Symbiosis (2023) 90:111–125

https://doi.org/10.1007/s13199-023-00925-9

Secondary metabolites from endophytic fungi: Production, methods

of analysis, and diverse pharmaceutical potential
Vivek Kumar Singh1 · Awanish Kumar1

Received: 22 January 2023 / Accepted: 22 May 2023 / Published online: 8 June 2023
© The Author(s), under exclusive licence to Springer Nature B.V. 2023

Abstract
The synthesis of secondary metabolites is a constantly functioning metabolic pathway in all living systems. Secondary
metabolites can be broken down into numerous classes, including alkaloids, coumarins, flavonoids, lignans, saponins, ter-
penes, quinones, xanthones, and others. However, animals lack the routes of synthesis of these compounds, while plants,
fungi, and bacteria all synthesize them. The primary function of bioactive metabolites (BM) synthesized from endophytic
fungi (EF) is to make the host plants resistant to pathogens. EF is a group of fungal communities that colonize host tissues'
intracellular or intercellular spaces. EF serves as a storehouse of the above-mentioned bioactive metabolites, providing
beneficial effects to their hosts. BM of EF could be promising candidates for anti-cancer, anti-malarial, anti-tuberculosis,
antiviral, anti-inflammatory, etc. because EF is regarded as an unexploited and untapped source of novel BM for effective
drug candidates. Due to the emergence of drug resistance, there is an urgent need to search for new bioactive compounds that
combat resistance. This article summarizes the production of BM from EF, high throughput methods for analysis, and their
pharmaceutical application. The emphasis is on the diversity of metabolic products from EF, yield, method of purification/
characterization, and various functions/activities of EF. Discussed information led to the development of new drugs and
food additives that were more effective in the treatment of disease. This review shed light on the pharmacological potential
of the fungal bioactive metabolites and emphasizes to exploit them in the future for therapeutic purposes.

Keywords Endophytic fungi · Secondary metabolites · Characterization · Bioactive · Therapeutics

1 Introduction of the world's population. In tropical and subtropical areas,

underprivileged populations are infected with malaria,
In recent years, the world population has faced many chal- accounting for about one million deaths (Cárdenas et al.
lenges in the field of healthcare. Its associated problem, 2021). Similarly, COVID-19 (Pokhrel and Chhetri 2021) and
including various diseases like cancer, diabetes, cardio- other pandemics as monkeypox (Bhattacharya et al. 2022),
vascular disorder, multiple drug resistance, etc. are major immunosuppressive disorders, and the appearance of highly
defiance for the human fraternity (Qadri et al. 2021; WHO virulent viruses open a new discussion for future treatment
2020). Even in the era of vaccines and drugs, infectious dis- and remedies to address those problems (Chatelain 2015).
eases are responsible for the high mortality rate. Diseases An international health agency prioritizes the conservation
like diarrhea cause the death of around 525 000 children of natural resources to create novel therapeutics. Plants are
under five years of age (Tesfaye et al. 2020). Around 33 major natural resources and have therapeutic potential that
million populations are infected with HIV and reported to has been tracked down thousand years ago and utilized for
be two million deaths last decade (Laga et al. 2015). Myco- the treatment of many diseases (Abel 2013). Today around
bacterium tuberculosis is recorded to infect around one-third 40% of modern medicines are plant-derived because of fewer
side effects. Plants generate various secondary metabolites,
which may be broken down into the chemical categories of
* Awanish Kumar
drawanishkr@gmail.com phenolics, terpenes, and alkaloids (Sharma and Singh 2021).
Secondary metabolites secreted by the plant during different
1
Department of Biotechnology, National Institute stress and developmental stages make them competitive in
of Technology, Raipur (CG), Raipur 492010, Chhattisgarh, their inhabitant (Pang et al. 2021). These small molecules
India

