Bioactive Secondary Metabolites from Endophytic Phoma spp.

Abstract

Phoma is an exceptionally polyphyletic genus of rapidly growing soil fungi under the phylum of Ascomycota. The genus of Phoma includes more than 2000 species observed as phytopathogen or endophytes. The endophytic Phoma spp. have been isolated from a range of tropical/subtropical plants, arid climate of mangrove, mountain, desert, and forest. Wide varieties of plant like tree, herb, shrub, grass, palm, and climber inhabit exclusive endophytic Phoma spp. The isolated endophytic Phoma has been recognized as important source of many novel and natural products that exhibit a wide range of biological activities. Few of the chief bioactive secondary metabolites obtained from diverse species of Phoma are phomin, phomodione, sesquiterpenoid, cytochalasin B, deoxaphomin, usnic acid, trichodermin, beta-sitosterol, cercosporamide, sirodesmin, phomasetin, etc. Moreover, many novel secondary metabolites produced by Phoma sp. act as bio-herbicide, while some of them can produce indoleacetic acid that promotes the growth of that particular plant in which they reside. The biomolecules of endophytic Phoma are reported as antimicrobial, anti-inflammatory, bio-herbicidal, antiangiogenic, cytotoxic, and anti-HIV. Therefore, the chapter aims to present the secondary metabolites of Phoma, its identification tools, and its bioactivity in various areas.

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© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
M. Rai et al. (eds.), Phoma: Diversity, Taxonomy, Bioactivities, and Nanotechnology,
https://doi.org/10.1007/978-3-030-81218-8_11
Bioactive Secondary Metabolites
fromEndophytic Phoma spp.
PramodKumarMahish, ShwetaSingh,
andRavishankarChauhan
Abbreviations
BEAS-2B Human bronchial epithelial cells
COSY Correlated spectroscopy
DV-3 Human dengue virus type 3
EtOAc Ethyl acetate
FT-IR Fourier-transform infrared
spectroscopy
GC-MS Gas chromatography-mass
spectrometry
H1N1 Inuenza A virus subtype
HeLa Henrietta Lacks (immortal cell line)
HIV Human immunodeciency virus
HL Human leukemia cell line
HMBC Heteronuclear multiple bond
correlation
HMQC Heteronuclear multiple quantum
coherence
IL Interleukin
LC-MS Liquid chromatography-mass
spectrometry
MCF-7 Breast cancer cell line
(MCF=Michigan Cancer
Foundation)
NMR Nuclear magnetic resonance
NOESY Nuclear Overhauser effect
spectroscopy
PAF Platelet-activating factor
ROS Reactive oxygen species
RS Reciprocal syncytial virus
SMMC Human hepatocarcinoma cell line
SW480 Human colorectal cancer cell lines
VOCs Volatile organic compounds
11.1 Introduction
Microbes and plants are found in continuous
interaction with each other. Among them, some
microbes cause symptomatic diseases, while
some are associated with benecial signicance
to the host plant. Endophytes are described as the
internal mycota of living plants. The word endo-
phyte was rst coined by de Bary in 1866. It
consists of two Greek words endon=within and
phyte=plant. It includes foliar to root symbionts
of fungi, bacteria, actinomycetes, and myco-
plasm (Arnold 2007). Endophytes are fungi that
colonize living plant tissue without causing any
immediate, overt negative effects (Khan et al.
2016).
The abundance of endophytic fungi is so vast.
The endophytes were isolated from nearly
300,000 land plant species with one or more
fungi (Arnold 2008). The term endophyte regu-
P. K. Mahish () · S. Singh
Department of Biotechnology, Government Digvijay
(Autonomous) P.G.College,
Rajnandgaon, Chhattisgarh, India
R. Chauhan
National Centre for Natural Resources (NCNR),
Pandit Ravishankar Shukla University,
Raipur, Chhattisgarh, India
11

206
larly alludes to a particular host type, a taxonomic
group of hosts, or the kind of tissue involved.
Microfungi are predominant parts of those arrays,
colonizing foliar and twig surfaces (epiphytes),
inside tissues of foliage (foliar endophytes),
young and adult bark (bark endophytes), as well
as wood (xylem endophytes and wood decom-
posers) (Stone etal. 2012).
Endophytic fungi are classied into two
groups clavicipitaceous endophytes
(C-endophytes) and nonclavicipitaceous endo-
phytes (NC-endophytes) which are based on the
taxonomy, tissue specicity, host range, ecology
function, etc. (Schaechter 2011). Clavicipitaceous
belongs to the Ascomycota associated with
grasses (Bacon and White 2000). These fungi are
present in the intracellular space of rhizome, leaf
sheath, and culms (Moy etal. 2000; Dugan etal.
2002). NC-endophytes found an association with
the tropical tree, boreal, and arctic/Antarctic
communities (Arnold et al. 2000; Gamboa and
Bayman 2001). These fungi belong to ascomyce-
tes and basidiomycetes.
