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Therapeutic agents from endophytes harbored in Asian medicinal plants

June 2020
Phytochemistry Reviews 19(3)

June 2020
19(3)

DOI:10.1007/s11101-020-09683-8

Authors:

Ayushi Sharma

Amity University

Harsha Kharkwal FRSC London

Amity University

Giriraj T Kulkarni

DIT University

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Endophytes are a diverse group of microorganisms present in plant tissues which include fungi and bacteria and have been utilized as therapeutic agents. They are known to produce different secondary and primary metabolites, which can be used in therapy of various diseases. The primary objective of this review is to provide an insight of symbiotic relationship between the endophytes and medicinal plants, specifically belonging to Asia, and also to give detailed information about the novel bioactive secondary metabolites produced from endophytes, that serve as potential therapeutic agents. We performed a Pubmed-based literature search and considered publications including research and review papers related to endophytes, the chemical constituents isolated from them and their therapeutic applications. Endophytes have a symbiotic relationship with the host medicinal plants. They provide specific advantages to plants such as nitrogen fixation. They also produce biologically active secondary metabolites such as alkaloids, flavonoids, terpenes/terpenoids, polyphenols, xanthenes, anthraquinones, cytochalasins, benzofurans, steroids, lignans, polysaccharides and plant growth hormones. Many of these compounds have therapeutic applications such as antimicrobial, antioxidant, anticancer, and anti-inflammatory. Endophytic microbes also constitute an important source for drug discovery. This review comprehends the use of endophytes as therapeutic agents.

Various mechanisms employed by bacterial endophytes in handling different conditions of environmental stress

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Contribution of different Asian countries to the biodiversity of endophytes isolated from medicinal plants

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Pharmacological activities of different endophytes produced by Asian medicinal plants

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Therapeutic agents from endophytes harbored in Asian

medicinal plants

Ayushi Sharma .Bhanu Malhotra .Harsha Kharkwal .Giriraj T. Kulkarni .

Nutan Kaushik

Received: 23 July 2019 / Accepted: 13 May 2020

ÓSpringer Nature B.V. 2020

Abstract Endophytes are a diverse group of

microorganisms present in plant tissues which include

fungi and bacteria and have been utilized as therapeu-

tic agents. They are known to produce different

secondary and primary metabolites, which can be used

in therapy of various diseases. The primary objective

of this review is to provide an insight of symbiotic

relationship between the endophytes and medicinal

plants, speciﬁcally belonging to Asia, and also to give

detailed information about the novel bioactive sec-

ondary metabolites produced from endophytes, that

serve as potential therapeutic agents. We performed a

Pubmed-based literature search and considered pub-

lications including research and review papers related

to endophytes, the chemical constituents isolated from

them and their therapeutic applications. Endophytes

have a symbiotic relationship with the host medicinal

plants. They provide speciﬁc advantages to plants such

as nitrogen ﬁxation. They also produce biologically

active secondary metabolites such as alkaloids,

ﬂavonoids, terpenes/terpenoids, polyphenols, xan-

thenes, anthraquinones, cytochalasins, benzofurans,

steroids, lignans, polysaccharides and plant growth

hormones. Many of these compounds have therapeutic

applications such as antimicrobial, antioxidant, anti-

cancer, and anti-inﬂammatory. Endophytic microbes

also constitute an important source for drug discovery.

This review comprehends the use of endophytes as

therapeutic agents.

Keywords Bacterial endophytes Fungal

endophytes Medicinal value of Asian plants 

Secondary metabolites Therapeutic agents

Introduction

Plants and their parts have been used as a source of

medicinal bioactive compounds against numerous

forms of ailments since time immemorial. The tradi-

tional medicinal systems of Asia, such as Ayurveda,

Siddha, Tibetan and Chinese systems have found and

used the therapeutic value of numerous plants for

curing diseases and healing injuries using natural

medicines widely distributed throughout the globe.

Momordica charantia L., known as Karela, is respon-

sible for suppression of blood sugar levels (Naik et al.

2003); Zingiber ofﬁcinale, commonly known as

A. Sharma N. Kaushik (&)

Amity Food and Agriculture Foundation, Amity

University Uttar Pradesh, Noida, Uttar Pradesh, India

e-mail: nkaushik5@amity.edu

B. Malhotra H. Kharkwal

Amity Institute of Phytomedicine and Phytochemistry,

Amity University Uttar Pradesh, Noida,

Uttar Pradesh, India

G. T. Kulkarni

Amity Institute of Pharmacy, Amity University Uttar

Pradesh, Noida, Uttar Pradesh, India

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Phytochem Rev

https://doi.org/10.1007/s11101-020-09683-8(0123456789().,-volV)(0123456789().,-volV)

Ginger, is used to prevent nausea and improve

digestion (Mascolo et al. 1989); Cinnamomum zey-

lanicum, known as Dalchini, is an antibacterial agent

(Ranasinghe et al. 2013). Not only plants but in recent

years, microorganisms associated with plants have

come out with products with high therapeutic poten-

tial. Endophytes are the endosymbiotic group of

microorganisms; mostly bacteria or fungi that colo-

nize the inter- and/or intracellular parts of plant tissues

(Butin 2000). Many plants harbor microbial endo-

phytes within their tissues without any symptoms of

infection; the symptomless interaction with microbes

is apparently non pathogenic to weakly or slightly

pathogenic depending upon the type of microbial

species. The presence of endophytes in plant tissues

has profound inﬂuence on the inclusive ﬁtness, their

interactions with pathogens, and the production of

bioactive compounds of pharmaceutical importance

(Maheshwari 2017; Rosenblueth and Martı

´nez-

Romero 2006). The most common examples of the

association of a microbe with a plant can be that of

nitrogen-ﬁxing bacteria in leguminous plants, or the

close association of fungi and plant in the form of

mycorrhizae. Endophytic microorganisms are diverse

groups associated with various tissues and organs of

terrestrial and aquatic plants; since their infections are

symptomless their isolation and identiﬁcation is done

by dissecting the plant tissue via laboratory analysis

(Franche et al. 2009; Burns and Hardy 2012; Hardoim

et al. 2008).

Medicinal plants are traditionally used worldwide

as remedies for the treatment of various diseases and

the composition of bioactive compounds produced by

these medicinal plants varies widely depending on the

plant species and their association with microbes.

Although, a vast majority of medicinal plants have

been well-studied with respect to their phytochemical

constituents and respective pharmacological proper-

ties, interactions between host and microbes remain

poorly understood (Ko

¨berl et al. 2013). Recently,

research on endophytic microorganisms has increased

due to their intimate interaction with the host species,

and it is believed that the phytochemical constituents

of plants are related directly or indirectly to the

interactions of endophytic organisms with their host.

Asia is a continent which harbors numerous medicinal

plants with potent biological activities. In fact, many

of the biological and therapeutic activities of these

plants are due the association with fungal or bacterial

endophytes. The present review highlights different

chemical classes of medicinally active compounds

obtained from different bacterial and fungal endo-

phytes reported in various Asian medicinal plants.

Endophytes

The endophytes harbored by plants include bacteria,

fungi, archaea, and even unicellular eukaryotes, such

as amoebae and algae (Van Der Heijden and Bardgett

2008; Correa and Flores 1995; Tremouillaux-Guiller

et al. 2002). These endophytic microorganisms play

crucial roles in growth, development, stress tolerance,

adaptation, and ﬁtness of plants. The ability of plant

endophytes to produce secondary plant metabolites

while being associated with the host plant was

discovered about two decades ago (Stierle et al.

1993; Lee et al. 1996). In the following years it has

become more and more evident that not only plants,

but also their pathogens or endophytes can contribute

to their patterns of secondary metabolites production.

The potential of endophytes to synthesize secondary

metabolites have contributed to various biotechnolog-

ical applications as they have the ability to survive

within their host plant for a long duration than

pathogens without harming the host plant (Mercado-

Blanco and Lugtenberg 2014). Endophytes are ubiq-

uitous, they interact complexly with their host plants

and sometimes they produce extremely unusual and

novel valuable organic substances that possess a

therapeutic value. Bacterial endophytes that reside in

the internal plant tissues have the capability to mimic

and produce the bioactive metabolites of the host

plant: novel secondary metabolites products, such as

terpenes, alkaloids, steroids, phenols, quinones, tan-

nins, and saponins that serve as antibacterial, antimi-

crobial, or anticancerous agents (Ludwig-Mu

¨ller

2015).

