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White, J. Fungal Endophytes: Sources of Medicines. Encyclopedia. Available online: https://encyclopedia.pub/entry/7551 (accessed on 27 July 2024).
White J. Fungal Endophytes: Sources of Medicines. Encyclopedia. Available at: https://encyclopedia.pub/entry/7551. Accessed July 27, 2024.
White, James. "Fungal Endophytes: Sources of Medicines" Encyclopedia, https://encyclopedia.pub/entry/7551 (accessed July 27, 2024).
White, J. (2021, February 24). Fungal Endophytes: Sources of Medicines. In Encyclopedia. https://encyclopedia.pub/entry/7551
White, James. "Fungal Endophytes: Sources of Medicines." Encyclopedia. Web. 24 February, 2021.
Fungal Endophytes: Sources of Medicines
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This entry is adapted from the peer-reviewed paper 10.3390/microorganisms9010197

Fungal endophytes are well-established sources of biologically active natural compounds with many producing pharmacologically valuable specific plant-derived products.

Fungal Endophytes

1. Introduction

Several recent reports suggest that natural products may play a substantial role in the drug discovery and development process as a source of diverse and novel templates for future drugs[1][2][3][4]. With the rapidly evolving recognition that significant numbers of natural products are either produced by microbes or a result of microbial interactions with their hosts, the area of endophyte research for natural products is positioned to take the drug discovery and development process to the next level [5][6]. In the backdrop of the past 25 years of studies, endophytes may be defined as a polyphyletic group of unique microorganisms residing in healthy living internal tissues of the plants with covert and/or overt positive effects on their hosts. They establish a variety of intricate biological intra- and inter-relationships among them and with their hosts, respectively. Endophytes are able to produce a multitude of secondary metabolites with diverse biological activities[7][8][9]. However, merely 0.75–1.50% of known plant species has been explored for their endophytes yet. So, the opportunity to find new potential bioactive metabolites from cryptic endophytic microorganisms of nearly 374,000–400,000 plant species congruently occupying millions of biological niches is considered high [5][10]. This opportunity has increased further with the innovative discovery of biosynthesis of Taxus derived anticancer compound ‘taxol’ from its endophytic fungus T. andreanae in 1993 by Stierle et al.[11]. This discovery leads to renewed attention in endophytic fungi for isolating plant-derived medicinal compounds [12][13][14]. Later, a series of works revealed that a reasonable number of plant-derived compounds are synthesized by endophytes rather than hosts[9][15]. However, there are unsettled and contradictory reports regarding the phylogenetic origin of genes related to the biosynthesis pathway of such plant-derived compounds in host plants and their microbial endophytes [16]. The above facts prompted us to use the word “plant/host-derived” rather than “plant/host-origin” for such compounds. Nevertheless, it is now an established fact that endophytes can co-/produce, induce, and/or modify a plethora of “specific plant-derived” metabolites in-/outside of host plants[17][12][14]. Such discoveries opened the new horizons for the up-scaled production of plant-derived medicinal compounds from endophytes. The recent increase in demand for natural products and difficulties in accessing them from plants make endophytes interesting targets for the assessment and isolation of typical host-derived compounds[18][19]. Since medicinal plants are an inherent source of many therapeutic compounds, it is vital to explore their endophytes to isolate such compounds. The current review aims to provide an up-to-date overview on the globally isolated specific plant-derived bioactive compounds synthesized by fungal endophytes from the period 1993 to mid-2020. It will also focus on applications and modes of actions of such compounds. This review will also provide insights about different challenges in employing endophytes as an alternative source for the synthesis of plant-derived bioactive compounds and their application in drug discovery. Its outcome would certainly lead to strategize the use of endophytes as an efficient novel source for plant-derived metabolites. 

