

674. Chen Y, Krol J, Sterkin V, Fan W, Yan X, Huang W, Cino J, Julien

C. 1999. New process control strategy used in as rapamycin fermen-

tation. Process Biochem 34:383–389. http://dx.doi.org/10.1016

/S0032-9592(98)00108-3.

675. Fauth U, Zahner H, Muhlenfeld A, Achenbach H. 1986. Galbonolides

A and B: two non-glycosidic antifungal macrolides. J Antibiot 39:1760–

1764. http://dx.doi.org/10.7164/antibiotics.39.1760.

676. Göker M, Klenk H. 2013. Phylogeny-driven target selection for large-

scale genome-sequencing (and other) projects. Stand Genomic Sci

8:360–374. http://dx.doi.org/10.4056/sigs.3446951.

677. Meier-Kolthoff JP, Auch AF, Klenk HP, Goker M. 2013. Genome

sequence-based species delimitation with conﬁdence intervals and im-

proved distance functions. BMC Bioinformatics 14:60. http://dx.doi.org

/10.1186/1471-2105-14-60.

678. Meier-Kolthoff JP, Auch AF, Klenk HP, Göker M. 2013. Highly par-

allelized inference of large genome-based phylogenies. Concurrency

Comput Pract Experience 26:1715–1729. http://dx.doi.org/10.1002/cpe

.3112.

679. Letunic I, Bork P. 2011. Interactive Tree of Life v2: online annotation

and display of phylogenetic trees made easy. Nucleic Acids Res 39:W475–

W478. http://dx.doi.org/10.1093/nar/gkr201.

Essaid Ait Barka is a professor of Plant Physi-

ology at the University of Reims. He studied

Plant Biology at the Cady Ayad University in

Marrakesh (1988) and got his Ph.D. from Reims

University (1993), on the plant reaction to low

temperatures stress. As a postdoc at Laval Uni-

versity (Canada) and Penn State University

(USA), he worked as research professor at

NSAC (Nova Scotia, Canada). He is interested

in the interactions between plants and patho-

genic/nonpathogenic microorganisms, and his

current research is directed toward basic and applied aspects of using bene-

ﬁcial microorganisms as microbial inoculants to promote plant growth and

provide biological resistance against plant biotic and abiotic stresses. His

investigations aim to understand the molecular mechanisms of cross talk

between plant defense signal transduction pathways and beneﬁcial microor-

ganisms. He has many partnerships with the private and public sectors and is

coinventor of two patents in the ﬁeld of biocontrol.

Christophe Clément is a Professor at the Uni-

versity of Reims, France. He received his

Ph.D. in Plant Physiology from the University

of Reims, France, in 1994. He obtained the

head position of the lab in 2001. His research

is focused on the physio-molecular analysis of

plant responses to both biotic and abiotic

stresses.

Gilles P. van Wezel is a Professor of Molecular

Biotechnology, at the Institute of Biology at Le-

iden University. He studied biochemistry at the

Free University in Amsterdam (1987) and per-

formed his Ph.D. investigation in the group of

Leendert Bosch in Leiden (1994) on the control

of translational genes in Streptomyces. As a post-

doc (EU Human Capital Mobility) in the labo-

ratory of Mervyn Bibb at the John Innes Centre

in Norwich (United Kingdom), he worked on

the control of carbon metabolism in Streptomy-

ces, and the link between sugar utilization and antibiotic production is still a

major theme in his research. His current research focuses on the systems

biology of growth, cell division, and antibiotic production of Streptomyces.A

major application is the activation of silent biosynthetic gene clusters and

elucidation of novel molecules with bioactivity against multidrug-resistant

pathogens.