Some endophytes are known to increase nutrient

uptake and to enhance the growth of the host plant

(Santoyo et al. 2016). Endophytic plant growth

promoting bacteria can facilitate plant growth in

agriculture and horticulture following mechanisms

similar to those employed by rhizospheric plant

growth promoting bacteria (Santoyo et al. 2016).

The ability of bacterial endophytes to promote the

growth of their host plant can be either direct or

indirect. Direct promotion of growth occurs when a

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Phytochem Rev

bacterium increases the level of plant growth hor-

mones (auxin, cytokinin, or gibberelins) and facilitates

the acquisition of essential nutrients (such as N or P),

or indirectly, when the damage to host plants follow-

ing infection by certain pathogens is decreased,

basically through pathogen inhibition by plant growth

promoting bacterial endophytes (Smith et al. 2008).

Recent estimations suggest that Earth contains ca.

300,000 species of plants, most of which contain

endophytes (Santoyo et al. 2016). In fact, bacterial and

fungal endophytes have been found in every plant

species that has been examined. An endophyte-free

plant is a rare exception (Partida-Martı

´nez and Heil

2011). Research also suggests that plants without

endophytes are less capable to cope with pathogen and

environmental-related stress conditions (Malinowski

and Belesky 2000; Kuldau and Bacon 2008).Thus,

endophytes improve the plant’s ability to tolerate

various types of abiotic and biotic stresses, and

improve resistance of host plants to insects and

pathogens by producing phyto hormones and other

biologically active compounds (Tan and Zou 2001). A

typical example where there have been several studies

on the plant-endophyte relationship is that of grasses,

such as tall fescue, where it has been demonstrated that

their endophytes produce various toxins that discour-

age insects and the activity of grazing animals (Hill

1998). Endophyte-harboring grasses are often resistant

to attack by certain insects as compared to those

grasses which do not harbor endophytes (Rogerson

et al. 1997; Clay 1988). An annual grass species,

Lolium persicum, commonly known as Persian darnel,

a troublesome weed for wheat farmers has been

extensively studied as far as endophytes are concerned

(White and Cole 1985).

Endophytic diversity

Endophytes associated with plants can be either

prokaryotic or eukaryotic. Prokaryotic endophytes

include bacteria and archaea whereas eukaryotic

endophytes include fungi, algae, and amoeba. Bacte-

rial endophytes associated with plants are often

actinomycetes or mycoplasmas. However, a total of

16 different bacterial phyla have been reported as

endophytes, with most of species belonging to the

phyla Actinobacteria,Firmicutes, and Proteobacteria

(Golinska et al. 2015). The isolation and

characterization of plant endophytes using 16S rRNA

gene-based techniques has identiﬁed taxonomic

groups, like Clavibacter,Cellulomonas,Curtobac-

terium and Microbacterium (all of them Actinobacte-

ria)orPseudomonas (Proteobacteria), with

substantial colonizing potential (Elvira-Recuenco

and van Vuurde 2000).

Bacteria of the genus Actinomycetes belong to the

phylum Actinobacteria, which develop mycelia and

form spores. For these reason they had mistakenly

reported as transitional forms between the fungi and

bacteria in earlier days (Watson and Williams 1974),

although they are true bacteria. Actinobacteria are

typically Gram-positive, ﬁlamentous bacteria, widely

distributed in both terrestrial and aquatic ecosystems.

They are an important group of soil microbes with

high potential for producing different bioactive

metabolites, including antimicrobial and, anticancer-

ous compounds (Yu et al. 2010; Amna et al. 2006;

Kusari et al. 2009; Gangadevi and Muthumary 2008).

In fact, for years they have been the largest producer of

different antibiotics against many deadly microbial

diseases (Christina et al. 2013). Out of the total

number of bioactive metabolites produced by these,

45% are produced by actinobacteria alone and among

these, 76% of the compounds are reported from a

single genus, Streptomyces (Passari et al. 2018).

Prominent examples of bioactive compounds pro-

duced by Streptomyces include naphthomycins, cle-

thramycin, kakadumycins, munumbicins and others

(Sanglier et al. 1993). Kitasatospora sp., another

important member of this group, is associated with

Taxus baccata, and has been described as a paclitaxel

producer (Caruso et al. 2000).

Mycoplasmas (phylum Tenericutes) have also been

reported as plant endophytes. They are the smallest

group among self-replicating bacteria. Their genome

contains a minimum set of genes essential for growth

and replication including a cell membrane and full

translation machinery but, unlike other prokaryotes,

the mycoplasmas characteristic lack a cell wall

(Jalgaonwala et al. 2011; Gouda et al. 2016). The

existence of these endophytic mycoplasmal commu-

nities within Bryopsis algae was depicted and it was

found that the algae favoured the entry of certain

bacteria of possible ecological importance within its

cell, providing a conclusive evidence of macroalgal-

bacterial endobioses (Hollants et al. 2011).

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Phytochem Rev

Prokaryotic endophytes whose 16S rRNA gene

sequences are present in databases comprise members

of 23 recognized phyla, including 21 from Bacteria

and 2 from Archaea (Euryarchaeota and Thau-

marcheota) (Clarridge 2004). Archaeal endophytes

have been detected in rice, coffee cherries and maize

roots (Sun et al. 2007; Oliveira et al. 2013; Chelius and

Triplett 2001).

Eukaryotic endophytes mainly consist of fungi.

Fungi constitute a heterotrophic group of organisms

with a symbiotic relationship with a wide variety of

autotrophic organisms. Based on their phylogeny and

taxonomy, endophytic fungi are either clavicipita-

ceous (Class 1, which infect some grasses conﬁned to

cool regions), or the non-clavicipitaceous endophytes

(Classes 2, 3 and 4, which reside within tissues of non-

vascular plants, ferns and allies, conifers and angios-

perms particularly limited to the Ascomycota or

Basidiomycota) (Rodriguez et al. 2009). Important

examples of bioactives produced by fungal endo-

phytes include Penicillins from Penicillium sp. and

Taxol, a powerful anticancer drug from Taxomyces

andreanae (Slichenmyer and Von Hoff 1991). Some

relevant characteristics of bacterial and fungal

endophytes with respect to their host plants are

described in Table 1.

Plants can harbor very large numbers of fungal

endophytes. Brucea javanica (L.) Merr., a member of

Simaroubaceae family is used in traditional medicine

with a wide spectrum of biological effects like

anticancerous, antibabesial, antitrypanosomal, anti-

protozoan, antimalarial, and anti-inﬂammatory. This

plant was shown to harbor no less than 83 different

strains of fungal endophytes of the species Tricho-

derma,Fusarium,Penicillium, and Aspergillus.

Among these, Trichoderma sp. produced glycosides

which had potent antimutagenic and antioxidant

activities (Okuyama et al. 1990).