2. Plant-Derived Bioactive Natural Products from Fungal Endophytes

A wide array of secondary metabolites in fungi is biosynthesized from very few key precursor compounds by slight variations in basic biosynthetic pathways and can be classified into nonribosomal peptides, polyketides, terpenes, and alkaloids. Nonribosomal peptides are biosynthesized by multimodular nonribosomal peptide synthetases (NRPS) enzymes using both proteinogenic and nonproteinogenic amino acids. Polyketides are biosynthesized by polyketide synthase (PKS) enzymes from acetyl-CoA and malonyl-CoA units. Terpenes consisting of isoprene subunits are biosynthesized from the mevalonate pathway catalyzed by terpene cyclase enzymes. Alkaloids are nitrogen-containing organic compounds biosynthesized as complex mixtures through the shikimic acid and the mevalonate pathways, as they are usually derived from aromatic amino acids and dimethlyallyl pyrophosphate[20]. Other classes of fungal secondary metabolites are linked with the above four groups of compounds. For ease and better understanding, we have classified different fungal secondary metabolites as alkaloids, coumarins, flavonoids, lignans, saponins, terpenes, quinones, and xanthones, and miscellaneous compounds. Coumarins are a class of lactones consisting of a benzene ring fused to a α-pyrone ring and are mainly biosynthesized by the shikimic acid pathway from cinnamic acid. Flavonoids are synthesized by the phenylpropanoid pathway from phenylalanine using enzymes phenylalanine ammonia lyase (PAL), chalcone synthase, chalcone isomerase, and flavonol reductase [21]. Lignans are low molecular weight polyphenols biosynthesized by enzymes pinoresinol-lariciresinol reductase (PLR), PAL, cinnamoyl-CoA reductase (CCR), and cinnamyl-alcohol dehydrogenase (CAD)[22]. Saponins are glycosides containing a non-sugar triterpene or steroid aglycone (sapogenin) attached to the sugar moiety. Saponins are derived from intermediates of the phytosterol pathway using enzymes oxidosqualene cyclases (OSCs), cytochromes P450 (P450s), and UDP-glycosyltransferases (UGTs) [23]. Quinones are biosynthesized through several pathways; for example, isoprenoid quinones are synthesized by the shikimate pathway using chorismite-derived compounds as precursors, terrequinone by NRPS from L-tryptophan, dopaquinone by tyrosinase from tyrosine, and benzoquinone by catechol oxidase/PKS from catechol[24]. Xanthones comprise an important class of oxygenated heterocyclics biosynthesized through the polyacetate/polymalonate pathway by the internal cyclization of a single folded polyketide chain[25].

2.1. Plant-Derived Alkaloids from Fungal Endophytes

After a systematic literature survey, we enlisted 19 plant-derived medicinal alkaloids that have been produced by different endophytic fungi (Table 1), and some important alkaloids are described below.

Table 1. Plant-derived alkaloids produced by endophytic fungi.