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112 V. K. Singh, A. Kumar

exert a significant impact on plants themselves and also on ecology, proliferation, fitness, and steer the evolution of their
humans and other organisms (Teoh 2016). life (Krings et al. 2007). Plant systems change their habits
Plants are the natural inhabitant of microorganisms as from water to terrestrial atmosphere with many challenges
they form a symbiotic association with them to accomplish like nutrient-deficient soil, high carbon dioxide varying
one and all requirements. Endophytes (endosymbiotic temperature conditions, and water availability. Fungal endo-
microbes colonize in plants) and microbes and their bioactive phytes provided tolerance to the plant during adverse condi-
metabolites are important natural sources for promising tions and fixed them in the soil. In the evolutionary period,
therapeutic agents. The therapeutic potential of endophytes fungal endophytes evolved themselves in the plant envi-
and their metabolites as biotherapeutic agents has garnered ronment through an alteration of genetic behavior, uptake
a lot of interest (Xia et al. 2022). Endophytes are associated of the DNA, and started producing secondary metabolites
with the healthy tissue of the plant (Sadrati et al. 2013) and (Arora and Ramawat 2017). At least one plant harbour one
reside in the interior sections of the plant, such as the root, or more fungal endophytes, especially woody plants contain-
the stem, the petiole, and other components that are referred ing hundreds of species of fungal endophytes. The fungal
to as endophytes (Ma et al. 2013; Deepthi et al. 2018). In endophytes are found in different geographical and climate
1898, Vogl was the first person who reported that endophytic regions, fin-ray ubiquitously distributed, and rich in species
mycelium was present in the grass seeds of Latium teinutentuin diversity. The abundance of fungal endophytes with great
(Waghunde et al. 2021). Around 300,000 plant species, each extent, ubiquitous nature, diversity, and wide range of eco-
individual having one or more endophytes and having one to logical functions are shown to be greatly adapted for plants
hundred strains of endophytes varying according to the host under worldwide distribution and selective pressure (Rod-
system (Gao et al. 2018). They got much attention when it riguez et al 2009).
became apparent that entophytes can produce bioactive All these findings indicate that fungal endophytic popu-
secondary metabolites with varied molecular structures, which lation colonization inside the host tissue confers tolerance
are barely impersonated by synthetic chemistry (Mengistu under specific environmental stresses condition and is
2020). Endophytes play a crucial role in plant development, responsible for the survival of plants. Extensive research
and survival, and regulate some defense mechanisms. They on fungal endophytes (FE) found their crucial role in abi-
are formed to be a composite equilibrium to achieve the otic and biotic stress tolerance, nutrient supply, growth, and
host boundary and build a mutualistic association with the plant development. When searching for natural products
host (Alam et al. 2021; Nanda et al. 2019). During stressed mediated by endophytes, researchers may explore EF. It
conditions in the plant, endophytes secreted a range of is well established that many bioactive metabolites (BM)
secondary metabolites in plant cells and incorporated them with potential pharmacological effects are produced by EF
into the stressed pathways (Nanda et al. 2019). Secretion of (Tiwari and Bae 2022). The bioactive compounds produced
stress-controlled molecules like gibberellins (GB), cytokinin by EF albeit receiving much less attention. The development
(CIS), salicylic acid (SA), and indole-3-acetic acid (IAA) and production of biomass need a thorough understanding
enhance plant growth and development and is responsible of endophyte ecology, bioactive components, and the bio-
for many physiological changes in the plant (Shekhawat et al. transformation of substrates. Considering the information
2021; Duc et al. 2018; Shaffique et al 2022). available on EF, the article is aimed to review the sampling,
The biochemical and pharmaceutical industries rely on optimization, production, and extraction of the secondary
endophytic fungi as a source of new therapeutic biomol- metabolites from EF and the pharmacological relevance of
ecules that could be immune-suppressant compounds, the different bioactive metabolites produced by endophytic
anti-cancer drugs, plant growth promoters, anti-microbial fungi associated with plants (Fig. 1).
volatiles, insecticides, anti-oxidants, and antibiotics, offer
significant potential for application in medicine. Further-
more, endophytic microorganisms can lessen a plant's capac- 2 Sampling and optimization of media
ity to endure nutritional deficiency, high temperatures, salt, for the production of BM from EF
trace metals, and water scarcity (Eid et al. 2021). Amylase,
cellulase, lyase, and laccase are important enzymes that have The first steps in sampling and isolation of bioactive
significant industrial applications and endophytes play a role molecules from EF are collecting plant material having
in their synthesis (Sharma et al. 2021). Research suggested EF from different geographical areas and pre-processing
that the fungal endophytes found to be heterotrophic organ- the plant material, which may involve surface cleaning,
isms with various life cycles in natural ecosystems form a slicing, and selecting media. Surface sterilizing agents
symbiotic relationship with plants. The fossil record also like mercuric chloride ­(HgCl2), ethanol, etc., are used to
reported that endophytic fungi and host plants were associ- wash and surface sterilize the plant components (leaves,
ated for 400 million years and intimately involved in the stems, seeds, etc.) (Bisht et al. 2016). They are subsequently

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Secondary metabolites from endophytic fungi: Production, methods of analysis, and diverse… 113

Fig. 1  Entry and Colonization of the fungal endophytes in response metabolites to modulate plant defense, plant growth, and functional
to biotic (herbivores and pathogens) and abiotic (drought, salin- role in the pharmacology
ity, heavy metals, and others) stresses and production of secondary

diced and cultured in LB media on a PDA (potato dextrose to manufacture myriads of BM. These include antibiotics,
agar) plate. Hyphal tips are harvested from the fungus and anti-oxidants, pigments, enzymes, etc. (Mrudula and
then transferred to PDA slants, where they are tested for Murugammal 2011; Patil et al. 2016). Similarly, cellulase
bioactive secondary metabolites after an extended period of enzyme production from Pestalotiopsis sp (Chen et al.
incubation (Sharma et al 2016). It is vital to build a suitable 2011) and glucoamylase from Aspergillus flavus (Karim
cultivation system for commercial use because EF can et al 2017) has been performed previously. Vimal and
produce many biologically active metabolites. Endophytes Kumar 2022 reported optimized production of medically
can be grown through liquid-submerged or solid-state important L-asparaginase enzyme under solid-state
fermentation (SSF). EF fermentation is fruitful, continuous, and submerged fermentation from agricultural wastes.
and environmentally beneficial. Submerged culture Similarly, microorganisms are cultured on Wheat bran,
produces mycelial biomass and bioactive metabolites Cajanuscajan (red gram), Phaseolus mungo (mung bean),
faster. It needs less time and has fewer contamination risks. and Glycine max (soybean) bran in solid-state fermentation
Extensive research has been done on bioactive compounds (SSF). Chitosan production by A. terreus was reported by
produced by endophytic fungus in submerged fermentation. submerged fermentation in the optimized condition (Abo
In liquid fermentation, temperature, pH, aeration, and Elsoud et al. 2023). SSF from fungal cultures provides
agitation affect secondary metabolite production. In various advantages over submerged fermentation to
addition, each of these different characteristics has been manufacture bioactive chemicals in the food, agricultural,
optimized, which has led to an increase in the overall and pharmaceutical industries. Furthermore, this includes
production of BM (Debbab et al. 2013; Brader et al 2014). comparatively improved productivity, greater product
Various researchers used liquid-submerged fermentation concentrations, and simple equipment requirements for the