Host-endophyte interactions

The colonization by endophytes of host plants is

inﬂuenced by speciﬁc chemicals produced by host

plants that induce chemotaxis (Badri et al. 2009;

Bacilio-Jime

´nez et al. 2003). Through long-term co-

evolution of endophytes different types of secondary

metabolites are produced by the host plants as a

Table 1 Summary of interactions of bacterial and fungal endophytes with their host plants

Criteria Bacterial endophyte Fungal endophyte

Host

spectrum

Broad spectrum host infection Broad spectrum host infection usually depending upon

the habitat

Mode of

infection

Passive colonization through wounded plant cells or

tissues and actively via enzymes or using vectors

Mostly through stomata, cell walls, wounded tissue

Root growth Inter- and/or intra-cellular colonization with slow

growth and low densities

Inter- and/or intra-cellular colonization with extensive

growth

Tissue

colonized

Primarily intercellular tissues with growth also seen in

vascular tissue

Vascular tissues are mostly not colonized

Types of

interactions

with host

Commensalism, mutualism, pathogenic Mutalism, commensalism, pathogenic

Physiological

effect

Little information available A variety of active interactions and balanced antagonism

is observed

Source of

nutrition

Component of the symplast and apoplast, host exudates,

dead cortex cells, cellular debris

Component of the symplast and apoplast, storage

materials of spores and cellular debris

Specialized

structures

Nodule formation Mycorrhizae, nodules

Beneﬁts to

host cell

Growth promotion, N-ﬁxation, secretion of

phytohormones metabolites antagonistic to plant

pathogens and insects, synthesis of antibiotics and

useful compounds

Growth promotion via secretion of phytohormones,

improved access to mineral nutrients, combating

pathogen stress, synthesis of antibiotics and useful

compounds

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Phytochem Rev

resistance mechanism to pathogens. Hence, the host

secondary metabolites, which act as obstacles for the

colonization of endophytes, induce the secretion of

matching detoxiﬁcation enzymes such as cellulase,

lactase, xylanase, and protease, by the endophytes

(Khare et al. 2018; Jia et al. 2016).

Once the endophytes get entry into the tissues of the

host-plant, they can assume a quiescent (latent) state,

either for the whole lifetime of the host plant

(neutralism) or for an extended period of time

(mutualism or antagonism) until environmental con-

ditions are favourable for endophyte or the ontoge-

netic state of the host changes to the advantage of the

endophyte (Sieber 2007).

During the long period of co-existence and evolu-

tionary co-adaptation, endophytes can establish dif-

ferent types of relationships/interactions with the host

plants, which may be categorized as a continuum of

mutualism,antagonism,orneutralism. The factors

affecting on the population structure of the endophytes

are the genetic background, nutrient level, and

ecological habitats of the host plants. These factors,

in turn, confer some beneﬁts, such as the induced

growth, increased resistance to diseases, and accumu-

lation of bioactive compounds (Fira

´kova

´et al. 2007).

Hence, the mutual interaction between endophytes and

host plants can inﬂuence the formation of certain

bioactive compounds having medicinal properties,

which can be used by humans. In other words, the

presence of endophytes can enhance the medicinal

properties of the host plants.

Bacterial endophytes

Endophytic bacteria are so diverse that they have been

reported from every plant studied. Many of the

bacterial endophytes are also present in the rhizo-

sphere environment, which attracts microorganisms

because of the presence of rhizodeposits and root

exudates (Compant et al. 2010).

Bacterial endophytes possess an advantage over

bacteria inhabiting the rhizosphere, because they live

within plant tissues and are in direct contact with the

plant cells and hence can readily exert a direct

beneﬁcial effect rather than those present in the soil.

Indeed, bacterial populations of the rhizosphere also

have the potential to enter and colonize the plant roots.

In fact, endophytic bacterial diversity is known to

parallel that in the rhizosphere, which acts as a primary

source of endophytic colonization (Rosenblueth and

Martı

´nez-Romero 2006). The rhizosphere provides a

highly competitive environment for microorganisms

to occupy spaces and nutrients. For these reasons, only

Table 2 Overview of some of the popular Asian medicinal plants and their associated endophytes (Shahroorana et al. 2006)

Bacterial endophyte Host plant Family Activity Region

Penicillium fumicalsuri Azadirachta indica Meliaceae Antifungal India

Aspergillus niger Azadirachta indica Meliaceae Antifungal India

Fusarium oxysporium Curcuma longa Zingiberaceae Antifungal India

Bacillus subtilis Aloe vera Liliaceae Antibacterial India

Escherichia coli; Proteus

vulgaris

Curcuma longa Zingiberaceae Antibacterial India

Bacillus amyloliquefaciens Scutellaria.baicalensis Lamiaceae Broad-spectrum antibacterial and

antifungal activities

China

Staphylococcus aureus Azadirachta indica Meliaceae Antimicrobial activity India

Bacillus thuringiensis Andrographis

paniculata

Acanthaceae Anti-infective property India

Pseudonocardia sp. Artemisia annua Asteraceae Antimalarial compound artemisinin China

Pseudomonas sp. Zingiber ofﬁcinale Zingiberaceae Antimicrobial India

Pseudomonas viridiﬂava Lactuca sativa Asteraceae Antifungal China,

Taiwan

Streptomyces sp. GT

20021503

Bruguiera

gymnorrhiza

Rhizophoraceae Anti HIV Bangladesh

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Phytochem Rev

those organisms which highly competitive will pro-

liferate in this microenvironment and can execute a

direct effect on plant growth and development either is

potentially beneﬁcial or pathogenic in nature (Kandel

et al. 2017).

Bacterial endophytes employ different mechanisms

to gain entry into the plant tissues. Except for some

seed-endophytes, the most common access pathway

into the plant tissues is through primary and lateral

root cracks, and wounded plant tissues (Sprent and de

Faria 1988). Other sites through which endophytes

gain entry into host plants include stomata on leaves

and young stems; lenticels in the periderm of stems

and roots; and germinating radicles; sometimes also

through lateral roots or root hair cells (Baldani et al.

1983; Tarrand et al. 1978).

The growth of plants may be inhibited by a large

number of different biotic and abiotic factors which

cause environmental stress including temperature,

high light intensities, ﬂooding, drought, wounding,

radiation, predation, pathogens, nematodes, high salt

concentrations, and the presence of toxic compounds.

Recent molecular studies on endophytes have high-

lighted that they not only promote plant growth but

also suppress the activities of pathogens, help solubi-

lize phosphate and other nutrients, and contribute to

assimilate nitrogen for plants (Johnston-Monje and

Raizada 2011). When PGPB (Plant Growth Promoting

Bacteria) are present, they may employ different

strategies to combat environmental stresses as dis-

played in Fig. 1(Glick 2012).

Endophytes of Asian medicinal plants and their

bioactive compounds

Endophytes are a promising source of novel com-

pounds with potent biological activities some of which

are attributed to their host medicinal plants as shown in

Table 2. Antibiotics or hydrolytic enzymes can be

released by endophytes present in plants to prevent

colonization of microbial plant pathogens or to

prevent insect and nematode infection. Endophytes

can produce a variety of secondary metabolites also

produced by their hosts. For example, anticancer drug

camptothecin is a potential bioactive compound co-

produced by the plants as well as their associated

endophytes (Soujanya et al. 2017).

Endophytic actinobacteria associate with their host

at a very early stage of the plant development.

Maximum numbers of endophytic actinobacteria have

been recovered from roots followed by stems and least

in leaves (Golinska et al. 2015). However, some of

them are also able to enter through the stomata.

Woody plants offer greater diversity of actinobacteria

in comparison to herbaceous plants and, generally, the

association of actinobacteria in roots is most common,

as they are natural dwellers of soil that easily come in

contact with plant roots (Maheshwari 2017).

The co-production of bioactive compounds in some

cases evolves independently in plants and their

microbial counterparts while, in other cases, horizon-

tal gene transfers between the plant host and its

endophytes have long been hypothesized to explain

their contribution to the co-production of these

bioactive molecules. The pressing need for novel

chemical compounds targeting human diseases in

order to curb drug-resistant microbes in life-threaten-

ing infections has recently stimulated research on

novel bioactive compounds from endophytes present

in medicinal plants. As an example, Mukai et al.

(2009) used natural products targeting microbial

pathogens to treat drug resistant Mycobacterium

tuberculosis. Table 3summarizes reported therapeu-

tic effects of endophytes having Asian medicinal

plants as their hosts.