Endophytes show host selection when the
endophyte forms a relationship with two related
ora but demonstrate a preference in one particu-
lar host (Cohen 2006). The endophyte also dem-
onstrates host preference; it is used when
endophytes show common occurrence on a par-
ticular host (Paulus et al. 2006). Fungal endo-
phytes are the course of attention by scientic
communities from the last few decades because
of its promising benets to the host plant in a dif-
ferent way.
The molecule produced by organisms that are
not essential for their development, growth, and
survival is known as secondary metabolites. The
term “secondary metabolites” was coined by
Albrecht Kossel in 1891. Bacteria, fungi, and
plants are the fundamental living organisms
responsible for the production of secondary
metabolites. Microbial secondary metabolites are
petite biomolecules delivered during the late
development stage (Sanchez and Demain 2011).
The production of secondary metabolites from
the fungal source has little advantages like easy
growth, manipulation, low nutrient requirement,
and simple extraction process. Endophytic fungi
associated with plants are a valuable source of
phenolics, alkaloids, polyketides, steroids,
enzymes, peptides, and quinines (Meena et al.
2019).
Since the discovery of anticancer Taxol from
endophytic fungi, the attraction of scientic com-
munities rises to investigate molecules from
plant-associated microbes, which leads to the
nding of antibacterial, antiviral, antioxidant,
immunosuppressant, anti-inammatory, antidia-
betic, and anticancer metabolites (Uzma et al.
2019). Endophytic fungi are also the source of
oxidative and hydrolytic extracellular enzymes
which are useful in healthcare, textile, beverage,
food, leather, and confectionery industries
(Mishra etal. 2019).
Endophytes are vast hidden biodiversity of
fungal ora as they are little explored in the
developing countries having rich plant resources
(Rodriguez etal. 2009). Therefore, there is a high
probability of investigating potential endophytic
fungi with various applications in therapeutics,
agriculture, and biotechnology.
11.2 Endophytic Phoma
Phoma is a well-known genus of phylum
Ascomycota, class Dothideomycetes, order
Pleosporales, and family Didymellaceae
(Bennett et al. 2018). There are about 2000
Phoma species that have been identied through-
out the world (Boerema etal. 2004). Phoma was
reported as soil born, saprophytic, plant patho-
gen, and endophytes. The identication of Phoma
can be determined by its morphological charac-
teristics (Rai and Rajak 1993). The colonies of
Phoma give greenish-gray to brown in agar
media. The formation of asexual spore is known
as conidia with unicellular and hyaline as well as
different in shape (Boerema etal. 2004). Pycnidia
can be observed as asexual fruiting bodies which
are globose to subglobose to pyriform with a dark
appearance. The ostioles are found single or mul-
tiple (Aveskamp etal. 2008). Thick-walled veg-
etative cells within hyphae or at hypha are known
as chlamydospores (Guégan etal. 2016; Choi and
Kim 2017).
P. K. Mahish et al.

207
The presence of endophytic Phoma has been
recorded from continents like Asia, Europe,
Africa, North America, Australia, and South
America. More endophytes are investigated from
the Indian subcontinent, China, California,
Mediterranean, Peru, Brazil, etc. (Gazis and
Chaverri 2010; Bharathidasan and Panneerselvam
2011; Moricca et al. 2012; Maheswari and
Rajagopal 2013; Tan et al. 2018a; Chen et al.
2020; Gama etal. 2020). Phoma is reported from
host plants of almost all kinds of the climatic
conditions like tropical, subtropical, arid, and
mangroves (Loro et al. 2012; Humzah et al.
2018). Host plants of the mountain, desert, forest,
mangrove, and river belt also contain Phoma as
endophytic fungi (Guo et al. 2008; Sun et al.
2012; El-Nagerabi et al. 2013; Du etal. 2020).
Tree, herb, shrub, grasses, and palm inhabits the
endophytic Phoma which are perennial and ever-
green (Gazis and Chaverri 2010; Ghimire etal.
2011; Rivera-Orduña et al. 2011; Khan et al.
2016; Selim etal. 2018). The fungi were obtained
from various parts of plants like leaf, stem, root,
petioles, barks, etc. (Fernandes et al. 2015; Szucs
et al. 2018; Radiastuti etal. 2019).
The nding of the new natural and eco-
friendly bioactive compound is always a focused
eld of researchers. The agrochemical and phar-
maceutical areas are very good examples of such
a eld. In the recent year, phomodione, cerco-
sporamide, phomenon, phomin, cytochalasins,
and dehydrophomin were identied from Phoma
as novel secondary metabolites. These metabo-
lites showed a signicant role of antiviral, anti-
fungal, antibacterial, antiprotozoal, anticancer,
and weedicide activities (Elkhateeb and Daba
2020).