13
114 V. K. Singh, A. Kumar

fermentation process of BM (Patil et al 2016). Lovastatin, in the structural characterization of BM. According to
a potent medication for decreasing blood cholesterol, was Madhusudhan et al. (2015), X-ray diffraction (XRD) is also
extracted from the healthy tissues of Taxusbaccata by an promising for crystalline biomolecules.
endophytic fungus, A. niger PN2, using SSF with wheat
bran as the substrate (Raghunath et al. 2012). Further, we 3.1 TLC
discuss the production and extraction of the SM from EF.
TLC analysis was used to extract the bioactive components
of Pestalotiopsis neglecta BAB-5510, a fungal endophyte
3 Production and extraction that was isolated from the leaves of Cupressus torulosa D.
of the secondary metabolites (SM) Don. Two distinct fractions were observed on the silica gel
from endophytic fungi (EF) TLC plates after being developed in dichloromethane and
methanol at a ratio of 90:10, with the second fraction hav-
Biomolecules like polysaccharides, polypeptides, ing an ­Rf value of 0.79. TLC was employed to separate the
unsaturated fatty acids, and glycoproteins are commonly extracted secondary metabolites synthesized by fungal endo-
known as elicitors. EF produces the elicitors or signaling phytes, which have been isolated from Mentha piperita. The
molecules stimulated by the bioactive phytochemical ­Rf values of the metabolites that were isolated from bacterial
accumulation in plants. Some of them provide defense endophytes were found to be quite comparable to those that
to plants against disease-causing organisms. They also were obtained by the TLC chromatogram.
stimulate the production of several phytochemicals,
including alkaloids, flavonoids, terpenoids, saponins, 3.2 GC–MS
and phenols (Chandran et al. 2020). The oligosaccharide
components of Colletotrichum gloeosporioides' crude According to the findings of gas chromatography performed
endophytic mycelium have been demonstrated to on Pestalotiopsis neglecta BAB-5510, the most important
stimulate artemisinin synthesis in hairy root cultures active compounds of Pestalotiopsis sp. BAB-5510 are
of Artemannua (Hussain et al. 2015). The bacterial culture nonadecane (19.74%), 1,2,3-propanetriol, 1-acetate (17.21%),
was incubated at 32 °C in broth for 36 h, whereas fungal bis (2-Ethylhexyl) phthalate (14.41%), and 4 Hpyran-4-one,
cultures were incubated at 28 °C for two weeks with 150 rpm 2,3-dihydro-3,5-d (Bunaciu et al. 2015). The GC–MS spectra
shaking. Several solvents were employed alone or in revealed that these metabolites were terpenes, more notably
combination to extract metabolites. Ethyl acetate, methanol, cinnamaldehyde, cinnamyl alcohol, and eugenol (Kumar et al.
dichloromethane, hexane, and ethanol are routinely used to 2017) and GC–MS is particularly suitable to identify volatile
extract metabolites from the culture broth. The solubility of organic compounds.
the desired component determines the extraction solvent.
Equal amounts of solvents were added to the filtrate and 3.3 HPLC & LC–MS
agitated for 10 min until two transparent immiscible layers
appeared. The extracted compounds were separated from Silica gel column chromatography and high-performance liquid
the solvent using a funnel. The solvent was evaporated and chromatography were used to purify BMs. The Taxus cuspi-
the compound was dried in a rotator vacuum evaporator to date culture media was treated with di-chloromethane to extract
produce the crude metabolite (Bhardwaj et al. 2015). The taxol, which was then purified and quantified by employing
crude extract was diluted with dimethyl sulphoxide and kept HPLC. Finally, the structure of taxol was confirmed by utilizing
at 4 °C. Phytochemical screening was conducted to look LC–MS and H-NMR spectroscopy (Sharma et al. 2016). Ethyl
for alkaloids, saponins, tannins, flavonoids, steroids, sugars, acetate was used to extract vinblastine and vincristine from the
and cardiac glycosides (Mathew et al. 2012). The isolation fungus endophyte Fusarium oxysporum.
and characterization methods of secondary metabolites
isolated from fungal endophytes are discussed in Table 1 and 3.4 NMR
in this section; we discuss some high throughput methods
precisely used for analysis of SM from EF. Chromatographic To evaluate the molecular masses of the purified compounds,
methods such as TLC and HPLC were employed to get electrospray ionization mass spectrometry (ESI–MS) and
the secondary metabolite extract as pure as feasible. The tandem mass spectrometry (MS–MS) followed by nuclear
recovered fractions are usually analyzed by the use of gas magnetic resonance (NMR) analysis utilized by Kumar et al.
chromatography-mass spectrometry (GC–MS), Fourier 2013. They performed isolation, purification, and charac-
transform infrared (FTIR), and nuclear magnetic resonance terization of Vinblastine and Vincristine from EF Fusarium
(NMR). NMR and MS are the principal techniques exploited oxysporum isolated from Catharanthus roseus.

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 Table 1  Isolation, characterization, and their functional role of secondary metabolites isolated from fungal endophytes
Endophytes Compound Host plant Genome Class of Activity/Function Yield Growth media/extraction Method of Characterization Reference
size of compound medium purification
Endophytes
(Mb)