Nearly every Asian country grows and exploits a

variety of medicinal plants which provide great

substitutive remedy options. The presence of many

endophytes in Asian medicinal plants has been

reported. In the Indian state of Meghalaya, 705 fungal

endophytes have been isolated from 5 ethno-medicinal

plants customarily preserved in ‘‘sacred forests’’

(Bhagobaty and Joshi 2011). Monarda citriodora

plants collected from the Indian state of Jammu and

Kashmir have been shown to harbor 28 different

fungal endophytes with anticancer and antimicrobial

activities (Katoch et al. 2017). Different endophytes

isolated from medicinal plants of Asian countries

produce some effective bioactive compounds with

notable therapeutic activities. Some of them are

summarized in Table 4. Among these 50 endophytes

listed together with their bioactivity, India contributes

the maximum with 52%, followed by China (14%), Sri

Lanka (12%) and Thailand (6%), with minor contri-

butions from Soth Korea, Bangladesh, Japan and

Malaysia (Fig. 2). Most of the compounds found are

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Phytochem Rev

Table 3 Therapeutic activities of endophytes and their signiﬁcance in Asian medicinal plants

Medicinal

plant species

Endophyte

isolated

Type of

endophyte

Biological activity Compoud identiﬁed Country References

Acanthus

ilicifolius

Aspergillus ﬂavipes Fungi Cytochalasin Z17 (2) and rosellichalasin (8) showed cytotoxic activities

against A-549 cell lines

Cytochalasins India Taechowisan

et al. (2006)

Allium

ﬁstulosum

Streptomyces sp. Bacteria Antifungal activity, Streptomyces produces novobiocin as a major

metabolite having antimicrobial activity

Fistupyrone 70Demethylnovobioc

in, 500-demethylnovobioc in,

Novobiocin

Japan Maggini et al.

(2017)

Alpinia galanga Streptomyces

sp.Tc022

Bacteria Very strong antibacterial and antifungal activities Actinomycin D Thiland Sufaati (2016)

Alpinia

oxyphylla

Streptomyces sp.

YIM66017,

Bacteria Radical scavenging activity 2,6-dimethoxy terephthalic acid,

yangjinhualine a, a-

hydroxyacetovanil lone and

cyclo(gly-trp)

China Marrs and Watt

(2006)

Artemisia annua

Bacillus cereus Bacteria Antioxidant, preventing DNA damage Artemisinin China Roy et al.

(2015)

Aucuba

japonica

Streptomyces sp.

TP-A0556

Bacteria Antibiotic activity against Gram-positive and -negative bacteria TPU-0031-A and B novobiocins Japan Liu et al.

(2017)

Azadirachta

indica

Pestalotiopsis sp. Fungi Exhibited maximum radical scavengingactivity, antihypertensive,

antibacterial

NI India Li et al. (2017)

Berberis lycium Pseudomonas

putida

Bacteria Antimicrobial activity Heneicosane; Pyrrolo[1,2-a]

pyrazine-1,4-dione,1-

Pentadecene in ppbp25

Pakistan Sheoran et al.

(2015)

Bruguiera

gymnorrhiza

Streptomyces

albidoﬂavus

Bacteria Secondary metabolites produced by streptomyces bacteria which has

antifungal activity

Antimycin A18 China Igarashi (2004)

Catharanthus

roseus

Streptomyces

thermoviolaceus

NT1

Bacteria Antibacterial activity Granaticinic acid India Huang (2001)

Centella

asiatica

Bacillus subtilis Bacteria Antifungal by Inhibiting disease Incidence caused By the hemibiotrophic

fungus Colletotrichum higginsianum

NI India Zhou et al.

(2013)

Cistanches

deserticola

Penicillium

chrysogenum

Fungi Neurocyte protection effectagainst oxidative stress-induced cell death in

SH-SY5Ycells having activities in preventing and treating cranial nerve

diseases

Chrysogenamide A China Samaga and

Rai (2015)

Cryptomeria

japonica

Streptomyces sp.

TP-A0456

Bacteria Twonovel butyrolactone antibiotics, Cedarmycins A and B, having potent

antimicrobial activity

Cedarmycins Japan Phongpaichit

et al. (2006)

Echinacea

purpure a

Arthrobacter sp. Bacteria Alkylamides increase the TNF mrna expression in macrophages and

monocytes binding the cannabinoid CB2 receptor. It also decreases

mitogens-induce dinterleukin-2 secretion in Jurkat-T cells and show an

in vitro inhibitory activity of the enzymes lipoxygenase and the

cyclooxygenase

Alkylamides Russia Hasegawa et al.

(2006)

Ferulasongorica Arthobacter,

Rhodococcus

Bacteria Antifungal NI China Lin et al.

(2008)

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Phytochem Rev

Table 3 continued

Medicinal

plant species

Endophyte

isolated

Type of

endophyte

Biological activity Compoud identiﬁed Country References

Garcinia

atroviridi s

Botryosphaeria sp. Fungi Antimicrobial activity NI India Gangwar et al.

(2017)

Gymnema

sylvestre

Penicillium

oxalicum

Fungi Antidiabetic agent, endophytic fungi isolated from G. Sylvestre, produced

gymnemagenin

Gymnemagenin India Deshmukh

Sunil et al.

(2015)

Hypericum

japonic um

Entrophospora

infrequens

Fungi Antimicrobial and free radical scavenging activities and production of

anticancerous compound

Camptothecin India Lin et al.

(2010)

Maytenus

hookeri

Streptomyces sp. Bacteria Naphthomycin K showed evident cytotoxicity against P388 and A-549

cell lines

Naphthomycin K, A and E China Lu and Shen

(2007)

Maytenus

hookeri

Streptomyces sp. Bacteria Polyketides antifungal, antiparasitic, antitumor activities Sorbicillin and N-acetyltyramine China Zhao et al.

(2006)

Maytenus

hookeri

Alternaria alternata Fungi Antibacterial, antifungal Tricycloalternarene China Preveena and

Bhore (2013)

Nothapodytes

foetida

Neurospora sp. Fungi The presence of an anticancer compound camptothecin in this fungus as a

source of production of precursor anticancer drug molecule

Camptothecin India Rehman et al.

(2008)

Phaius

tankervilleae

Fusarium solani Fungi Antimalarial Quinine Indonesia Yan et al.

(2010)

Pteridium

aquilinum

Streptomyces

hygroscopicus TP

-A0451

Bacteria Macrolide antibiotic Clethramycin ﬁghts different types of bacterial

infections affecting the skin and respiratory system

Clethramycin China Singh et al.

(2012)

Ricinus

communis

Alternaria sp. Fungi Acetylcholinesterae (ache) inhibitor, potent insecticidal activity NI India Parthasarathy

and

Sathiyabama

(2014)

Taxus mairei Paecilomyces sp. Fungi Antitumor and antifungal activities NI China Sasaki et al.

(2001)

Tinosporacrispa Streptomyces

olivochromogenes

Bacteria Antidiabetic Alpha glucosidase inhibitor

compounds

Indones

Qiao et al.

(2007)

Tridax

procumbens

Linn.

Cronobacter

sakazakii,

Bacillus

methylotrophicus

Bacteria Treatment of wounds and injuries, antimicrobial activity; activity against

chloroquine-resistant P. falciparum (Dd2)

NI Malaysia Rakotoniriana

et al. (2012)

Withania

somnifera

Alternaria altern

ata

Fungi Antifungal NI India Tejesvi et al.

(2008)

Zingiber

ofﬁcinale

Streptomyces

aureofaciens

CMUAc130

Bacteria Antitumor activity 4-arylcoumarins Thiland Aiyama et al.

(1988)

NI not identiﬁed

123

Phytochem Rev

Table 4 Endophytes isolated from Asian medicinal plants with their therapeutic activities and compounds

Endophyte Host plant Therapeutic activity Compound Place References

Phialemonium

curvatum

Passiﬂora edulis Antifungal; anti-oxidant;

brine shrimp lethality

3-Indole acetic acid; solaniol;

uridine

Sri Lanka Rathnayake

et al. (2018)

Teratosphaeria sp. Pinus clausa Cytotoxicity Teratosphaerone A;

monosporascone

Sri Lanka Padumadasa

et al. (2018)

Fusarium

decemcellulare

Flacourtiainermis Anticoagulant;

antithrombiotics

Shikimic acid Sri Lanka Qader et al.

(2018)

Bipolaris

sorokiniana

Costus speciosus Toxicity against brine

shrimps

Helminthosporal acid and

helminthosporol

Sri Lanka Qader et al.