Biology of Actinobacteria

March 2016 Volume 80 Number 1 mmbr.asm.org 43Microbiology and Molecular Biology Reviews

on November 30, 2015 by guesthttp://mmbr.asm.org/Downloaded from

Oligomycin-producing Streptomyces sp. newly isolated from Swiss soils efficiently protect Arabidopsis thaliana against Botrytis cinerea

Article

Full-text available

Jun 2024

Botrytis cinerea is a necrotrophic phytopathogen able to attack more than 200 different plant species causing strong yield losses worldwide. Many synthetic fungicides have been developed to control this disease, resulting in the rise of fungicide-resistance B. cinerea strains. The aim of this study was to identify Streptomyces strains showing antagonistic activity against B. cinerea to contribute to plant protection in an environmentally friendly way. We isolated 15 Actinomycete strains from 9 different Swiss soils. The culture filtrates of three isolates showing antifungal activity inhibited spore germination and delayed mycelial growth of B. cinerea . Infection experiments showed that Arabidopsis thaliana plants were more resistant to this pathogen after leaf treatment with the Streptomyces filtrates. Bioassay-guided isolation of the active compounds revealed the presence of germicidins A and B as well as of oligomycins A, B, and E. While germicidins were mostly inactive, oligomycin B reduced the mycelial growth of B. cinerea significantly. Moreover, all three oligomycins inhibited this fungus’ spore germination, suggesting that these molecules might contribute to the Streptomyces ’s ability to protect plants against infection by the broad host-pathogen Botrytis cinerea . IMPORTANCE This study reports the isolation of new Streptomyces strains with strong plant-protective potential mediated by their production of specialized metabolites. Using the broad host range pathogenic fungus Botrytis cinerea , we demonstrate that the cell-free filtrate of selected Streptomyces isolates efficiently inhibits different developmental stages of the fungus, including mycelial growth and the epidemiologically relevant spore germination. Beyond in vitro experiments, the strains and their metabolites also efficiently protected plants against the disease caused by this pathogen. This work further identifies oligomycins as active compounds involved in the observed antifungal activity of the strains. This work shows that we can harness the natural ability of soil-borne microbes and of their metabolites to efficiently fight other microbes responsible for significant crop losses. This opens the way to the development of environmentally friendly health protection measures for crops of agronomical relevance, based on these newly isolated strains or their metabolic extracts containing oligomycins.

Probiotic potential of Streptomyceslevis strain HFM-2 isolated from human gut and its antibiofilm properties against pathogenic bacteria

Article

Full-text available

Jun 2024
BMC MICROBIOL

Background Antimicrobial resistance (AMR) is a serious worldwide public health concern that needs immediate action. Probiotics could be a promising alternative for fighting antibiotic resistance, displaying beneficial effects to the host by combating diseases, improving growth, and stimulating the host immune responses against infection. This study was conducted to evaluate the probiotic, antibacterial, and antibiofilm potential of Streptomyces levis strain HFM-2 isolated from the healthy human gut. Results In vitro antibacterial activity in the cell-free supernatant of S. levis strain HFM-2 was evaluated against different pathogens viz. K. pneumoniae sub sp. pneumoniae, S. aureus, B. subtilis, VRE, S. typhi, S. epidermidis, MRSA, V. cholerae, M. smegmatis, E. coli, P. aeruginosa and E. aerogenes. Further, the ethyl acetate extract from S. levis strain HFM-2 showed strong biofilm inhibition against S. typhi, K. pneumoniae sub sp. pneumoniae, P. aeruginosa and E. coli. Fluorescence microscopy was used to detect biofilm inhibition properties. MIC and MBC values of EtOAc extract were determined at 500 and 1000 µg/mL, respectively. Further, strain HFM-2 showed high tolerance in gastric juice, pancreatin, bile, and at low pH. It exhibited efficient adhesion properties, displaying auto-aggregation (97.0%), hydrophobicity (95.71%, 88.96%, and 81.15% for ethyl acetate, chloroform and xylene, respectively), and showed 89.75%, 86.53%, 83.06% and 76.13% co-aggregation with S. typhi, MRSA, S. pyogenes and E. coli, respectively after 60 min of incubation. The S. levis strain HFM-2 was susceptible to different antibiotics such as tetracycline, streptomycin, kanamycin, ciprofloxacin, erythromycin, linezolid, meropenem, amikacin, gentamycin, clindamycin, moxifloxacin and vancomycin, but resistant to ampicillin and penicillin G. Conclusion The study shows that S. levis strain HFM-2 has significant probiotic properties such as good viability in bile, gastric juice, pancreatin environment, and at low pH; proficient adhesion properties, and antibiotic susceptibility. Further, the EtOAc extract of Streptomyces levis strain HFM-2 has a potent antibiofilm and antibacterial activity against antibacterial-resistant clinical pathogens.