Plant-Derived Alkaloids Activities/Applications Plant Source Endophytic Source Host Plant References
Aconitine Anticancer, anti-inflammatory, anti-neuralgic, cardiotoxic Aconitum spp. Cladosporium cladosporioides Aconitum leucostomum [26]
Berberine Antibiotic, antidiabetic, antihypertensive, antiproliferative hepatoprotective, hypolipidemic, vasodilator Berberis spp.,
Coscinium fenestratum, Hydrastis canadensis, Phellodendron amurense		 Alternaria sp. Phellodendron amurense [27]
Fusarium solani Coscinium fenestratum [28,29]
Caffeine CNS stimulant Coffea spp.,
Theobroma cacao		 Anonymous endophytes Osbeckia chinensis,
Osbeckia stellata,
Potentilla fulgens		 [30]
Camptothecin Antitumor Camptotheca acuminata,
Miquelia dentata,
Nothapodytes nimmoniana,
Ophiorrhiza spp.		 Entrophospora infrequens Nothapodytes foetida [31]
Entrophospora infrequens Nothapodytes foetida [32]
Neurospora sp. Nothapodytes foetida [33]
Valsa mali Camptotheca acuminata [34]
Nodulisporium sp. Nothapodytes foetida [35]
Fusarium solani Camptotheca acuminata [36]
Botryosphaeria parva,
Diaporthe conorum,
Fusarium oxysporum,
Fusarium sacchari,
Fusarium solani,
Fusarium subglutinans,
Fusarium verticillioides, Galactomyces sp.,
Irpex lacteus, Phomopsis sp.,
Fusarium sp.		 Nothapodytes nimmoniana [37]
Xylaria sp. Camptotheca acuminata [38]
Fusarium solani Apodytes dimidiata [39]
Botryosphaeria dothidea Camptotheca acuminata [40]
Alternaria alternata,
Fomitopsis sp., Phomopsis sp.		 Miquelia dentata [41]
Trichoderma atroviride Camptotheca acuminata [42]
Aspergillus sp. Camptotheca acuminata [36]
Fusarium oxysporum Nothapodytes foetida [43]
Capsaicin Anti-inflammatory, gastro-stimulatory Capsicum annuum Alternaria alternata Capsicum annuum [44]
Homoharringtonine Anticancer Cephalotaxus spp. Alternaria tenuissima Cephalotaxus sp. [45]
Huperzine A Acetylcholinesterase inhibitor, Alzheimer’s treatment Huperzia serrata Acremonium sp. Huperzia serrata (syn. Lycopodium serratum) [46]
Blastomyces sp., Botrytis sp. Phlegmariurus cryptomerianus [47]
Penicillium chrysogenum Huperzia serrata [48]
Shiraia sp. Huperzia serrata [49]
Cladosporium cladosporioides Huperzia serrata [50]
Colletotrichum sp.,
Trichoderma sp.		 Huperzia serrata [51]
Paecilomyces tenuis Huperzia serrata [52]
Aspergillus flavus, Mycoleptodiscus terrestris, Penicillium griseofulvum Huperzia serrata [53]
Penicillium sp. Huperzia serrata [54]
Fusarium sp. Phlegmariurus taxifolius [55]
Fusarium sp. Huperzia serrata [56]
Peimisine,
Imperialine-3b-D-glucoside		 Antiasthmatic,
antitumor,
expectorant		 Fritillaria spp. Fusarium sp. Fritillaria unibracteata
var. wabuensis		 [57,58]
Fusarium redolens Fritillaria unibracteata
var. wabuensis		 [59]
Piperine Anti-inflammatory, anticancer,
antimicrobial, antidepressant, hepatoprotective		 Piper longum,
Piper nigrum		 Periconia sp. Piper longum [60]
Colletotrichum gloeosporioides Piper nigrum [61]
Mycosphaerella sp. Piper nigrum [62]
Phomopsis sp. Oryza sativa [63]
Cinchona alkaloids:
Quinine,
Quinidine, Cinchonidine, Cinchonine		 Antimalarial,
antiarrhythmic,
analgesic		 Cinchona spp. Arthrinium, Fomitopsis, Diaporthe, Penicillium, Phomopsis, Schizophyllum Cinchona ledgeriana [64]
Fusarium incarnatum, Fusarium oxysporum (only quinine and cinchonidine) Fusarium solani
(only quinine)		 Cinchona calisaya [65]
Rohitukine Anticancer,
CDK inhibitor,
cytotoxic		 Amoora rohituka
Dysoxylum binectariferum,		 Fusarium proliferatum Dysoxylum binectariferum [66]
Fusarium oxysporum,
Fusarium solani		 Dysoxylum binectariferum [67]
Gibberella fujikuroi Amoora rohituka [67]
Sanguinarine Anticancer, antimicrobial, anti-inflammatory antioxidant,
antihelmintic, neuroprotective		 Macleaya cordata,
Sanguinaria canadensis		 Fusarium proliferatum Macleaya cordata [28,68]
Sipeimine Antibechic, anti-ulcer Fritillaria spp. Cephalosporium corda Fritillaria ussuriensis [69]
Solamargine Anticancer, cytotoxic Solanum nigrum Aspergillus flavus Solanum nigrum [70]
Swainsonine Toxicosis in livestock Astragalus,
Oxytropis spp.,
Swainsona canescens		 Embellisia sp. Astragalus, Oxytropis spp. [15,71]
Undifilum cinereum,
U. fulvum		 Astragalus lentiginosus, Astragalus mollissimus [72]
Fusarium tricinctum Oxytropis deflexa,
Oxytropis kansuensis		 [73]
Undifilum sp. Swainsona canescens [74]
Vinblastine,
Vincristine		 Antitumor Catharanthus roseus
(syn. Vinca rosea)		 Alternaria sp. Catharanthus roseus [75]
Fusarium oxysporum Catharanthus roseus [76]
Fusarium oxysporum Catharanthus roseus [77]
Talaromyces radicus Catharanthus roseus [78]
Eutypella spp. Catharanthus roseus [79]
Geomyces sp. Nerium indicum [80]
Vincamine Antihypertensive, vasodilator Vinca minor Anonymous Vinca minor [81]

2.2. Plant-Derived Coumarins (Benzopyrones) from Fungal Endophytes

Coumarins have been routinely employed as herbal remedies since the onset of herbal medicine. It was first isolated as a natural product from seeds of Dipteryx odorata (Coumarouna odorata) [102]. A total of seven medicinally important specific plant-derived coumarins are produced by fungal endophytes (Table 2).

Table 2. Plant-derived coumarins produced by endophytic fungi.