(2017)

Fusarium sp.;

Aspergillus niger

Opuntia dillenii Antibacterial Equisetin Sri Lanka Ratnaweera

et al. (2015)

Aspergillus

awamori

Musa acuminata Brine shrimp toxicity;

antibiotic

4-Methoxybenzyl

7-phenylacetamido-3-vinyl-

3-cephem-4-carboxylate

Sri Lanka Bandara et al.

(2015)

Lasiodiplodia

theobromae

Morinda citrifolia Cytotoxicity against

human breast cancer

Taxol India Pandi et al.

(2011)

Alternaria

macrospora

Berberis aristata

Antibacterial activity;

antioxidant

Compound not reported India Sharma et al.

(2018a,b)

Alternaria

alternata

Azadirachta

indica

Antimicrobial Dichloronitromethane India Chatterjee

et al. (2019)

Rosellinia sanctae-

cruciana

Albizia lebbeck Cytototoxicity Jammosporin A India Sharma et al.

(2018a,b)

Streptomyces

parvulus

Abutilon indicum Antibiotic Actinomycin D, actinomycin

X0band fengycin

India Chandrakar

and Gupta

(2019)

Penicillium

canescens

Polygonum

chinense

Antioxidative and DNA

protective capacities;

antimicrobial

Germacrene; phthalic acid

ester; quercetin

India Das et al.

(2018)

Colletotrichum

gloeosporioides

Centella asiatica Anti-inﬂammation;speed

wound healing;

stimulate new cell

growth

Asiaticoside India Gupta et al.

(2018)

Colletotrichum sp. Tinospora

cordifolia

Active against

hyperuricemia

Allopurinol India Kapoor and

Saxena

(2018)

Penicillium

citrinum

Tragia

involucrata

Cytotoxic activity against

cancer cells

Phenolic and ﬂavonoid

content

India (Danagoudar

et al. 2018)

Cochliobolus sp. Aerva lanata Antioxidant; antidiabetic

and anti-inﬂammatory

Phenolic and ﬂavonoid

content

India Shoba and

Mythili

(2017)

Bacillus

thuringiensis

Picrorhiza kurroa Antimicrobial-effective

against several human

pathogens

Bacitracin; Gramicidin S;

Polymyxin

India Raina et al.

(2018)

Paraconiothyrium

sp.

Zingiber

ofﬁcinale

Antimicrobial activity Dantron India Anisha et al.

(2018)

Ascomycetes Mimosops elengi Antiinﬂammatory and

anticancer activities;

cytotoxicity

Ergoﬂavin India Deshmukh

et al. (2009)

Nigrospora oryzae Nyctanthes

arbor-tristis

Inhibition against

Salmonella paratyphi,a

causal agent of typhoid

fever in humans

Antibiotic like ciproﬂoxacin India Gond et al.

(2012)

123

Phytochem Rev

Table 4 continued

Endophyte Host plant Therapeutic activity Compound Place References

Fusarium

oxysporum

Juniperus

recurva

Precursor for the

chemical synthesis of

the anticancer drugs

like etoposide,

teniposide and

etopophose phosphate

Podophyllotoxin India Kour et al.

(2008)

Pestalotiopsis

species

Terminalia

arjuna

Antioxidant and anti-

hypertensive activity

Compound not reported India Tejesvi et al.

(2008)

Aspergillus terreus Achyranthes

aspera

Anticancer activity Terrein India Goutam et al.

(2017)

Enterobacter sp. Sida cordifolia Antibacterial activity

against Klebsiella

pneumonia,Escherichia

coli and Salmonella

typhi and

Immunomodulatory

Compound not reported India Rajan et al.

(2016)

Aspergillus

fumigatus

Justicia beddomei Cytotoxicity to cancer

cell line

Alkaloids; anthraquinones;

ﬂavonoids; phenols

India Prabavathy

and

Nachiyar

(2014)

Trichoderma lixii Bacopa monnieri Antifungal activity

against Candida

albicans

Tribacopin AV India (Katoch et al.

2019)

Chaetomium

arcuatum

Semecarpus

anacardium

Cytotoxicity Eugenetin and

6-hydroxymethyleugenin

India Kumar et al.

(2017)

Ralstonia sp. Aloe vera Antimicrobial activity

Pseudomonas

aeruginosa,

Staphylococcus aureus,

and Escherichia coli

Compound not reported India Sinha et al.

(2015)

Aspergillus ﬂavus Aegle marmelos Antimicrobial activity

against common human

bacterial and fungal

pathogens

Bioﬂavonoid rutin India Patil et al.

(2015)

Colletotrichum

gloeosporioides

Justicia

gendarussa

Anticancer Taxol India Gangadevi

and

Muthumary

(2008)

Aspergillus

ﬂocculus

Markhamia

platycalyx

Antimicrobial;

Anticancer; anti-

trypanosomal

cis-4-hydroxymellein,

5-hydroxymellein, diorcinol,

botryoisocoumarin A and

mullein

South

Korea

Tawﬁke et al.

(2019)

Bacillus

amyloliquefaciens

Oryza sativa Cytotoxic (S)-2-hydroxy-N-((S)-1-((S)-

8-hydroxy-1-

oxoisochroman-3-yl)-3-

methylbutyl)-2-((S)-5-oxo-

2,5-dihydrofuran-2-

yl)acetamide

South

Korea

Shahzad et al.

(2018)

Colletotrichum

gloeosporioides

Huperzia serrata Treatment of Alzheimer’s

disease

Huperzine A China Shu et al.

(2014)

Eupenicillium sp. Erythronium

japonicum

Decne

Inhibitory effects on the

proliferation of breast

cancer cells;

cytotoxicity

Geodin; 30-chlorotrypacidin China Lu et al.

(2016)

123

Phytochem Rev

Table 4 continued

Endophyte Host plant Therapeutic activity Compound Place References

Xylaria sp. Ginkgo biloba L Antibacterial and

antifungal activities

in vitro against

Staphylococcus aureus

7-Amino-4-methylcoumarin China Liu et al.

(2008)

Aspergillus tamarii Ficuscarica Antimicrobial activities

against Bacillus subtilis,

Staphylococcus aureus,

Pseudomonas

aeruginosa,

Escherichia coli,

Penicillium

chrysogenum,Candida

albicans

Malformin E China Ma et al.

(2016)

Fusarium Dysosma

versipellis

Antimicrobial or

anticancer activity

Podophyllotoxin China Tan et al.

(2018)

Penicillium sp.,

Aspergillus sp.

Ginkgo biloba Antidepressant;

neuroprotective;

antioxidant, anti-

inﬂammatory

5-Hydroxy-2-[(2S, 3R, 4S, 5S,

6-R)-3,4,5-trihydroxy-6-

(hydroxymethyl) oxan-2-yl]

oxybenzoate. Bilobalide

China Fei et al.

(2016)

Colletotrichum,

Fusarium,Phoma

and Penicillium

Pereskia bleo Anticancer Asparaginase China Chow

et al.(2015)

Alternaria sp. Erythrina

variegata

Antiangiogenic activity Altersolanol Thailand Pompeng

et al. (2013)

Fusarium

oxysporum

Dendrobium

lindleyi

Antimutagenic Gibepyrone A, pyrrolo [1,2-a]

pyrazine-1,4-dione;

Hexahydro-3-(2-

methylpropyl)

Thailand Bungtongdee

et al. (2019)

Micromonospora Maklamphueak Antimicrobial activity

against Gram-positive

bacteria

Maklamicin Thailand Igarashi et al.

(2011)

Aspergillus sp. Swietenia

macrophylla

Antimicrobial activity

against human

pathogens

2-(2,4,5-

trichlorophenoxy)propanoic

acid

Malaysia Leong et al.

(2018)

Fusarium solani Cassia alata Cytotoxicity against

Brine Shrimp;

antimicrobial and

antioxidant activity

Napthaquinones and Aza-

anthraquinones

Bangladesh Khan et al.