11.3 Secondary Metabolites
ofEndophytic Phoma
Several thousands of fungus species are very
diverse in their morphological characters. The
word fungus on hearing it always clicks in our
mind that is an infective agent that spreads so
many kinds of infection. But, the fungus is a rich
source of natural metabolite producer despite
only being an infectious agent. Secondary metab-
olites produced by the endophytes may directly
or indirectly inuence the host plant in many
ways like protecting from plant pathogen or
inducing the production of secondary metabolites
from the host plant, etc.
The genus Phoma is one of the fungal endo-
phytes reported from many plant species (Bennett
et al. 2018) and comes under plant pathogenic
fungi that cause many kinds of diseases in plant,
viz., lesions in leaves, stems, pods, and blossoms,
discoloration in hypocotyl, cotyledons, etc.
(Cimmino et al. 2008; Mahish and Ghritlahare
2017). Although Phoma spp. are parasites, they
are tremendous sources of natural metabolites
also. Phoma spp. are morphologically similar,
but discrimination of the species is based on the
culture characteristics, growth conditions, and
the most impotent the production of secondary
metabolites. Some metabolites are directly pro-
duced by them or some are induced. Secondary
metabolites produced by Phoma have many phar-
maceutical, clinical, or biotechnological applica-
tions (Uzma etal. 2019; Chen etal. 2020).
Different Phoma species produce distinct
metabolites and have different biotechnological
exploitations (Rai etal. 2020). Two new isochro-
manone derivatives (3S,4S)-3,8-dihydroxy-6-
methoxy-3,4,5-trimethyl-lisochroman-1-one and
methyl (S)-8 hydroxy-6-methoxy-5-methyl-4a-
(3-oxobutan-2-yl)benzoate are produced by
Phoma sp. PF2 is isolated from Artemisia prin-
ceps Pamps (Kim etal. 2018). Some Phoma spe-
cies produce new secondary metabolites with
symbiont such as Phoma sp. YUD17001 pro-
duces ve new compounds promoter A, B, and C,
and phexandiols A and B with co-culture of
Armillaria sp. (Li et al. 2019). Along with ter-
restrial Phoma sp., marine Phoma spp. are also
an enormous source of different secondary
metabolite contents enolides, lactone, quinine,
phthalate, diterpenes, etc. and are different from
terrestrial Phoma sp. (Ostarhage etal. 2000; Rai
etal. 2018). It is reported that they also synthe-
size amino acid derivative like Phoma herbarum
PSU-H256 and can synthesize tyrosine derivative
temezine M and phomarosine A, B, and C, and
hydantoin derivatives S-5-isoprppyl-3-
methoxyimidazolidine- 2,4-dione and S-5-(4-
hydroxybenzoyl)-3-isobutyrylimidazolidine- 2,4-
11 Bioactive Secondary Metabolites fromEndophytic Phoma spp.

208
dione show weak antibacterial activity (Maha
etal. 2017). Fermentation broth of Phoma sp. YE
3135 obtained from Aconitum vilmorinianum
contained rare 14-nordrimane-type sesquiterpe-
noid along with 6-methoxymellein;
7-hydroxy- 3,5-dimethylisochromane-1-one;
norlichxanthone; 6-methylsalicylic acid; and
gentisyl alcohol with antiviral activity (Liu etal.
2019). Macrophin, rosellisin, 2-(2-hydroxy- 5-6-
methylene- 1,4-benzodioxin-2(3H)-one, and
methoxyphenoxy acrylic acid were isolated rst
time from Phoma macrostoma endophyte of the
medicinal plant Glycyrrhiza glabra with cyto-
toxic potential (Nalli et al. 2019). Phoma sp.
SYSU-SK-7 produces polyketides colletotric B,
3-hydroxy-5-methoxy-2,4,6-trimethylbenzoic
acid, colletotric C, chaetochromone D, and
8-hydroxy-pregaliellalactone having an antimi-
crobial activity (Chen etal. 2018). Some Phoma
spp. produce growth promoters like gibberellin
and cytokinin (Kedar et al. 2014) and volatile
compounds like ethanol, 1-butanol, 1-hexane,
2-(p-anisyl)-4-methyl, epi-
bicyclosequiphellandrene, butanoic acid, propa-
noic acid, hexadecanoic acid, dodecanoic acid,
etc. (Strobel etal. 2011). Along with the phoma-
lactone, (3R)-5-hydroxymellein, and emodin,
Hussain etal. (2014) isolated new dihydrofuran
derivatives known as phomafuranol. Some sec-
ondary metabolites of endophytic Phoma spp. are
summarized in Table11.1.
11.4 Bioanalytical Techniques
toDetermine Secondary
Metabolites ofPhoma
Species
It is very interesting to know that 6 of the 20 com-
monly prescribed medications are secondary
metabolites of fungal origin (Rai etal. 2009). In
this connection, the genus Phoma was introduced
more than 180 years ago having numerous sig-
nicant secondary metabolites which include
antimicrobials, mycoherbicides, and phytotox-
ins. However, one of the chief challenges is the
identication of such novel secondary metabo-
lites. In metabolomics, eventually, all paths lead
to the identication and quantication of certain
key compounds. To be sure, without key com-
pound distinguishing proof, the consequences of
any metabolomic investigations are biochemi-
cally uninterpretable (Wishart 2011). Due to the
huge chemical diversity and characters of most
metabolites and metabolomic data, respectively,
metabolite identication is intrinsically difcult.