Report of Endophytes in Neem Tree of Bhopal

Article

Mar 2024

Roopali Jain Adarsh Lalit

Diversity and distribution of biosynthetic gene clusters in agricultural soil microbiomes

Article

Full-text available

Mar 2024

Bacterial secondary metabolites serve as an important source of molecules for drug discovery. They also play an important function in mediating the interactions of microbial producers with their living environment and surrounding organisms. However, little is known about the genetic novelty, distribution, and community-level impacts of soil bacterial biosynthetic potential on a large geographic scale. Here, we constructed the first catalog of 11,149 biosynthetic gene clusters (BGCs) from agricultural soils across China and unearthed hidden biosynthetic potential for new natural product discovery from the not-yet-cultivated soil bacteria. Notably, we revealed soil pH as the strongest environmental driver of BGC biogeography and predicted that soil acidification and global climate change could damage the biosynthetic potential of the soil microbiome. The co-occurrence network of bacterial genomes revealed two BGC-rich species, i.e., Nocardia niigatensis from Actinobacteriota and PSRF01 from Acidobacteriota, as the module hub and connector, respectively, indicating their keystone positions in the soil microbial communities. We also uncovered a dominant role of BGC-inferred biotic interactions over environmental drivers in structuring the soil microbiome. Overall, this study achieved novel insights into the BGC landscape in agricultural soils of China, substantially expanding our understanding of the diversity and novelty of bacterial secondary metabolism and the potential role of secondary metabolites in microbiota assembly. IMPORTANCE Bacterial secondary metabolites not only serve as the foundation for numerous therapeutics (e.g., antibiotics and anticancer drugs), but they also play critical ecological roles in mediating microbial interactions (e.g., competition and communication). However, our knowledge of bacterial secondary metabolism is limited to only a small fraction of cultured strains, thus restricting our comprehensive understanding of their diversity, novelty, and potential ecological roles in soil ecosystems. Here, we used culture-independent metagenomics to explore biosynthetic potentials in agricultural soils of China. Our analyses revealed a high degree of genetic diversity and novelty within biosynthetic gene clusters in agricultural soil environments, offering valuable insights for biochemists seeking to synthesize novel bioactive products. Furthermore, we uncovered the pivotal role of BGC-rich species in microbial communities and the significant relationship between BGC richness and microbial phylogenetic turnover. This information emphasizes the importance of biosynthetic potential in the assembly of microbial communities.

Analysis of microbial communities in solid and liquid pig manure during the fertilization process

Article

Full-text available

Jan 2024

Utilizing livestock manure as organic fertilizer in sustainable agriculture is crucial and should be developed through an appropriate manufacturing process. Solid–liquid separation contributes to reducing odor, managing nutrients in livestock excretions, and lowering the cost of transporting manure to arable soil. To investigate the impact of fermentation after solid–liquid separation, we examined the specific correlation between chemical properties and bacterial communities in solid–liquid manures before and after the fermentation process. In terms of chemical properties before fermentation, the levels of electrical conductivity, nitrogen, ammonium nitrogen (NH4⁺-N), potassium, sodium, and chloride were higher in the liquid sample than in the solid sample. However, the chemical components of the liquid sample decreased during fermentation, which could be attributed to the low organic matter content. Many chemical components increased in the solid samples during fermentation. Fifty-six bacterial species were significantly correlated with NH4⁺-N and phosphorus. Following fermentation, their abundance increased in the solid samples and decreased in the liquid samples, indicating the potential for NH4⁺-N release or phosphorus mineralization from organic matter. These results provide information regarding changes in nutrient and bacterial formation when applying the fermentation process after solid–liquid separation.