(2018)

Fusarium sp. Maackia

chinensis

Antimicrobial activity

against Pseudomonas

aeruginosa and

Staphylococcus aureus

Fusapyridons A Japan Tsuchinari

et al. (2007)

Pestalotiopsis

microspora

Artocarpus

heterophyllus

Cytotoxicity against

murine leukemia

(6S,7S,8R)-hydroxypestalotin Indonesia Riga et al.

(2019)

Trichoderma

koningiopsis,

Aspergillus

sydowii and

Trichoderma lixii

Sonneratia alba Antimicrobial and

cytotoxic activities

Compound not reported Indonesia Handayani

et al. (2018)

Lecythophora sp. Alyxia

reinwardtii

Antifungal activity

against strains of

Aspergillus fumigatus

and Candida kruzei

Lecythomycin; 23-methyl-3-

(1-O-mannosyl)-

oxacyclotetracosan-1-one

Indonesia Sugijanto

et al. (2011)

123

Phytochem Rev

effective antimicrobials (46%) followed by those with

anticancer activity (40%) (Fig. 3). The fungus Col-

letotrichum gloeosporioides, isolated from the medic-

inal plant Huperzia serrata native to China, is

responsible for an effective treatment of Alzheimer’s

disease due to the production of Huperzine A.

Endophytes of Asian medicinal plants are a great

source of anticancer compounds with pharmaceutical

value, such as Jammosporin A, Podophyllotoxin and

Taxol (Table 4). Taxol is a notable diterpenoid, orig-

inally isolated from the Paciﬁc yew tree Taxus

brevifolia. It has shown a promising activity against

breast cancer. Endophyte-based taxol production

would be covetable alternative source for such phar-

maceutical product at a reduced cost (Caruso et al.

2000). Terrein, a compound with antimicrobial and

anti-tumor activity was recently obtained from an

endophytic Aspergillus terreus isolated from the

Indian medicinal plant Achyranthes aspera (Goutam

et al. 2017). Brefeldin A, a lactone antiviral was

isolated from an endophytic Penicillium sp. isolated

from Panax notoginseng native to China. Its anti-

cancer and antiviral activities have been reported (Xie

et al. 2017). Similarly, another compound, Versi-

coumarin A, with cytotoxic activity against human

tumor cells, was obtained from Aspergillus versicolor

isolated from Paris marmorata used in traditional

Chinese medicine (Yan et al. 2016). Two novel

cytochalasans, namely Phomopchalasins A and B

with anticancer and anti-inﬂammatory potential have

been isolated from an endophytic Phomopsis sp.

fungus from Isodon eriocalyx, native to China

(Kapoor and Saxena 2018). Isolation of Allopurinol,

a well known medication initially sold under the brand

name Zyloprim, with activity against hyperuricemia,

has been reported from a Colletotrichum sp. endo-

phyte isolated from Tinospora cordifolia (Kapoor and

Saxena 2018). Other endophytes from Asian medic-

inal plants have been reported to produce functional

anti-inﬂammatory compounds, such as Asiaticoside

and Ergoﬂavin (Table 4).

Bioactive compounds from endophytes

The bacterial and fungal endophytes of different

medicinal plants produce a variety of biologically/

therapeutically active compounds. Some important

classes of bioactive compounds obtained from endo-

phytes of Asian medicinal plants are enlisted in

Table 5 Classes of bioactive compounds isolated from endophytes of Asian medicinal plants

Chemical class Examples

Alkaloids Taxol, camptothecin, vincristine, nodulisporic acid

Flavonoids and ﬂavonols Kaempferol

Terpenes and terpenoids Elemene, subglutinol A and B, phomoarcherin A, B and C, gibberellic acid

Anthraquinones 1,4-Dihydroxyanthraquinone, emodin, aloe-emodin, rhein

Polyphenols Curcumin

Xanthenes Ergoﬂavin

Cytochalasins Cytochalasin H, J and E

Benzofurans Pestacin, isopestacin

Steroids Beta sitosterol

Polysaccharides Mycelial polysaccharide

Antimicrobials Nocardithiocin, javanicin, cryptocandin

Lignans Podophyllotoxin

Alkyl salicylic acids Salaceyin A and B

Carboxylic acids Cinnamic acid

123

Phytochem Rev

Table 5. The structures of some of the important

compounds are given in Fig. 4.

Many alkaloids have been reported from endo-

phytes. Taxol (1), a potent anticancerous drug pro-

duced by Paciﬁc yew is also produced by an

endophytic fungus Bartalinia robillardoides Tassi,

isolated from a medicinal plant, Aegle marmelos

Correa ex Roxb (Gangadevi et al. 2007)Kitasatospora

sp., another endophyte associated with Taxus baccata,

and has been described as a paclitaxel producer

(Caruso et al. 2000).

Another alkaloid, Camptothecin (2), a potent anti-

neoplastic agent, has been reported from the endo-

phyte Entrophospora infrequens found inhabiting

Nothapodytes foetida. This compound has been shown

to exhibit signiﬁcant in vitro cytotoxicity against

different human cancer cell lines (A-549 for lung

cancer, HEP-2 for liver cancer, OVCAR-5 for ovarian

cancer) (Puri et al. 2005). The well-known anticancer

alkaloid Vincristine (3), has been isolated from

endophytic mycelia sterilia inhabiting Catharanthus

roseus (Yang et al. 2004).

Many biologically active ﬂavonoids, terpenoids

and polyphenolics have been reported from endo-

phytes. Secondary metabolites of an active endophytic

fungus from the roots of Curcuma wenyujin were

isolated and identiﬁed as curcumin (17), 1,4-dihy-

droxyanthraquinone (13), cinnamic acid (30), gib-

berellic acid (12), and kaempferol (5). Elemene (6), a

sesquiterpene, exerts anti-cancerous effects on brain,

lung, breast, colon, prostate, cervical, laryngeal, and

ovarian carcinomas by blocking the cell cycle pro-

gression and modulating the G2 cell cycle checkpoint.

It was found among the metabolites produced by the

endophytic fungi, Penicillium frequentans (EF03) and

P.baarnense (EF11), which were isolated from

Curcuma zedoaria (Yan et al. 2014; Eun et al.

2010). Nodulisporic acid (4), a novel indole diterpene,

has been isolated from Nodulisporium sp., an endo-

phyte from Bontia daphnoides. It is an insecticidal

agent, which works by activating glutamate-gated

chloride channels (Demain 2000). Phomopsis archeri,

an endophytic fungus from Vanilla albindia has been

reported to produce phomoarcherins A–C (9–11),

aromatic sesquiterpenes with antimalarial activity

Plant growth promoting bacteria in

environmental stress

ACC (1-Aminocyclopropane-

1-Carboxylate) Deaminase

Indole-3-acetic acid

synthesis

Anti freeze proteins

Trehalose

Production of stress hormone

Ethylene

Enterobacter sp. NBRI K28

Auxin further promotes transcription

of ACC synthase gene leading to

ethylene production

Pseudomonas fluorescens biotype G

(N3)

Cause ice nucleation in chilling stress

Sphingomonas spp.

Activity against draoght, salinity,

extreme temprature conditions

Pseudomonas sp. AKM-P6 tolerance

of sorghum and wheat seedlings to

high temperature stress

Fig. 1 Various mechanisms employed by bacterial endophytes in handling different conditions of environmental stress

123

Phytochem Rev

against Plasmodium falciparum (Hemtasin et al.

2011).

Rheum palmatum L., a very popular Chinese

rhubarb, is a medicinal plant with important con-

stituents like anthraquinones, including emodin (14),

aloe-emodin (15), rhein (16), etc. Rhein naturally

occurs in anthraquinone fraction in this plant and

possesses potent antitumor, anticancerous, anti-in-

ﬂammatory, antimicrobial properties. A total of 14

strains of rhein-producing endophytic fungi isolated

from R.palmatum were classiﬁed as Fusarium solani

by using rDNA sequencing and spore morphology

techniques (You et al. 2013).