Coumarins Activities/Applications Plant Source Endophytic Source Host Plant References
Bergapten,
Meranzin		 Antioxidant,
psoriasis treatment		 Balanites aegyptiaca,
Citrus bergamia,
Grapefruit peel		 Penicillium sp. Avicennia [103]
Botryodiplodia theobromae Dracaena draco [104]
Isofraxidin Anticancer, anti-obesity, cardioprotective, neuroprotective, hyper pigmentation Acanthopanax senticosus,
Sarcandra glabra		 Annulohypoxylon bovei var. microspora Cinnamomum sp. [105,106]
Marmesin Anticancer, antihelmintic,
antioxidant, antisyphilitic, purgative		 Ammi majus,
Balanites aegyptiaca		 Fusarium sp. Mangrove [107]
Mellein Antibacterial, antifungal,
antihepatitis c, larvicidal,
phytotoxic		 Alibertia macrophylla,
Litsea akoensis,
Garcinia bancana,
Moringa oleifera,
Stevia lucida		 Septoria nodorum Conifer [108]
Penicillium janczewskii Prumnopitys andina [109]
Botryosphaeria mamane Anonymous [110]
A xylariaceous fungus Sapindus saponaria [111]
Annulohypoxylon bovei var. microspora Cinnamomum sp. [106]
Penicillium sp., Xylaria sp. Alibertia macrophylla,
Piper aduncum		 [112]
Annulohypoxylon squamulosum Cinnamomum sp. [113]
Nigrospora sp. Moringa oleifera [114]
Arthrinium (Apiospora montagnei) Anonymous [115]
Xylaria sp. Garcinia sp. [116]
Pezicula sp. Forsythia viridissima [117]
Xylaria cubensis Litsea akoensis [118]
Scopoletin,
Umbelliferone		 Antifungal,
antioxidant, anti-inflammatory		 Artemisia scoparia,
Scopolia carniolica
(syn. Scopolia japonica),
Viburnum prunifolium		 Penicillium sp. Avicennia [

2.3. Plant-Derived Flavonoids from Fungal Endophytes

Flavonoids are pigments of edible plants consisting of two benzene rings at either side of a three-carbon ring. Multiple substitutions in this basic structure produce several classes of derivatives, such as flavones, isoflavones, flavonols, flavanones, catechins, and anthocyanins. We found 12 different biologically active plant-derived flavonoids (Table 3) recovered from fungal endophytes and important flavonoids are described below.

Table 3. Plant-derived flavonoids produced by endophytic fungi.

Plant-Derived Flavonoids Activities/Applications Plant Source Endophytic Source Host Plant References
Apigenin Antibacterial, anticancer,
antioxidant, antihyperglycaemic,
lipid peroxidation, sedative,
thyroid dysfunction		 Cajanus cajan, Cephalotaxus harringtonia, Matricaria chamomilla, vegetables Colletotrichum sp. Ginkgo biloba [132,133,134]
Chaetomium globosum Cajanus cajan [135]
Paraconiothyriu mvariabile Cephalotaxus harringtonia [136]
Cajanol Anticancer, antimicrobial, antiplasmodial Cajanus cajan Hypocrealixii Cajanus cajan [137]
Chalcone Antibacterial, antifungal,
antitumor, anti-inflammatory		 Cleistocalyx operculatus,
Members of Leguminosae, Asteraceae, Moraceae		 Ceriporia lacerata Cleistocalyx operculatus (syns. Eugenia operculata, Syzygium operculatum) [138]
Chrysin Antiaging, anticonvulsant,
antidiabetic, anti-inflammatory,
antimicrobial, anxiolytic,
hepatoprotective		 Passiflora incarnata Alternaria alternata, Colletotrichum capsici, Colletotrichum taiwanense Passiflora incarnata [139]
Curcumin Anti-inflammatory, antioxidant, antitumor Curcuma spp. Chaetomium globosum Curcuma wenyujin [140]
Anonymous Curcuma wenyujin [141]
Kaempferol Antibacterial, antidiabetic,
anti-inflammatory, antioxidant, antitumor		 Fruits, vegetables, medicinal herbs Annulohypoxylonboveri var. microspora,
Annulohypoxylon squamulosum		 Cinnamomum sp. [106,113]
Fusarium chlamydosporum Tylophora indica [142]
Mucor fragilis Podophyllum hexandrum [143]
Luteolin Anti-inflammatory, antioxidant, immunomodulatory Fruits, vegetables,
medicinal herbs		 Annulohypoxylon boveri var.
microspora		 Cinnamomum sp. [106]
Aspergillus fumigatus Cajanus cajan [144]
Quercetin Anticancer, anti-inflammatory
antioxidant		 Fruits, vegetables Aspergillus nidulans,
Aspergillus oryzae		 Ginkgo biloba [145]
Annulohypoxylon squamulosum Cinnamomum sp. [113]
Nigrospora oryzae Loranthus micranthus [146]
Rotenone Insecticide, pesticide, piscicide Derris elliptica Penicillium sp. Derris elliptica [147]
Rutin Antioxidant, cardioprotective, neuroprotective Aegle marmelos
Ginkgo biloba,
Nerium oleander,
Pteris multifida,
fruits, vegetables		 Anonymous Pteris multifida [148]
Chaetomium sp. Nerium oleander [149]
Xylaria sp. Ginkgo biloba [
 

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