Soil prokaryotic characterization in response to natural moisture gradient in the temperate grassland ecosystems

Article

Full-text available

Nov 2023
J PLANT ECOL-UK

Soil moisture, which is an important factor affecting ecosystem function, can maintain microbial activity and ultimately change the microbial community by altering vegetation diversity and controlling the diffusion and transport of soil nutrients. To explore the effects of soil water content (SWC) on soil prokaryotic community, we established a study area covering a natural soil moisture gradient and subdivided it into high (HW, 4.80 ± 1.18%), medium (MW, 2.17 ± 0.09%) and low water contents (LW, 1.85 ± 0.14%) in the grassland ecosystem along the south shore of Hulun Lake in Inner Mongolia, China. Environmental factors were determined by field surveys and laboratory analyses. Soil prokaryotes were determined by high-throughput sequencing techniques. Vegetation characteristics and soil physicochemical properties had a significant effect on prokaryotic richness diversity, and SWC was the most important factor influencing prokaryotic richness diversity. In the MW, the number of differential prokaryotes was lowest, and prokaryotic microorganisms had the highest diversity and relative abundance at the phylum level, which may reflect less intrinsic variation and higher overall activity of the prokaryotic community in the MW. In addition, HW and LW had lower prokaryotic diversity and relative abundance at the phylum level, and phenotypic predictions for both groups indicated a more tolerant prokaryotic community. In summary, the prokaryotic community responded significantly to the natural moisture gradients in grassland ecosystems along the south shore of Hulun Lake, and both too high and too low soil moisture increased prokaryotic stress resistance.

Ecological relevance of flagellar motility in soil bacterial communities

Article

Full-text available

Apr 2024

Flagellar motility is a key bacterial trait as it allows bacteria to navigate their immediate surroundings. Not all bacteria are capable of flagellar motility, and the distribution of this trait, its ecological associations, and the life history strategies of flagellated taxa remain poorly characterized. We developed and validated a genome-based approach to infer the potential for flagellar motility across 12 bacterial phyla (26 192 genomes in total). The capacity for flagellar motility was associated with a higher prevalence of genes for carbohydrate metabolism and higher maximum potential growth rates, suggesting that flagellar motility is more prevalent in environments with higher carbon availability. To test this hypothesis, we applied a method to infer the prevalence of flagellar motility in whole bacterial communities from metagenomic data, and quantified the prevalence of flagellar motility across 4 independent field studies that each captured putative gradients in soil carbon availability (148 metagenomes). As expected, we observed a positive relationship between the prevalence of bacterial flagellar motility and soil carbon availability in all datasets. Since soil carbon availability is often correlated with other factors that could influence the prevalence of flagellar motility, we validated these observations using metagenomic data acquired from a soil incubation experiment where carbon availability was directly manipulated with glucose amendments. This confirmed that the prevalence of bacterial flagellar motility is consistently associated with soil carbon availability over other potential confounding factors. This work highlights the value of combining predictive genomic and metagenomic approaches to expand our understanding of microbial phenotypic traits and reveal their general environmental associations.

Long-term rice-duck farming promotes more complex and stable bacterial communities