Thus, a lot of exertion in metabolomics over the
previous decade has been centered around mak-
ing metabolite identication accurate and
quicker. In this context, nuclear magnetic reso-
nance (NMR) spectroscopy is a perfect analytical
tool for the characterization of metabolites
(Wilson and Burlingame 1974). This analytical
tool is one of the rst techniques to be adopted in
metabolomics as a nonbiased tool that allows the
identication of novel compounds. NMR is par-
ticularly amenable to detecting compounds that
are less traceable to LC-MS/GC-MS analyses,
such as amines, sugars, or volatile liquids having
molecular weight> 500Da, or relatively nonre-
active compounds (Reo 2002). Generally, the 1H
and/or 13C NMR spectrum is sufcient for posi-
tive identication since NMR data offer two or
three orthogonal measures concerning a com-
pound’s identity such as chemical shifts, peak
intensities, and spin coupling patterns (Wishart
2008).
In line, using NMR spectroscopy very
recently, four new polyketides, particularly bel-
lidisin A (Fig. 11.1a) and bellidisins B-D, were
isolated from Phoma bellidis (Wang etal. 2019).
The absolute congurations and structures of
these polyketides were determined by 1D and 2D
NMR. In their investigation, they noticed that
bellidisin D exhibited stronger cytotoxicity
against human cancer cell lines HL-60, A549,
SMMC-7721, MCF-7, and SW480 in compari-
son to cisplatin—a standard cytotoxic drug
(Wang et al. 2019). In the same year, Liu etal.
(2019) also reported phomanolide (Fig.11.1e), a
new rare 14-nordrimane-type sesquiterpenoid
from an endophytic fungus Phoma sp. isolated
from the roots of Aconitum vilmorinianum. The
structure of this compound was determined by
combined analyses of the 1H-1H COSY, HMBC,
HMQC, and NOESY spectra. The coupling series
from H-1 to H-3 and from H-6 to H-9 could be
without a doubt set up by following connections
P. K. Mahish et al.

209
Table 11.1 Secondary metabolites from endophytic Phoma
S. no. Fungi Secondary metabolites Bioactivity References
1Phoma bellidis
Neergaard
Polyketides Cytotoxic Wang etal. (2019)
2Phoma betae
A.B.Frank
Diterpenes, aphidicolin Antifungal Oikawa etal. (2001)
Spiciferones A, G–H, spiciferol A Anticancer Tan etal. (2018b)
Taxol Anticancer Kumaran etal. (2012)
3Phoma
cucurbitacearum
(E.M.Fries)
P.A.Saccardo
Thiodiketopiperazine Antimicrobial Arora etal. (2016)
4Phoma etheridgei
Hutchison and
Hiratsuka
Phomalone, dihydrobenzofuran Antifungal Ayer and Jemenez
(1994)
5Phoma fungicola
Aveskamp, Gruyter,
and Verkley
Polyketide spiciferone A Herbicidal Mohamed etal.
(2017)
6Phoma glomerata
(A.C.J. Corda)
Wollenw and
Hochapfel
Salvianolic acid Cholesterol control Li etal. (2016)
7Phoma herbarum
G.D. Westendorp
Brefeldin A, nonenolides like herbarumin I and
herbarumin II
Phytotoxin Rai etal. (2009)
3-Nitrophthalic acid Phytotoxin Vikrant etal. (2006)
Terezine M, phomarosine A–C,
S-5-isoprpyl-3-methoxyimidazolidine- 2,4-dione
Antibacterial and
cytotoxic
Maha etal. (2017)
Gentisyl alcohol Antagonistic to
plant pathogen
Gupta etal. (2016)
Gibberellin Growth promoter Hamayun etal. (2009)
Tanshinone Growth promoter Chen etal. (2020)
8Phoma lingam
(Tode)
Desmazières,
J.B.H.J.
Sirodesmin PL, deacetylsirodesmin Phytotoxin Rai etal. (2009)
9Phoma macrostoma
J.P.F.C. Montagne
Macrophin Anticancer Nalli etal. (2019)
10 Phoma medicaginis
Malbranche and
Roumeguère
Brefeldin A Antifungal Weber etal. (2004)
Glucosidases Growth promoter Khan etal. (2016)
Paclitaxel Anticancer Zaiyou etal. (2017)
11 Phoma
multirostrata (P.N.
Mathur, S.K.