Alternariaalternata Taxol Taxuschinensis var. 33.67 Alkaloids Anticancer, Cyto- 84.50 mg/mL PDB medium HPLC LC–MS, H NMR (Shankar Naik 2019)
mairei toxicity, Methanol extraction
Fusariumoxysporum Vincristine Catharanthusroseus 52.60 Alkaloids Anticancer 67 ug/L PDB medium TLC and UV–Vis spec- (Kumar et al. 2013)
Ehtyle acetate extraction HPLC troscopy, ESI–
MS/MS, and 1
H NMR
Penicilliumcitrinum Huperzine A Huperziaserrata 32.19 Alkaloids Treating for Alz- 1.38 mg/L PBD Medium TLC and ESI–MS, LC– (Thi Minh et al. 2019)
heimer’s disease Chloroform & Meth- HPLC MS, H NMR
(AD) anaol extraction
Nectriahaematococca Quercetin Zingibernimmonii (J. 54.43 flavonoid Anti-oxidant 5.82 ± 0.2 mg/ PBD Medium HPLC ESI–MS and ( Das et al. 2017)
Graham) glycosides gm Ethyl acetate extraction MS–MS
Fusariumsolani Camptoth- Camptothecaacuminata 51.74 Quinolone Anticancer (1.2 to 152 fold) PDB medium Chloro- TLC and ESI–MS (Kaur et al. 2020)
ecin Alkaloids form and methanol HPLC
(4:1 v/v)
Biscogniauxiacylin- Isofraxidin Rice (Oryza sativa) - Polyketides Antibacterial activ- 2.5 mg/1.5 KG PDA medium TLC 1H NMR, ESI– (Wu et al. 2019)
drospora ity, Anti-oxidant, Methanol extraction MS
Anticancer
Phomopsis sp. Gallic acid Acer ginnala - Phenol anti-oxidant, anti- 29.25 mg/gm PDA medium HPLC ESI-NMR (Qi et al 2009)
inflammatory, Methanol extraction
anti-microbial,
anti-cancer
Alternaria sp. Berberin Coptischinensis _ Isoquinoline Antibacterial, antidia- 9.313 μg/gm PDA medium TLC, MS-NMR (Zhang et al. 2016)
alkaloid betic, antihyperten- Methanol extraction HPLC
sive,
Secondary metabolites from endophytic fungi: Production, methods of analysis, and diverse…

Colletotrichumgloe- Piperine Piper nigrum 57.60 Alkaloids anti-diabetic, – PDA medium Ethyl HPLC HPLC and (Chithra et al. 2014)
osporioides antidiarrheal, acetate extraction LCMS
anti-oxidant,
antibacterial
Phomopsisvexans Lovastain Solanumxanthocarpum 59.78 Polyketide Controlling the 550 mg/L PDA,Czapek Dox broth TLC, FT-IR, UV, C (Parthasarathy and
blood cholesterol medium. Ethyl acetate HPLC NMR, and LC– Sathiyabama 2015)
level extraction MS analyses
Fusariumoxysporum Diosgenin Dioscoreazingiberensis 52.60 triterpenoids Antitumor, Anti- 5.21 mg/L PDA medium HPLC GC–MS, LC–MS (Biswas et al. 2020)
inflammatory Ethyl acetate, methanol
extraction

13
115
 Table 1  (continued)
116

Endophytes Compound Host plant Genome Class of Activity/Function Yield Growth media/extraction Method of Characterization Reference
size of compound medium purification

13
Endophytes
(Mb)
Epicoccumnigrum Hypericin Hypericumperforatum 34.73 Benzopyr- Antidepressants, 320.4 ng/mg PDB medium HPLC HPLC-HRMS, (Vigneshwari et al.
enes` antitumorsand Ethylacetate, extraction HRMS/MS 2019)
antiviral
Fusariumoxysporum Ginkolide B Ginkgo biloba 52.60 Diterpenoids Anti-inflammatory, 0.2 mg/mL PDB medium TLC HPLC/ ESI–MS (Cui et al. 2012)
Antiallergic Ethyl acetate, extraction and 13C-NMR
Colletotrichumcoc- Tyrosol Houttuyniacor- 50.24 Phenolic Anti-microbial 2.3 mg/mL PDB medium TLC 1H NMR-MS (Talukdar et al. 2021)
codes data Thunb glycosides Ethyl acetate, extraction

Alternaria spp. Emodin Hypericumperforatum 33.67 Hydroxyanth- Antibacterial, 20.8 ng/mg PDB medium HPLC HPLC-HRMS, (Vigneshwari et al.
raquinones Antiulcer, Anti- Ethyl acetate, extraction HRMS/MS 2019)
inflammatory,
Anticancer, and
Antinociceptive
Penicilliumfrequen- Curcumin Curcuma wenyujin - phytopolyl- anti-microbial, 12.6 mg/5.213 g PDA medium Czapek silica ESI–MS,1H (Yan et al. 2014)
tans phenol anti-cancer, anti- medium column NMR
inflammatory and chloroform–methanol chroma-
anti-oxidant extraction tography,
TLC
Annulohypoxylon- Cinnamic Oryza sativa - Phenolic acid anti-oxidant and 1.5 mg /2.8 gm PDA &RGYmedium, TLC UV, ESI–MS,1H (Cheng et al. 2011)
boveri var. micro- acid antibacterial N -butanol,chloroform- NMR
spora activities, ethyle acetate extrac-
tion
V. K. Singh, A. Kumar
Secondary metabolites from endophytic fungi: Production, methods of analysis, and diverse… 117