A Xanthene, Ergoﬂavin (18), was isolated from the

leaf endophytes of Mimusops elengi, an Indian

medicinal plant (Family Sapotaceae). Ergoﬂavin is a

dimeric xanthene linked at position-2, belonging to the

ergochrome class of compounds with reported anti-

cancer activity (Deshmukh et al. 2009). Secalonic acid

D, another compound belonging to the ergochrome

class and a mytocoxin, has been isolated from a

mangrove endophytic fungus. This compound has

exhibited cytotoxicity against HL60 and K562 cells

(Zhang et al. 2009).

Wagenaar et al. (2000) have reported three novel

cytochalasins (19–21)—cytochalasin H, cytochalasin

J and cytochalasin E—from Rhinocladiella sp. inhab-

iting Tripterygium wilfordii (Wagenaar et al. 2000).

These compounds have been reported to exhibit

antitumor activity.

Benzofurans are another important class of com-

pounds with reported antioxidant properties. Pestacin

(22) and isopestacin (23) have been reported from

Pestalotiopsis microspore, residing in Terminalia

morobensis. Pestacin acts by cleaving reactive C–H

bonds (Harper et al. 2003), whereas, isopestacin

scavenges superoxide and hydroxyl free radicals

(Strobel et al. 2002). Another isobenzofuranone

derivative, 4,6-dihydroxy-5-methoxy-7-methylph-

thalide, with potent antioxidant properties, has been

obtained from Cephalosporium sp. AL031, which is

an endophyte from Sinarundinaria nitida (Huang et al.

2012).

Endophytes from different medicinal plants have

been reported to produce many novel antibacterial and

antifungal agents (Wang et al. 2012; Silva et al. 2010).

Beta sitosterol (24), an important steroidal molecule,

has been reported from Phoma sp., which is endo-

phytic in Arisaema erubescens. This compound

exhibited antifungal and antibacterial activity against

many pathogenic fungi and plant pathogenic bacteria

(Hussain et al. 2015).

Javanicin (27), an antibacterial naphthaquinone,

active against Pseudomonas sp. was isolated from

Chloridium sp., which is an endophyte of Neem

(Azadirachta indica) (Kharwar et al. 2008). Another

antifungal agent, cryptocandin (28), was obtained

from endophytic Cryptosporiopsis cf. quercina, and

exhibited antifungal activity against Candida albicans

and Trichophytonrubrum (Strobel et al. 1999).

Nocardia pseudobrasiliensis produced a compound

called Nocardithiocin (26) active against Mycobac-

terium tuberculosis H37Rv (Mukai et al. 2009). The

actinomycetes, especially from the genus Strepto-

myces, are valuable and provide over two-thirds of the

antibiotics and bioactive compounds used for treating

diseases. Streptomyces sp. collected from Allium

ﬁstulosum suppresses infection of Alternaria brassi-

cicola on Chinese cabbage seedlings. Kakadumycins

are novel antibiotics obtained from Streptomyces sp.

NRRL 30566, an endophyte organism of Grevillea

pteridifolia (Castillo et al. 2003). The fungal endo-

phytes Penicillium griseofulvum,Purpureocillium

lilacinum,Aspergillus oryzae,Periconia sp., and

Fusarium sp., isolated from Tephrosia purpurea, have

been used as biocontrol agents against plant fungal

pathogenic strains. This plant is already known for its

activity in treating hepatitis, but recent studies have

reported it to possess additional bioactivities, such as

antimicrobial, anti-inﬂammatory, anticancer, and anti-

ulcer activities (Luo et al. 2015).

Fig. 2 Contribution of different Asian countries to the biodi-

versity of endophytes isolated from medicinal plants

123

Phytochem Rev

In other cases, the endophyte produces elicitors that

affect production of bioactive compounds by the plant

host. This has been shown for the endophyte Fusarium

oxysporium Dzf17, isolated from the rhizomes of

Dioscorea zingiberensis. Polysaccharide elicitors

from the fungus were shown to alter growth and

diosgenin production by the host plant. Li et al. (2011)

studied the effects of time of addition and polysac-

charide concentration on the plant, and found the

water-extracted mycelial polysaccharide (WPS) to be

the most effective polysaccharide.

Podophyllotoxin (25) and other related aryl tetralin

lignans with potential anticancer activity have been

reported from the endophytic phytopathogenic fungus

Trametes hirsute (Puri et al. 2006). Cytotoxic activity

of 6-alkalysalicilic acids, salaceyins A (29a) and

B (29b) from the endophyte bacterium Streptomyces

laceyi MS53 isolated from Ricinus communis in Korea

was demonstrated against human breast cancer cell

line SKBR3, with IC50 values of 3.0 and 5.5 mg ml

-1

(Kim et al. 2006).

Three immunomodulatory compounds, named as

BS, GS, and YS, have been isolated from Pestalo-

tiopsis leucothe¨s, an endophytic fungus from the

Chinese medicinal plant Tripterygium wilfordiia.BS

inhibited the production of cytokines such as IL-2,

interferon (IFN)-c, interleukin (IL)-1b, and tumor

necrosis factor (TNF)-a, by peripheral blood mononu-

clear cells (PBMNC), and of soluble IL-2 receptor

expression, also a T cell speciﬁc immunosuppressant.

BS also moderately inhibited immunoglobulin (Ig) G

and M. In contrast, GS exhibited both suppression and

enhancement of PBMNC proliferation in the presence

of stimulants, and YS was found to be 10% less active

than BS in all assay systems (Kumar et al. 2005). Sim-

ilarly, subglutinol A and B (7–8), immunomodulatory

compounds have been isolated from Fusarium subg-

lutinans, an inhabitant of Tripterygium wilfordiia

(Strobel and Daisy 2003). Free radicals scavenging

bioactive components were produced by endophytic

fungi isolated from leaves, stems, roots and branches

of Ligustrum lucidum, where over 101 strains were

found (Yoshinaga and Kameyama 2001).

The endophytes associated with medicinal plants

may also provide greater insight into the plant-

endophyte interaction and evolution of mutualism

and symbiotic relationships. The mechanism that

enables these microbes to interact with their host

plants provides isolation of various compounds of

biotechnological importance. Several aspects such as,

Fig. 3 Pharmacological activities of different endophytes produced by Asian medicinal plants

123

Phytochem Rev

the combination of metabolic pathways of plants and

endophytes that are responsible for the bioactivity,

similarity/variability of genetic control for synthesis

of secondary metabolites between host plant and

endophytes, are still not clear. In order to address these

aspects, it is necessary to understand the physiology

and biochemistry of endophytic organisms for their

roles in secondary metabolite production. Clearly,

more research on the development of novel technolo-

gies and methodologies is needed for using them in the

medical, pharmaceutical, and agricultural ﬁelds.

ALKALOIDS

(1) Taxol

(2) Camptothecin

(3) Vincristine

(4) Nodulisporic acid

Fig. 4 Structures of important, biologically active compounds isolated from endophytes of Asian medicinal plants

123

Phytochem Rev

FLAVONOIDS/ FLAVONOLS

(5) Kaempferol (6) Elemene

(7) Subglutinol A (8) Subglutinol B

(9) Phomoarcherin A

Fig. 4 continued

123

Phytochem Rev

TERPENES/ TERPENOIDS

(10) Phomoarcherin B (11) Phomoarcherin C

(12) Gibberilic Acid

ANTHRAQUINONES

(13) 1,4-Dihydroxy-anthraquinone (14) Emodin

Fig. 4 continued

123

Phytochem Rev

ANTHRAQUINONES

(16) Rhein(15) Aloe Emodin

POLYPHENOLS

(17) Curcumin

XANTHENES

(18) Ergoflavin

Fig. 4 continued

123

Phytochem Rev

CYTOCHALASINS

(19) Cytochalasin H

(20) Cytochalasin J

(21) Cytochalasin E

Fig. 4 continued

123

Phytochem Rev

(23) Isopestacin(22) Pestacin

BENZOFURANS

STEROIDS

(24) Beta-sitosterol

LIGNANS

(25) Podophyllotoxin

Fig. 4 continued

123

Phytochem Rev

ANTIMICROBIALS

(26) Nocardithioci

(27) Javanicin

Fig. 4 continued

123

Phytochem Rev

(28) Cryptocandi

Fig. 4 continued

123

Phytochem Rev

Conclusion

Endophytes need to be explored more and widely

researched owing to their capability to synthesize

bioactive compounds used in combating numerous

pathogenic diseases. These organisms have been

proven to be a dependable source of bioactive and

chemically novel compounds and shown to be useful

for novel drug discovery. The co-production of

bioactive compounds in some cases evolved indepen-

dently in plants and their microbial counterparts while,

on the other hand, horizontal gene transfers between

the plant host and its endophytes have been repeatedly

hypothesized as a mechanism for the co-production of

these bioactive molecules. The pressing need for novel

chemical compounds targeting human diseases in

ALKYL SALICYLIC ACIDS

(29) Salaceyin A (a) and Salaceyin B (b)