Menon, and
Thirum.) Dorenb
and Boerema
Multirostratin A, 20-oxo-deoxaphomin, deoxaphomin,
cytochalasin A, cytochalasin B, cytochalasin Z2,
cytochalasin F
Anticancer Chen etal. (2014)
Ergocytochalasin A Antiviral Peng etal. (2020)
12 Phoma radicina
section Paraphoma
radicina
(McAlpine)
Morgan-Jones and
J.F. White
Cryptotanshinone Growth promoter Teimoori-Boghsani
etal. (2020)
13 Phoma sorghina
(P.A. Saccardo)
Boerema, Dorenb.,
and Kesteren
6-Methylsalicylic acid, epoxydon, desoxyepoxydon,
phyllostine, 2,3′-dihydroxy-4-methoxy-5′,6-dimethyl
diphenyl ether, and epoxydon 6-methylsalicylate ester
Phytotoxin Venkatasubbaia etal.
(1992)
(continued)
11 Bioactive Secondary Metabolites fromEndophytic Phoma spp.

210
Table 11.1 (continued)
S. no. Fungi Secondary metabolites Bioactivity References
14 Phoma sp.Cyperin-2-O-R-D-glucoside Anticancer Wu etal. (2018)
Phomalichenones A–D Anti-inammatory Kim etal. (2018)
Thiodiketopiperrazine derivatives Antimicrobial Arora etal. (2016)
Gibberellic acid Growth promoter Khan etal. (2014)
Anthraquinone, 7-(γ,γ)-dimethylallyloxymacrosporin,
macrosporin, 7-methoxymacrosporin,
tetrahydroaltersolanol B, altersolanol L, and
ampelanol
Antifungal and
antibacterial
Huang etal. (2017)
Phomadecalins A–D and phomapentenone A Antibacterial Che etal. (2002)
Phomaketides A–E, pseurotin A3, pseurotin G Antiangiogenesis,
anti-inammatory
Lee etal. (2016)
Phomapyrrolidones A–C Antituberculosis Wijerante etal. (2013)
YM-215343 Antifungal Shibazaki etal. (2004)
Pyrenopherol, dihydropyrenophorin Antimicrobial Zhang etal. (2008)
Phomodione Antifungal Hoffman etal. (2007)
Isochromanone derivatives like (3S,4S)-3,8-
dihydroxy-6-methoxy-3,4,5-trimethyl-lisochroman-1-
one, methyl (S)-8
hydroxy-6-methoxy-5-methyl-4a-(3-oxobutane-2-yl)
benzoate
Inhibitory activity
in nitric oxide
Kim etal. (2018)
Phomaethers A–C, 2,30-dihydroxy-4-methoxy-50,6-
dimethyl diphenyl ether, diaportinol,
desmethyldiaportinol, citreoisocoumarin,
citreoisocoumarinol
Antibacterial Shi etal. (2017)
2-Hydroxy-6-methylbenzoic acid Antibacterial Zhang etal. (2012)
Squalestatin S1 Cholesterol control Aldred etal. (2001)
Epoxydines A and B Antifungal,
antibacterial
Qin etal. (2010)
Barceloneic acid A, barceloneic acid C, questin Antibacterial Xia etal. (2014)
Barceloneic acid A Anticancer Jayasuriya etal.
(1995)
Methyl 2-(2-formyl-3-hydroxy-5-methylphenoxy)-5-
hydroxy-3-methoxybenzoate, asterric acid, methyl
asterrate, 9(Z),12(Z)-nonadecadienoic acid and
orsellinic acid
Cytotoxic Fang etal. (2012)
Cryptophomic acid, cryptodiol, cryptotriol, and
dihydroisocoumarin derivative
Antibacterial Elsebai etal. (2018)
Phomanolide Antiviral Liu etal. (2019)
3,16-Diketoaphidicolan Antibacterial Dai etal. (2010)
Equisetin Anti-HIV Singh etal. (1998)
Biopolymer Herbicidal Luft etal. (2019)
(10′S)-verruculide B, vermistatin, dihydrovermistatin,
(S,Z)-5-(3′,4′-dihydroxybutyldiene)-3-propylfuran-
2(5H)-one, nafuredin
Inhibitor of protein
tyrosine
phosphatases
Gubiani etal. (2017)
1-Methoxy-3,5′-dimethyl-2,3′-oxybiphenyl-5,1′,2′-
triol
Antidiabetic Sumilat etal. (2017)
Thiodiketopiperazines Anticancer Kong etal. (2014)
Pleofungins A, B, C, and D Antifungal,
antibiotics
Aoyagi etal. (2007)
Alpha tetralone, (3S)-3,6,7-trihydroxy-alpha-
tetralone, trichodermin, cercosporamides
Cytotoxic Wang etal. (2011)
Squalestatin S1 Cholesterol control Aldred etal. (2001)
15 Phoma terrestris
H.N.Hansen
Ergoavin Anti-inammatory
and anticancer
Deshmukh etal.