4 Pharmaceutical application 4.2 Siderophore

of the endophytic fungal secondary
metabolites Micronutrient metals including nickel, copper, zinc, and iron
are essential for soil plants and microorganisms, however,
EFs are eminent for their competence in synthesizing a dis- their bio-availability is often low due to environmental fac-
tinct variety of pharmacologically significant chemicals with tors (Satapute et al. 2019). Reduced bioavailability of Fe(III)
immense therapeutic promise, including antiviral, antifungal, directly results from forming insoluble oxyhydroxide phases
antibacterial, antitumor, and anti-cancer activity. Various EFs in response to harsh environmental conditions. Due to a lack
are potential sources of plant growth factors and hormones. of iron, plants develop chlorosis and have lessened metabolic
Some endophytes have been demonstrated to release a broad activity and biomass. In response to various stresses, plants,
spectrum of extracellular enzymes, such as phosphatase and microbes have evolved a chelation strategy to increase
enzyme, which converts insoluble phosphates to soluble forms metal availability (Chowdappa et al. 2020). Endophytes
for easier assimilation by plants. Secondary metabolites of secreted small molecules called siderophores capable of
EFs have been demonstrated to strengthen the host's immune chelating iron and increasing the bioavailability of the iron
system, reducing the severity of infections and the damage molecule to the plant (Yadav 2018). The iron in the soil can
caused by pathogenic microorganisms (Sharma et al. 2021). be dissolved with the assistance of secreted siderophores,
The biocontrol systems of plants are responsible for the pro- which have a strong affinity for the substrate and the poten-
duction of various kinds of BMs, which shield plants against tial to assimilate it. The bacterial iron-siderophore complex
potentially lethal diseases and stimulate their development makes iron accessible for plant development while simulta-
(Santos et al. 2018; Hardoim et al. 2015). Their pharmaceuti- neously reducing the acquisition of iron by phytopathogens,
cal role was experienced against various diseases (Table 1) which restricts phytopathogen proliferation (Santos et al
and they are discussed below. 2018). Despite this, the chemical composition of different
microorganisms' siderophores can be somewhat distinct. For
instance, bacterial hydroxamates are composed of hydroxy-
4.1 Antibiotics lated and acylated alkylamines, whereas fungal hydroxamates
are composed of hydroxylated and acylated ornithine groups.
Antibiotic synthesis through metabolic pathways is widely Chelating compounds can be obtained from endophytic fungi
regarded as an effective strategy for protecting plants derived from Cymbidium aloifolium. This medicinal orchid
against illness. Phytopathogens can be inhibited by vari- can secrete exogenous siderophores and form stable com-
ous bioactive substances and out of them few have been plexes with the metal ion F ­ e3+. These metabolites have the
researched (Suryanarayanan 2013; Daguerre et al. 2017). great potential to act as antibacterial siderophores. In a similar
Endophytes produced diverse metabolites, most of which vein, a hydroxamate-type siderophore obtained from P. cry-
have anti-microbial properties. These metabolites include sogenum was found to possess potent antibacterial activities
alkaloids, flavonoids, peptides, phenols, polyketides, qui- against some of the most virulent phytopathogens, hence safe-
nones, steroids, and terpenoids (Lugtenberg et al. 2016; guarding peanuts and rice plants (Chowdappa et al. 2020). To
Fadiji and Babalola 2020). DAPG, also known as 2, 4-dia- evaluate the inhibitory efficacy of exogenous deferoxamine-B
cetyl phloroglucinol, is a phenolic antibiotic with a broad and siderophores-exochelin MS (a pentapeptide derivative)
spectrum of activity and has shown Pseudomonas spp. against methicillin-resistant Staphylococcus aureus, metallo-
It contributes to the biological control of plant diseases, lactamase producers Acinetobacter baumannii, and Pseu-
particularly soil-borne (Bonaterra et al. 2022). The novel domonas aeruginosa, disc diffusion, micro broth dilution,
alkaloid altersetin was isolated from the endophyte Alter- and turbidimetric growth tests were utilized (Gokarn and Pal
naria spp. showing substantial antibacterial activity against 2018). The combination of siderophores and antibiotics was
various pathogenic gram-positive bacteria. Fungal endo- effective against the drug-resistant isolates. They can treat
phytes isolated from Artemisia annua have been shown to antibiotic-resistant bacteria and acute iron intoxications such
inhibit the development of most phytopathogenic organ- as hemochromatosis by producing sideromycins. Evidence
isms in vitro by secreting n-butanol and ethylacetate (Fadiji suggests they help to treat malaria (Chowdappa et al. 2020),
and Babalola 2020). In addition, pseudomonads spp. gen- bioremediating mercury (Pietro-Souza et al. 2020), and other
erate cyclic lipopeptides (CLPs) amphiphilic molecules plant diseases. According to some research, microorganisms'
with chains of 7–25 amino acids that act as biosurfactants sensitivity to oxidative stress is lowered by siderophores. They
and are significant in biological control because of their can be used in cosmetics, cancer therapy, combat fish infec-
favourable competitive capability with numerous groups of tions, and against bacterial/fungal phytopathogens (Chow-
microorganisms (Flury et al. 2017; Bonaterra et al. 2022). dappa et al. 2020; Peralta et al. 2016).