CARBOXYLIC ACIDS

(30) Cinnamic Acid

(a)

(b)

Fig. 4 continued

123

Phytochem Rev

order to curb drug-resistant microbes in life-threaten-

ing infections has recently stimulated research on

novel bioactive compounds from endophytes present

in medicinal plants. It is imperative to review,

highlight, and build on previous successes, on-going

research and latest developments in research associ-

ated with endophytic microorganisms to draw the

attention of the research community toward this

emerging ﬁeld and possible exploitation of the avail-

able sources for their therapeutic uses in various ﬁelds,

such as the medical, pharmaceutical, agri-food and

cosmetics.

Acknowledgements We would like to thank Mr. Mahesh

Kumar from Amity Institute of Pharmacy for drawing the

structures. The support given by Department of Science and

Technology, Govt. of India under the Project No. DST/INT/

TUNISIA/P-04/2017 is thankfully acknowledged.

Compliance with ethical standards

Conﬂict of interest Authors declare none conﬂicts in interests

in writing of this article.

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Nov 2018

Microbial endophytes are present in all known plant species. The ability to enter and thrive in the plant tissues makes endophytes unique, showing multidimensional interactions within the host plant. Several vital activities of the host plant are known to be influenced by the presence of endophytes. They can promote plant growth, elicit defense response against pathogen attack, and can act as remediators of abiotic stresses. To date, most of the research has been done assuming that the interaction of endophytes with the host plant is similar to the plant growth-promoting (PGP) microbes present in the rhizosphere. However, a new appreciation of the difference of the rhizosphere environment from that of internal plant tissues is gaining attention. It would be interesting to explore the impact of endosymbionts on the host’s gene expression, metabolism, and other physiological aspects essential in conferring resistance against biotic and abiotic stresses. A more intriguing and inexplicable issue with many endophytes that has to be critically evaluated is their ability to produce host metabolites, which can be harnessed on a large scale for potential use in diverse areas. In this review, we discuss the concept of endophytism, looking into the latest insights related to the multifarious interactions beneficial for the host plant and exploring the importance of these associations in agriculture and the environment and in other vital aspects such as human health.

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Sep 2018

This study reports the chemical investigation and bioactivity of the secondary metabolites produced by the endophytic fungus Fusarium solani isolated from Cassia alata Linn. growing in Bangladesh. This plant was collected from conservation forest in Bangladesh and belongs to the Caesalpiniaceae family. The endophytic fungus Fusarium solani was isolated from the tissue of root of this plant. The fungal strain was identified by morphological characters and DNA sequencing. The crude organic extract of the fungal strain was proven to be active when tested for cytotoxicity against Brine Shrimp Lethality Bioassay, antimicrobial and antioxidant activity. The bioactivity guided fractionation of the ethyl acetate extract leads to the isolation of seven secondary metabolites in pure form. The structures of the isolated compounds were determined by the analysis of NMR and mass spectroscopic data. Bioassay investigation of the isolated secondary metabolites suggested aza-anthraquinones are more potent bioactive compounds as anticancer and antimicrobial agent.

Microbial natural products: A Past With a Future

Chapter

Jan 2007

Arnold L. Demain

Isolation of anticancer and anti-trypanosome secondary metabolites from the endophytic fungus Aspergillus flocculus via bioactivity guided isolation and MS based metabolomics

Article

Feb 2019
J CHROMATOGR B

This study aims to identify bioactive anticancer and anti-trypanosome secondary metabolites from the fermentation culture of Aspergillus flocculus endophyte assisted by modern metabolomics technologies. The endophyte was isolated from the stem of the medicinal plant Markhamia platycalyx and identified using phylogenetics. Principle component analysis was employed to screen for the optimum growth endophyte culturing conditions and revealing that the 30-days rice culture (RC-30d) provided the highest levels of the bioactive agents. To pinpoint for active chemicals in endophyte crude extracts and successive fractions, a new application of molecular interaction network is implemented to correlate the chemical and biological profiles of the anti-trypanosome active fractions to highlight the metabolites mediating for bioactivity prior to purification trials. Multivariate data analysis (MVDA), with the aid of dereplication studies, efficiently annotated the putatively active anticancer molecules. The small-scale RC-30d fungal culture was purified using high-throughput chromatographic techniques to yield compound 1, a novel polyketide molecule though inactive. Whereas, active fractions revealed from the bioactivity guided fractionation of medium scale RC-30d culture were further purified to yield 7 metabolites, 5 of which namely cis-4-hydroxymellein, 5-hydroxymellein, diorcinol, botryoisocoumarin A and mellein, inhibited the growth of chronic myelogenous leukaemia cell line K562 at 30 μM. 3-hydroxymellein and diorcinol exhibited a respective inhibition of 56% and 97% to the sleeping sickness causing parasite Trypanosoma brucei brucei. More interestingly, the anti-trypanosomal activity of A. flocculus extract appeared to be mediated by the synergistic effect of the active steroidal compounds i.e. ergosterol peroxide, ergosterol and campesterol. The isolated structures were elucidated by using 1D, 2D NMR and HR-ESIMS.

The chemical composition, antifungal, antioxidant and antimutagenicity properties of bioactive compounds from fungal endophytes associated with Thai orchids

Article

Nov 2018

Some plant‐derived bioactive compounds produced by fungal endophytes have been proven to have antimicrobial and antioxidant activities. In this study, endophytic fungi were isolated from 20 orchid samples collected in northern Thailand from 12 genera of orchids. In total, 97 isolates were isolated from the leaves (44.3%), stems (40.2%) and flowers (15.5%) of the orchid samples. The antifungal activity was investigated of the endophytic isolates against the plant pathogenic fungi. The results showed that 13 endophytic isolates provided antifungal activities against Fusarium sp., Colletotrichum sp. and Curvularia sp. The endophyte CK F05‐5, which was isolated from the flower part of Dendrobium lindleyi, was chosen for further testing because it the highest level of antifungal activity against Fusarium sp. The isolate CK F05‐5 was identified as Fusarium oxysporum on the basis of its ITS sequences of 5.8 s rRNA, and phytochemical analysis revealed the presence of coumarins. The ethyl acetate extract of CK F05‐5 was examined for its total phenolic content and antioxidant activity using Folin–Ciocalteu's reagent and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging assay, respectively. The phenolic content was 160.51 mg of GAE/g of extract, and the free radical scavenging activity was 89.61 µg/ml at the half maximal inhibitory concentration (IC50). The antimutagenic potential of the ethyl acetate extract of CK F05‐5 against Trp‐P‐1 mutagenic substances was determined using the Ames test which revealed that the extract of CK F05‐5 at 10 mg/plate had the highest antimutagenic activity against Trp‐P‐1 (51.2%) and 39.6% for strains TA98 and TA100, respectively. The active compounds present in the acetate extract of CK F05‐5 were examined using GC‐MS analysis, which displayed the presence of gibepyrone A, pyrrolo [1, 2‐a] pyrazine‐1, 4‐dione, hexahydro‐3‐(2‐methylpropyl) and indoleacetic acid as major components. Based on the results, this endophytic fungus contains various bioactive components that have various biological activities. This useful information could help in producing potentially valuable and novel pharmaceutical products.

Endophyte-Host Associations in Forage Grasses. I. Distribution of Fungal Endophytes in Some Species of Lolium and Festuca

Article

Mar 1985

Therapeutic agents from endophytes harbored in Asian medicinal plants

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