(2009)
N-amino-3-hydroxy-6-methoxyphthalimide and
5H-dibenz[B, F]azepine
Antimicrobial Park etal. (2015)
P. K. Mahish et al.

211
in the 1H-1H COSY spectrum and was the abso-
lute rst case of 14-nordrimane-type sesquiter-
pene till the present (Liu etal. 2019). Five new
metabolites, comprising phexandiols A
(Fig. 11.1d) and B and phomesters A-C, were
obtained by the co-culture of the endophytic fun-
gus Phoma sp. YUD17001 from Gastrodia elata
with Armillaria sp. (Li etal. 2019). Considering
the biogenetic origins, the absolute congura-
tions and structure of these compounds were
determined by Mosher’s method and electronic
circular dichroism spectra, following 1D and 2D
NMR spectroscopy (Li etal. 2019).
In 2018, ve new polyketides, particularly
colletotric B (Fig. 11.1c) and C, 3-hydroxy- 5-
methoxy-2,4,6-trimethylbenzoic acid, chaeto-
chromone D (Fig. 11.1b), and
8-hydroxy-pregaliellalactone B, were obtained
from the mangrove endophytic fungus Phoma sp.
SYSU-SK-7 (Chen etal. 2018). Their structures
were elucidated by analyses of extensive 1D and
2D NMR spectroscopic data following mass
spectrometry. Moreover, four new phomones,
phomone C (Fig. 11.1f) and phomones D–F,
were isolated from the endophytic fungus Phoma
sp. YN02-P-3 by Sang etal. (2017) which is the
primary case in point of 6-α,β-unsaturated ester-
2- pyrone dimers through intermolecular sym-
metrical cyclo-expansion. The chemical
structures of these phomones were elucidated
using FT-IR and 1D/2D NMR spectroscopic data
following the MS data (Sang etal. 2017). Thus,
an ample number of new secondary metabolites
from Phoma sp. were determined by extensive
NMR, FT-IR, and mass spectroscopic techniques
for the establishment of a novel drug.
11.5 Bioactivity
andBiotechnological
Signicance ofSecondary
Metabolites Obtained
fromEndophytic Phoma
In the constantly changing phase of today, we
always need to discover new drugs to save our
communities. The plants are like a boon for us.
We have been using the plant as medicine for a
very long time. Not only plants help us to produce
a new drug, there are rather lots of medicinal
metabolites produced by endophytes of host
plants that could be utilizesd in pharmaceutical
applications. The bioactivity of some metabolites
produced by Phoma sp. endophytes is described
below.
11.5.1 Antimicrobial Activity
In the past 30 years, 50% of drugs are natural
products or their derivatives. Moreover, the ade-
quacy of present-day drugs is signicantly dimin-
ishing particularly because of the ever-increasing
microorganism opposition that is right now an
issue of extraordinary general well-being con-
cern (Alpert 2016). Endophytes obtained from
Glycyrrhiza glabra Linn., designated as Phoma
GG1F1 closely related to Phoma cucurbita-
cearum and Phoma sp. URM 7221 from the
medicinal plant Schinus terebinthifolius (Silva
et al. 2017), showed signicant antimicrobial
activity. The chemical compounds from Phoma
GG1F1 extract are two thiodiketopiperazine
derivatives. Both the compounds inhibited the
growth of several bacterial pathogens especially
Staphylococcus aureus, Bacillus subtilis, and
Streptococcus pyogenes (Arora etal. 2016). One
new dihydrofuran derivative, named phomafura-
nol together with three known compounds, viz.,
phomalacton, (3R)-5-hydroxymellein, and emo-
din, produced by EtOAc extract of the culture of
Phoma sp. isolated from Fucus serratus, showed
good antifungal (Microbotryum violaceum)
activity and signicant antibacterial Bacillus
megaterium and antialgal Chlorella fusca activi-
ties (Hussain etal. 2014).
Phomaether A and 2,30-dihydroxy-4-
methoxy-50,6-dimethyl diphenyl present in
EtOAc concentrate of Phoma (TA07-1) from
Dichotella gemmacea, and many Phoma spp.
show noteworthy antibacterial activity toward
Gram-positive, Staphylococcus albus and S.
aureus, and Gram-negative bacteria, Escherichia
coli, Vibrio parahaemolyticus, V. anguillarum,
Staphylococcus albus (Huang et al. 2017), and
Mycobacterium phlei (Elsebai et al. 2018).
Inositol phosphorylceramide (IPC) synthase an
important factor for fungus viability is mostly
11 Bioactive Secondary Metabolites fromEndophytic Phoma spp.

212
targeted for fungal antibiotics (Figueiredo etal.
2005). One of the inhibitors of this metabolic
enzyme is pleofungins (also called F-15078) pro-
duced by the endophytes Phoma sp. SANK
13899 and is active against Saccharomyces cere-
visiae, Aspergillus fumigatus, Candida albicans,
and Cryptococcus neoformans (Aoyagi et al.