13
118 V. K. Singh, A. Kumar

4.3 Hydrolyzing enzyme Enterobacter, Klebsiella, Burkholderia, Pantoea, Rhizo-

bium, Bacillus, Rhodococcus, Acetobacter, etc., are famil-
Endophytes make lytic enzymes like amylases, lipases, iar endophytic IAA producers (Eid et al. 2021). IAA syn-
cellulases, pectinases, proteases, phosphatases, thesis also increases the size of bacterial cell walls, speeds
hemicellulases, chitinases, and 1, 3-glucanases (Mishra up the release of exudates, and makes more of the nutrients
et al. 2019), which help them form symbiotic relationships that help other beneficial bacteria thrive in the rhizosphere
with host plants and control of plant pathogens. Cellulase more accessible. As a result, IAA is the primary effector
produced by endophytic fungi such as Epicoccum nigrum, molecule of endophytic bacteria involved in phytostimu-
Trichoderma asperellum, and Alternaria longipes has lation, pathogenicity, and plant–microbe interaction (Ete-
been shown to suppress the development of Epicoccum sami et al. 2015). A specific form of bacterial endophyte
sorghinum, Alternaria alternata, Fusarium thapsinum, contains 1-aminocyclopropane-1-carboxylate deaminase,
and Curvularia lunata in vitro by hydrolyzing the cell which allows it to convert the ethylene precursor ACC
wall (Fadiji and Babalola 2020). The biocontrol efficacy into ammonia and beta-ketobutyrate. (Eid et al. 2021).
against tall fescue leafspot and sugar beet damping-off Due to the release of ACC deaminases, these bacterial
was reduced after mutations in the 1,3-glucanase genes endophytes can stimulate plant development in nitrogen-
of Lysobacteren zymogenes. The lytic enzymes produced limiting environments. Additional benefits include a more
by Streptomyces are also effective against cocoa witch robust immune system and increased resistance to abiotic
broom (Gao et al. 2018). Lytic enzymes produced by stress. In the case of sorghum plants, Pseudomonas bras-
endophytes are often more robust and can function on a sicacearum (SVB6R1) increases the expression of ACC
broader pH, temperature, and pressure range as compared deaminase, increasing the plant's resistance to salt stress
to enzymes produced using traditional chemical catalysts (Gamalero et al. 2020).
(Tiwari 2015). These features also bode well for the
commercial use of these enzymes in the food, detergent,
paper, pharmaceutical, energy, and biofuel industry (Rana 4.5 Nutrients
et al. 2019) because endophytic amylase hydrolyzes starch
by accelerating the creation of 1,4 glycosidic bonds The expansion of agricultural production is facilitated by
(Tiwari 2015). Bacterial pectinases, which depolymerize biofortification, which simplifies the uptake of nutrients
pectin linkages, are also widely utilized and have many by plants. Fungal endophytes can colonize plant struc-
applications in juice and food industries as well as in tures such as roots, stems, and leaves and they are less
paper/pulp production, composting, recycling, etc. (Haile likely to be outcompeted than microbes that live in the
and Ayele 2022). soil, therefore, they can be utilized as a replacement to
boost the plant's ability to fix nitrogen (Santos et al. 2018).
4.4 Growth‑promoting hormones The presence of many microorganisms in the soil allows
for the breakdown of insoluble phosphate and thus phos-
Plant growth stimulation is bolstered, and phytohormones phorus is made available to the plants (Alori et al. 2017).
produced by fungal endophytes alter the plant's shape In addition to their involvement in the release of organic
and form. This quality of endophytes has helped them acids into the soil, endophytes are also involved in the
progress in sustainable agriculture (Fadiji and Babalola solubilization of phosphate complexes and the conversion
2020). Phytohormones or plant growth regulators are of these compounds into the ortho-phosphates that plants
chemical substances that control, impede, or accelerate absorb more readily. Ca3(PO4)2 solubility was observed for
growth promotion and development of plants at low con- poplar endophyte strains WP5 and WP42, and subsequent
centrations (Damam et al. 2016). Many phytohormones, solubilization tests validated this observation (Kandel et al.
including auxins, gibberellins, abscisic acid, cytokinins, 2017; Khan et al. 2015; Varga et al. 2020). Selenobacteria
ethylene, strigolactones, brassinosteroids, and jasmonates is a plant endophyte that can draw selenium out of the soil
are produced by endophytic microorganisms (Santoyo and transmit it to the host plant, where it can be used to
et al 2016; Shahzad et al. 2016). The primary function promote plant development. Selenium biofortification in
of indole-3-acetic acid (IAA) in plants is to stimulate cell Glycine max may be enhanced by the endophyte Parabur-
growth and division. The IAA generated by the bacteria kholderia megapolitana (MGT9) during drought (Trivedi
in symbiosis facilitates nutrient availability, increases root et al. 2020). Zn solubilizing endophytes (such as B. subtilis
exudation, and encourages the growth of adventitious and DS-178 and Arthrobacter sp. DS-179) improve the trans-
lateral roots. The bacteria of the genera Azospirillum, location and enrichment of Zn to grain in specific Wheat
Herbaspirillum, Azotobacter, Alcaligenes, Pseudomonas, genotypes (Singh et al. 2018).

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Secondary metabolites from endophytic fungi: Production, methods of analysis, and diverse… 119