Article

Full-text available

Feb 2024
J SOIL SEDIMENT

Purpose Many studies have been carried out on rice-duck ecosystems, but they have focused mainly on soil physicochemical properties, the water environment, and economic benefits. Therefore, in this study, we investigated changes in soil physicochemical properties, soil bacterial communities, and soil enzyme activities in response to rice-duck farming. Methods In this study, a 3-year soil microbial ecosystem study was carried out using three treatments—non-rice-duck farming (CK), short-term rice-duck farming (SRDF), and long-term rice-duck farming (LRDF)—with high-throughput sequencing and other advanced technological tools. Additionally, we comprehensively explored the ecological mechanism of the rice-duck mode affecting the construction of the soil bacterial community, which provided a scientific theoretical basis for the transformation and balance of soil nutrients under long-term rice-duck farming. Results Compared to short-term rice-duck farming, long-term rice-duck farming can significantly increase soil fertility, particularly, soil organic matter, available N, P, and K. This study showed that short-term rice-duck farming might promote soil catalase and alkaline phosphatase activities, but the increasing trend of enzyme activities slowed with increasing years of cultivation. Soil urease and invertase activities exhibited an increasing trend with increasing years of rice-duck farming. With higher community richness and diversity indices than those of the non-rice and rice-duck farming fields, the soil bacterial community in the cultivated layer of the paddy field under the rice-duck farming paradigm had a more complex composition. Conclusion In short-term rice-duck farming, the structure and makeup of the soil bacterial community were more dynamic, and as the number of years of cocropping increased, the community started to stabilize. The chemical characteristics of the soil significantly impact the organization of the bacterial community. The main elements influencing the composition of the bacterial community were available potassium and phosphorus, with available potassium significantly and negatively correlated with soil bacterial abundance and available phosphorus significantly and negatively correlated with soil bacterial diversity.

South African actinobacteria: A treasure trove of novel bioactive metabolites for drug discovery

Article

Full-text available

Jan 2024
S AFR J SCI

Although South Africa is known as one of the most biodiverse countries in the world, based on its unique plants and animals, microorganisms have received much less attention. Microorganisms in general and actinobacteria in particular are an underexplored source of new medicines. Recent studies have demonstrated the presence of diverse cultivable actinobacteria from various biomes. However, investigations of the natural product diversity associated with these microorganisms are lacking. We hereby present a review of natural products isolated from South African actinobacteria together with their biological activities. Many of these natural products are structurally novel and include compounds belonging to the following classes: anthraquinones, isoflavonoids, ketolides, macrolides, macrolactams, tripeptides and depsipeptides. They show a wide range of biological activities including antibacterial, antifungal, cytotoxic and antitumour activities.

Isolation of active compounds from Streptomyces sennicomposti GMY01 and cytotoxic activity on breast cancer cells line

Article

Jan 2024

The occurrence of resistance to anticancer and the emergence of serious side effects due to chemotherapy is one of the main problems in cancer treatment, including breast cancer. The need for effective anticancer with a specific target is urgently required. Streptomyces are widely known as the potential producers of new anticancer molecules. Previously reported that the methanol extract of Streptomyces sennicomposti GMY01 isolated from Krakal Coast, Gunungkidul had very strong cytotoxic activity against MCF-7 and T47D breast cancer cells with IC50 values of 0.6 and 1.3 μg/mL, respectively. The following study aimed to isolate and identify active compounds of the S. sennicomposti GMY01 and evaluate its cytotoxic activity. The study was started by re-culturing and re-fermented optimization of S. sennicomposti GMY01 in a larger volume, then the bacteria were extracted using methanol following the bioassay-guided isolation of the extract obtained. The active compounds obtained were then structurally determined using UV/Vis spectroscopy, Fourier Transform-Infrared (FT-IR), Liquid Chromatography-Mass Spectroscopy (LC-MS), ¹H NMR, and ¹³C NMR and analyzed for their cytotoxic activity using MTT assay on MCF-7 and normal Vero cells line. The results showed that the culture of the S. sennicomposti GMY01 using Starch Nitrate Broth (SNB) media yields the best results compared to other culture media. An active anticancer compound namely mannotriose was successfully isolated from the methanol extract with an IC50 value of 5.6 μg/mL and 687 μg/mL against the MCF-7 and Vero cells lines, respectively, indicating that this compound showed strong cytotoxic activity with high selectivity.