2007). Phomafungin a cyclic lipodepsipeptide
exhibits a broad spectrum of antifungal activity
in very low concentration against Candida sp.,
Aspergillus fumigatus, and Trichophyton mentag-
rophytes (Herath etal. 2009). Likewise, barcelo-
neic acid C a new compound exhibited
antibacterial activities against Listeria monocyto-
genes and Staphylococcus pseudintermedius,
Bacillus cereus 13,061, and Gram-negative bac-
teria Salmonella typhimurium produced by
Phoma sp. JS752 (Xia etal. 2014). Several spe-
cies of Phoma have demonstrated antiviral activ-
ity, viz., Phoma sp. YE3135 from Aconitum
vilmorinianum possesses antiviral activity against
the H1N1 virus (Liu etal. 2019); even ergocyto-
chalasin A acts against DV-3 (human dengue
virus type 3), H1N1 virus, and RS virus (recipro-
cal syncytial virus) (Peng etal. 2020).
11.5.2 Anticancer Activity
Cancer is a multistage process. Cancer cells are
characterized by the aid of using the large repli-
cative potential, apoptotic resistance, invasive
ability, and one of the major causes of fatalities.
Many studies have indicated the possible prob-
ability of healthful plants that host endophytic
fungi capable of producing pharmacologically
natural medicine. The healthful properties of
those plants might be thanks to the endophytes
residing inside them (Uzma etal. 2019). Taxol
is a diterpene an extraordinarily anticancer drug
widely used in disease related to tissue prolif-
eration. It was isolated from the bark of the yew
tree of the Taxus genus. These trees are uncom-
mon and slow-developing, and a lot of bark may
be handled to get a modest quantity of the medi-
cation (Gangadevi and Muthumary 2007).
Taxadiene synthase (ts), a one of a kind quality
in the gene arrangement of the taxane skeleton,
was afrmed for Taxol biosynthesis. Phoma
betae is an excellent candidate for Taxol supply
and can serve as a potential species for genetic
engineering to enhance the production of Taxol
to a higher level (Kumaran et al. 2012).
Multirostratin A and 20-oxo-deoxaphomin
metabolites produced by the endophytic fungus
Phoma multirostrata EA-12 show moderate
cytotoxicity against ve tumor cell lines (HL-
60, A-549, SMMC-7721, MCF-7, and SW-480)
(Chen etal. 2014). Similarly, ergosterol, ergos-
terol peroxide (EP), and 9,11-dehydroergosterol
peroxide (DEP) produced by Phoma sp. show
anticancer property against different kinds of
cancer cell lines A549, J5, HeLa, and MCF-7
and normal lung cell line Beas-2b, as well as
macrophages RAW 264.7, and can induce apop-
tosis, autophagy, and ROS generation (Wu etal.
2018). Phoma sp. from the medicinal plant
Pereskia bleo produces hydrolyzer of
L-asparagine, L-asparaginase enzyme (Chow
and Ting 2014) that catalyzes the conversion of
L-asparagine to L-aspartate and ammonia
(Theantana etal. 2009); as asparagine helps to
grow cancer cell, this enzyme removes it from
the serum (Verma etal. 2007). Barceloneic acid
A, B, and barceloneic lactone from Phoma sp.
inhibit farnesyl protein transferase enzyme
which is related to Ras mutation and a factor to
induce tumor formation (Jayasuriya etal. 1995).
11.5.3 Anti-inammatory Activity
Agents that reduce pain, fever, swelling (edema),
and redness-like inammatory responses are
called anti-inammatory substances.
Inammation may result in autoimmune or auto-
inammatory disorders, neurodegenerative dis-
ease, or cancer. Using many anti-inammatory
substances is a new way to treat many of the dis-
eases with the use of metabolites like anticyto-
kine and inhibition of many enzymes (Dinarello
2010). Phomactin A derived from marine Phoma
sp. exhibits antagonistic activity against the PAF
platelet-activating factor which activates the
platelet aggregations involved in many inamma-
tory reactions, as well as respiratory reactions
P. K. Mahish et al.

213
(Sugano et al. 1991). Phomalichenone A pro-
duced from Phoma sp. EL002650 inhibits the
expression of the gene of inammatory agents
like tumor necrosis factor-α, nitric oxide synthase
(iNOS), cyclooxygenase-2 (COX-2), and many
other cytokines like IL-1 β and IL6 (Kim etal.
2018).
11.5.4 Anti-HIV Activity
Acquired immunodeciency syndrome (AIDS)
caused by HIV is a global health issue and has
always been a challenge for scientists (Pommier
et al. 2005). Many proteins are involved in the
multiplication of HIV, one of those is integrase.
Inhibition of integrase is antiretroviral therapy by
Fig. 11.1 Molecular structure of some secondary metab-
olites obtained from endophytic Phoma. (a) Bellidisin A
(Wang etal. 2019); (b) Chaetochromone D (Chen et al.