4.6 Phytoremediation camptothecin (extracted from A. niger) caused apoptosis

when given to colon cancer cell lines, and cell death occurs
As the global economy has become more industrialized over at dosages as low as 7.8 mg/L and as high as 1000 mg/L
the past century, various anthropogenic chemicals have been with the highest and lowest cell viability occurring at con-
released into the environment. These include polycyclic centrations of 11.85 and 65.13%, respectively (Aswani and
aromatic hydrocarbons (PAHs), petroleum hydrocarbons Soundhari 2018). Fusarium oxysporum generates the anti-
(PHC), halogenated hydrocarbons, salt, solvents, pesticides, cancer compound vinblastine in Cathranthus roseus, which
and heavy metals (Bisht et al. 2015). Microbe-assisted phy- is helpful against lymphoblastic leukemia and cancer cell
toremediation is a method that deals with these issues. Due lines HepG-2 at 7.48 g/mL (Kousar et al. 2022).
to endophytes' closer relationship with their host plants,
phytoremediation may be enhanced (Li et al. 2012). It has 4.8 Immunosuppressive activity
been discovered that many endophytes can withstand high
concentrations of heavy metals and degrade organic pollut- An immediate quench strategy to overcome graft rejection
ants. Because of their prolonged exposure to the high metal and autoimmune diseases; researchers have been looking for
concentrations stored in the hyperaccumulators of these a substance that might dampen the immune system (Raja-
plants, the endophytes associated with these plants may manikyam et al. 2017). Fungal endophytes can synthesize
have become more resistant to the negative consequences some substances with immunosuppressive effects (Egbuta
of metal exposure (Aishwarya et al. 2014). Furthermore, it et al. 2017). Synthetic chemical immunosuppressive medi-
has been demonstrated that releasing low-molecular-mass cations have serious side effects because of the time they
organic acids by specific endophytes might boost heavy- took to treat diseases. Infection risks like hyperlipidemia,
metal mobilization. For example, the organic acids produced nephrotoxicity, hypertension, and neurotoxicity have side
by endophytes caused the pH of a solution to fall when the effects from long-term usage of chemical immunosuppres-
water-soluble Pb concentration increased. When the con- sive medications (Hošková et al. 2017). A recent study has
centration of water-soluble Pb rose, the pH of the solution revealed that immunosuppressive medicines produced from
decreased because of the organic acids generated by endo- fungal endophytes are highly effective. Sydoxanthones A
phytes (Yongpisanphop et al. 2020). and B, 13-O-acetylsydowinin B, colutellin A, methyl peni-
phenone, dibenzofurane, xanthone derivatives, subglutinols
4.7 Anti‑cancer activity A and B, peniphenone, lipopeptide, benzophenone deriva-
tives, (-) mycousnine, etc. are used in the treatments. There
Cancer is the second largest cause of mortality worldwide was speculation that cyclosporin A, an immunosuppressant
due to its high incidence rate. Malignant cells kill 15 mil- medication, originated in the fungus Tolypocladiumin flatum
lion people annually, and the number is rising. Cancer can (El-Gowelli and El-Mas 2015). cyclosporin A, an extract
be treated with safe, biocompatible, less toxic, and more from the endophytic soil fungus Trichoderma polysporum,
resistant natural chemicals from endophytic organisms. was discovered as a critical immunosuppressive agent.
These natural chemicals are cancer treatment alternatives Endophytic fungus Fusarium subglutinan was discovered
to chemotherapeutic medicines. These natural chemicals are in Tripterygium wilfordii, where it produces noncytotoxic
anti-cancer and can control many malignancies. Due to their diterpene pyrenes and immunosuppressive Subglutinol A
abundance, they can be employed to treat cancer. Endophytic and B (Vasundhara et al. 2016; Adeleke et al. 2021).
fungi including Taxomyces andreanae, Seimatoantlerium
nepalense, Alternaria alternate, and Chaetomellaraphigera 4.9 Anti‑diabetic activity
have been linked to the production of the anti-cancer drug
paclitaxel (Kousar et al. 2022). Paclitaxel treats Kaposi's Recent research has suggested that endophytic fungus might
sarcoma, prostate, lung, and ovarian cancer (Weaver 2014). be a source of substances with anti-diabetic properties. The
It binds to tubulin and inhibits depolymerization during endophytic fungus Nigrosporaoryzae in Combretum dolicho-
cell division (Leung and Cassimeris 2019). Taxol isolated petalum leaves has been proven to lower fasting blood sugar
from sick Chilli plant fruits has shown cytotoxic activity in diabetic mice when its purified components are adminis-
against human cell lines MCF-7, HLK-210, and HL-251. tered (Uzor et al. 2017). These chemicals include abscisic
Endophytes Sinopodophyllum hexandrum and Dysosma acid, 70-hydroxy abscisic acid, and 4-des-hydroxyl alter-
veitchii generate podophyllotoxin which is used to treat solanol A. Indrianingsih and Tachibana (2017) showed that
leukemia, testicular, prostate, lung, and ovarian cancer 8-hydroxy-6,7-dimethoxy-3-methyl isocoumarins exhibit
(Leung and Cassimeris 2019). Camptothecin is an effective strong glucosidase inhibitory effect and are produced by the
cytotoxic compound for the treatment of solid tumors of endophytic fungus Xylariaceae spp. in the stem of Quercus-
the liver, bladder, lungs, and ovaries. A study found that gilva Blume. Oral administration of glucose and alloxan to