Streptomyces in Nature and Medicine: The Antibiotic Makers

Article

Feb 2007

David Alan Hopwood

This is an insider's account of 50 years of genetic studies of the soil-inhabiting microbes that produce most of the antibiotics used to treat infections, as well as anti-cancer, anti-parasitic and immunosuppressant drugs. The book begins by describing how these microbes - the actinomycetes - were discovered in the latter part of the nineteenth century, but remained a 'Cinderella' group until, in the 1940s, they shot to prominence with the discovery of streptomycin, the first effective treatment for tuberculosis and only the second antibiotic after penicillin to become a medical marvel. There followed a massive effort over several decades to find further treatments for infectious diseases and cancer, tempered by the rise of antibiotic resistance consequent on antibiotic misuse and over-use. The book goes on to describe the discovery of gene exchange in the actinomycetes in the context of the rise of microbial genetics in the mid-20th century, leading to determination of the complete DNA sequence of a model member of the group at the turn of the millennium. There follow chapters in which the intricate molecular machinery that adapts the organisms' metabolism and development to life in the soil, including antibiotic production, is illuminated by the DNA blueprint. Then comes an up-to-the minute account of the use of genetic engineering to make novel, hybrid antibiotics and a topical description of techniques to learn the roles of the thousands of genes in a genome sequence, throwing a powerful light on the biology of the organisms and their harnessing for increasing antibiotic prductivity. In the final chapter we return to the mycobacteria that cause tuberculosis and leprosy, the first actinomycetes to be discovered, and how methodology, in part derived from the study of the streptomycetes, is being applied to understand and control these still deadly pathogens.

Multicellular Development in Streptomyces

Chapter

Apr 2014

Clinical microbiology of coryneform bacteria.

Article

Jan 1997

Coryneform bacteria are aerobically growing, asporogenous, non-partially-acid-fast, gram-positive rods of irregular morphology. Within the last few years, there has been a massive increase in the number of publications related to all aspects of their clinical microbiology. Clinical microbiologists are often confronted with making identifications within this heterogeneous group as well as with considerations of the clinical significance of such isolates. This review provides comprehensive information on the identification of coryneform bacteria and outlines recent changes in taxonomy. The following genera are covered: Corynebacterium, Turicella, Arthrobacter, Brevibacterium, Dermabacter. Propionibacterium, Rothia, Exiguobacterium, Oerskovia, Cellulomonas, Sanguibacter, Microbacterium, Aureobacterium, "Corynebacterium aquaticum," Arcanobacterium, and Actinomyces. Case reports claiming disease associations of coryneform bacteria are critically reviewed. Minimal microbiological requirements for publications on disease associations of coryneform bacteria are proposed.

Epidemiology of infection by nontuberculous mycobacteria.

Article

Apr 1996

Joseph Falkinham

A Guide for the Classification of Streptomycetes According to Selected Groups. Placement of Strains in Morphological Sections1

Article

Jan 1958
Appl Microbiol

The medically important aerobic actinomycetes: epidemiology and microbiology.

Article

Jan 1994

Cell envelopes and classification

Article

Jan 1993

The vancomycin and ristocetin group of antibiotics

Article

Jan 1980

Nocardia species

Article

Jan 2000

Rhodococcus equi: an animal and human pathogen

Article

Jan 1991

John F Prescott

Recent isolations of Rhodococcus equi from cavitatory pulmonary disease in patients with AIDS have aroused interest among medical microbiologists in this unusual organism. Earlier isolations from humans had also been in immunosuppressed patients following hemolymphatic tumors or renal transplantation. This organism has been recognized for many years as a cause of a serious pyogranulomatous pneumonia of young foals and is occasionally isolated from granulomatous lesions in several other species, in some cases following immunosuppression. The last decade has seen many advances in understanding of the epidemiology, pathogenesis, diagnosis, treatment, and immunity to infection in foals. The particular susceptibility of the foal is not understood but can be explained in part by a combination of heavy challenge through the respiratory route coinciding with declining maternally derived antibody in the absence of fully competent foal cellular immune mechanisms. R. equi is largely a soil organism but is widespread in the feces of herbivores. Its growth in soil is considerably improved by simple nutrients it obtains from herbivore manure. About one-third of human patients who have developed R. equi infections had contact in some way with herbivores or their manure. Others may have acquired infection from contact with soil or wild bird manure. R. equi is an intracellular parasite, which explains the typical pyogranulomatous nature of R. equi infections, the predisposition to infection in human patients with defective cell-mediated immune mechanisms, and the efficacy of antimicrobial drugs that penetrate phagocytic cells.

Taxonomy, Physiology, and Natural Products of Actinobacteria

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