2018); (c) Colletotric B (Chen etal. 2018); (d) Phexandiols
A (Li etal. 2019); (e) Phomanolide (Liu etal. 2019); (f)
Phomone C (Sang etal. 2017)
11 Bioactive Secondary Metabolites fromEndophytic Phoma spp.

214
blocking integration over the T cell (Hajimahdi
and Zarghi 2016). The compounds equisetin and
phomasetin as a rst natural inhibitor isolated
from Phoma sp. MF6070 are inhibitors of inte-
grase that inhibit the integration reactions cata-
lyzed by preintegration complexes by HIV-1
(Singh etal. 1998; Hazuda etal. 1999).
11.5.5 Angiogenesis Inhibition
Angiogenesis is the formation of new blood
vessels and is diagnosed in numerous debilitat-
ing human diseases, together with cancer, age-
associated macular degeneration (AMD), and
numerous inammatory diseases (Carmeliet
2003). Edible red algae endophyte Phoma sp.
NTOU4195 produces polyketides phomaketide
A showing potent antiangiogenesis activity by
suppressing the tube formation of endothelial
progenitor cell along with signicant A549 cell
growth inhibition and anti-inammatory
activity.
11.5.6 Plant Growth Promotion
Some Phoma sp. can promote the growth of host
plants; this growth enhancement effect is at least
in part due to endophyte-producing growth hor-
mones. Phoma sp. isolated from Tinospora cor-
difolia and Calotropis procera induces the growth
of Zea mays (Kedar et al. 2014), and in rice, it
induces seed germination (Khan etal. 2016). It
has also been found that gibberellic acid-decient
rice cultivar (a dwarf variety of rice) shows an
increase in plant length when cultivated with cul-
ture ltrate of Phoma TK 2-4 a new strain of
Phoma herbarum and Phoma LK-13 from
Moringa peregrina (Hamayun et al. 2009).
Recently, tanshinone from Phoma herbarum
(Chen et al. 2020) and cryptotanshinone from
Phoma radicina section Paraphoma radicina
(Teimoori-Boghsani etal. 2020) were identied
and found signicant role in plant growth
promotion.
11.5.7 Bio-herbicide
Weeds are one of the primary issues looked at by
horticulturists, which are liable for huge misfor-
tunes in numerous vegetable yields. The use of
microbial bioproducts is an effective option in
contrast to weed control (Toredo etal. 2018). We
can reduce the problem of weeds in a more com-
fortable way through an integrated and coordi-
nated system. The use of synthetic compounds
couldn’t viably control the weeds and causes to
build up resistance in weeds as well as contami-
nates nature also (Radhakrishnan 2018).
Metabolites of Phoma sp. are one of the great
resources of bio-herbicide. Phoma macrostoma
is found to be used for biological weed control
and has great potential for the control of dande-
lion (Bailey etal. 2011) and now is registered as
a bio-herbicide in North America to control
broadleaved weed species in turfgrass (Bailey
etal. 2013).
11.5.8 Biofuel Production
It has been observed that many endophytes can
produce many volatile organic compounds
(VOCs) that show a special relationship between
plant, endophytes, and nature (Stadler and Schulz
2009). Endophytic fungi are now being recog-
nized as an unexplained source of volatile low
molecule hydrocarbon and can be used as a pro-
ducer of biofuel of the next generation directly
due to the low number of biosynthetic phases
(Bhagobaty 2015). It has been found that Phoma
sp. from Larrea tridentata (Creosote bush) pro-
duces volatile compounds such as sesquiterpe-
noids, some alcohol, and reduced form of
naphthalene derivatives along with the trans-
caryophyllene. All VOCs show the best antimi-
crobial property against Verticillium,
Ceratocystis, and Cercospora and least sensitiv-
ity for Sclerotinia, Trichoderma, Colletotrichum,
and Aspergillus (Strobel et al. 2011). Phoma
exigua is an excellent source of producing cellu-
lase and xylanase hydrolytic enzyme used in the
P. K. Mahish et al.

215
saccharication of biomass (Tiwari etal. 2013), a
process of breaking a complex carbohydrate into
simple monosaccharide sugar, key steps of bio-
ethanol production from biomass (Agwa et al.
2017).
11.6 Conclusion
Over the last few decades, exploring natural
sources for potential biomolecules has been
advanced incredibly. Microbial sources are sig-
nicant due to their easy operation, growth, and
manipulation. The biomolecules fulll the call
for pharmaceutical, food, beverage, agrochemi-
cal, textile, dye, and paint industries. Phoma spp.
are exceptionally interesting among the organ-
isms on account of their extensive abundance and
novel characteristics. The nonpathogenic plant
endophytes have been accounted for a signicant
source of many natural secondary metabolites of
antimicrobial, cytotoxic, and anti-inammatory
properties that may reach the medicinal demand.
The secondary metabolites of various Phoma
endophytes have been found as growth promoters
and also show antagonism against plant patho-
gens which are useful for agrochemical users.
Accordingly, the present chapter highlights the
diversity of endophytic Phoma, secondary
metabolites of novel signicance, identication
tools of metabolites, and bioactivity of mole-
cules. This compiled literature might encourage
new expansion in the eld and provide insight to
the researchers.
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