13
120 V. K. Singh, A. Kumar

Wistar albino rats accompanied with Salvadoraoleoides (Kumar et al. 2017). Alternaria alternate and Phomopsis spp.,
extracts of Phoma spp. and Aspergillus spp. induced anti- two fungal endophytes isolated from Thai medicinal plants,
diabetic and hypolipidemic effects (Ezekwesili and Ogbunu- have been shown to generate 3-nitro propionic acid and tenu-
gafor 2015). Endophytic fungi isolated from medicinal azonic acid, exhibit indecisive action against M. tuberculosis
plants such as Rauwolfia densiflora and Leucas ciliata have (H37Ra) (Kumar et al. 2017; Deshmukh et al. 2015). Endo-
been tested as a potential therapeutics for diabetes through phytic fungus Phomopsis spp. isolated from Garcinia adulcis
bioprospecting. There is evidence that compounds generated generates bioactive metabolites with anti-tuberculosis poten-
from Fusarium spp. and Alternaria spp. exhibit anti-diabetic tial (Kumar et al. 2017). These metabolites include phomoe-
action, suggesting that these fungal endophytes may serve as namide and phomonitroester. Benzopyran, diaportheone A
a source of multifunctional therapies (Adeleke et al. 2021). and B are bioactive chemicals produced by Diaporthe spp.
They are associated with the leaves of Pandanus amaryllifo-
4.9.1 Anti‑malarial activity lius and suppress aggressive strains of M. tuberculosis (Chep-
kirui and Stadler 2017).
Due to the rapid spread of anti-drug resistance malaria para-
sites in recent years, there is an urgent need for novel malaria 4.9.3 Antiviral
therapy drugs. It was shown that the anti-malarial activity
of two endophytic fungi, munumbicins E-4 and E-5, was Evidence suggests that endophytic fungi can create antivi-
twice as potent as that of chloroquine (Fadiji and Babalola ral drugs that are effective against a wide range of viruses,
2020). The endophyte Diaporthemiriciae is responsible for including HIV (Farooq et al. 2016), human CMV (Raekian-
producing the secondary metabolite epoxy cytochalasin H. syah et al. 2017), Dengue virus (Liu et al. 2019), and influ-
This compound exhibits robust anti-malarial suppression enza A (HINI) virus (Ambele et al. 2020). Antiviral activity
against a strain of Plasmodium falciparum resistant to chlo- has been found in two novel substances, cytonic acid A and
roquine (Ferreira et al. 2017). Ateba et al. (2018) found that cytonic acid B, which are isolated from Cytonaema spp.
the endophyte species Paecilomyces lilcinus and Penicillium With the use of mass spectrometry and nuclear magnetic res-
janthinellum are great resources for new compounds that are onance, the structures of ptrideside isomers were conferred,
active against Plasmodium falciparum and show potential leading to the identification of novel inhibitors of the pro-
in the treatment of malaria. It has been proven that various tease activity of human cytomegalovirus. Fungal endophytes
endophytic fungi, in addition to Aspergillus niger, Fusarium in the phyllosphere (leaves) of an oak tree (Quercuscoccif-
spp., and Nigrospora spp. can produce bioactive compounds era) generate the antiviral chemical Hinnuliquinone, which
with an antiplasmodial effect against Plasmodium falcipa- has been linked to the inhibition of HIV-1 protease activity
rum (Kaushik et al. 2014). (Adeleke et al. 2021). Alternaria tenuissima QUE1Se is an
endophytic fungus that generates altertoxins, a substance
4.9.2 Antituberculosis with potent anti-HIV-1 action. In addition to emerimidine
(A, B), dehydroaustin, austinol, aspernidine (A, B), austin,
Tuberculosis (TB), an infection of the lungs caused by Myco- emeriphenolicins (A, D), and acetoxydehydroaustin, many
bacterium tuberculosis, is a worldwide health concern. It has other compounds isolated from Emericella spp. (HKZJ) have
lasted for centuries and is one of the world's most devastating been found to have antiviral activity against the influenza A
illnesses. The World Health Organization (WHO) estimates virus (H1N1) (Raekiansyah et al. 2017). The antiviral activ-
that 10 million individuals are currently living with TB. End- ity of most medicinal plant mixtures is relatively high, even
ing the TB pandemic by 2030 is one of the health aims of in their crudest forms. Antiviral activity in certain actinomy-
the sustainable development goals of the United Nations. M. cetes has been demonstrated (Fadiji and Babalola 2020). The
tuberculosis has been proven to acquire resistance to numer- antiviral chemical 2-(furan-2-yl)-6-(2S, 3S, 4-trihydroxybu-
ous synthetic medications. To this end, it is crucial to keep tyl) pyrazine was initially isolated from the plant species
looking for new, natural antimycobacterial medicines that may Jishengella endophytica 161,111. This chemical is adequate
kill mycobacteria without causing resistance. Bioprospecting to combat the spread of the influenza A (H1N1) virus (Fadiji
for fungal endophytes as a cure for TB is an exciting field of and Babalola 2020; Raekiansyah et al. 2017).
study since many fungal metabolites are naturally antimyco-
bacterial. Azadirachta indica and Parthenium hysterophorus 4.9.4 Other pharmacological potentials of the endophytic
fungal endophytes have been found to exhibit antibacterial fungal secondary metabolites
effects against TB (Mane et al. 2017). Phomopsis spp., an
endophytic fungus isolated from Garcinia spp. is responsible In addition to their potential uses in food, agriculture,
for the production of Phomoxanthone A and B, which have medicine, and cosmetics, the bioactive metabolites found
been shown to suppress the development of M. tuberculosis in endophytes are excellent pharmaceutical sources for

13
Secondary metabolites from endophytic fungi: Production, methods of analysis, and diverse… 121

treating various disease conditions (Shukla et al. 2014). The molecular actors of fungal endophytes that are engaged in
metabolites generated by fungal endophytes contain a wide the production of biopharmaceuticals of human interest, more
variety of functional groups including alkaloids, flavonoids, research is required. In conclusion, the use of metagenomics
terpenoids, phenolic acids, quinones, steroids, benzopyra- in conjunction with next-generation sequencing technologies
nones, tannins, tetralones, and chinones (Gouda et al. 2016). is projected to open a wide variety of hitherto undiscovered
Half of all deaths worldwide are attributable to infectious pools of antimicrobials that are released by endophytic micro-
and parasitic disorders. It has been established that endo- organisms that have not yet been farmed. Endophytes have
phytes are the origin of a wide variety of commercially just come to be seen as an important contributor to the overall
accessible bioactive chemicals and secondary metabolites. pool of biological variety and numerous bioactive molecules
New compounds produced by endophytic microbes have secreted by as-yet-uncultivated endophytic microbes are not
shown promise as antibiotics, anti-inflammatory agents, explored. The resources that endophytes give may be used
cancer treatments, immunosuppressants, anti-diabetic activ- for a variety of purposes, including formulations and bio-
ity, anti-malarial activity, and even insecticides (Fadiji and prospecting. Because of this, further research into the biology
Babalola 2020). of endophytes is required if we want to benefit from the pres-
ence of these organisms in the sectors of agriculture, industry,
and medicine. The discovery of bioactive natural chemicals
5 Conclusion discovered in endophytic fungus has had an indelible impact
on the treatment of a variety of diseases, including cancer,
The purpose of this article is to gather updated knowledge diabetes, and neurological conditions. With the use of cutting-
on secondary metabolites of endophytic fungi, their pro- edge biotechnology like genetic engineering and the microbial
duction, methods of analysis, pharmaceutical potential, and fermentation process, these microbial resources may be better
application. Microorganisms that are endophytic to a plant utilized for human benefit.
provide benefits to the host plant and stimulate plant growth
Acknowledgements The authors thank the parent institute NIT Raipur
via several direct and indirect mechanisms of action. Fungal (CG), India, for continuous support and assistance during scientific
endophytes represent an inexhaustible reservoir of pharma- writing.
cologically essential compounds. Endophytic fungi are an
essential component for the production of novel biomolecules Declarations
for the biochemical and pharmaceutical industries. The fun-
Ethics declarations Not Required.
gal endophytes are in a pivotal position in producing certain
enzymes, such as amylase, cellulase, laccase, lyase, etc., that Consent for publication Not applicable.
have significant commercial and pharmaceutical applications.
Several promising pharmaceutical lead molecules have been Conflict of interest The authors declare no conflict of interest.
reported and derived from endophytic fungi. Because they
produce physiologically active metabolites that are immune
suppressants, anti-cancer agents, promote plant growth, anti-
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