key: cord-0060816-pmzow1bf
authors: Midhun, Sebastian Jose; Jyothis, Mathew
title: Pharmacological Applications of Bioactive Secondary Metabolites from Endophytes
date: 2021-03-26
journal: Endophytes
DOI: 10.1007/978-981-15-9371-0_5
sha: dbd82eb0de0753324590fb607ce00e17ee1b86ea
doc_id: 60816
cord_uid: pmzow1bf

Endophytes are reservoirs of new and effective bioactive compounds that generally belong to the classes such as terpenoids and steroids, fatty acid-derived substances and polyketides, alkaloids, nonribosomal polypeptides, and enzyme cofactors. These classes of compounds can be used for antimicrobial, insecticidal, cancer preventive, antioxidant, antiviral, antidiabetic, immunosuppressant, immunostimulant, and several other properties. Endophytes-derived secondary metabolites have tremendous applications in the field of agronomy, medicine, food, and cosmetics. Recent discoveries have shown that microbes associated with plants could be exploited as an important source for the development of new drugs. Finding novel molecules may combat terminal diseases, drug resistance, and other severe challenges related to human health. The newly developed drugs may be an effective contender for the treatment of newly developing diseases in humans as well as animals. This chapter aims to figure out the pharmacological uses of endophytes as a novel source of drugs against several diseases and other promising therapeutic use.

Bioactive metabolites produced by plants have been used for curing or preventing illness and other distress in humans as well as animals. The microbes associated with the plants are also reported to produce a variety of metabolites that may benefit the plant or help their survival. Most of the plants often provide a unique habitat for the survival and establishment of endophytes (Strobel and Daisy 2003) . Generally, endophytes are omnipresent organisms which are found in association with the internal tissues of the plant, at least a part of their life cycle, without causing direct or indirect infections or related symptoms (Strobel and Daisy 2003) . Fungi dominate as endophytes usually share a mutualistic relationship with the host plant. But bacterial endophytes are also found associated with plants and produce an array of biologically active secondary metabolites. Endophytic fungi, as well as bacteria, have been recognized as valuable resources for the production of novel biologically active secondary metabolites with tremendous application in the field of medicine, agriculture, food, etc.

Increased demand for the novel and active remedies for treating human conditions is growing. Recent antibiotic resistance issues, life threatening viruses, recurring problems emanated from organ transplant patients, various types of cancers, and other health conditions, etc. underscore the insufficiency of existing medication for the treatment of each medical problem. Here comes the application of endophytes in the field of pharmacology and medicine. Nearly 300,000 plat species have been existing in the earth; each plant is hosting a multitude of fungal as well as bacterial endophytes. In reference to endophytic biology, less than 5% of the plants have been studied for their endophytic diversity. However, the chances to found novel endophytic microorganisms among the multitude of vegetations in various niches and ecosystems are great. Biologically derived compounds or its products have remarkable therapeutic applications, as well as they instigate the development of synthetic methodologies to permit the likelihood of making analogs of innovative lead compounds or products with enhanced pharmaceutical activities. The secondary metabolite discovery and its production from endophytic organisms have materialized as a stirring area of study in biotechnology. A multitude of compounds with immense pharmaceutical importance has been identified and isolated from several endophytic organisms (Strobel and Daisy 2003; Tiwari et al. 2017; Kharwar et al. 2011) . This chapter aims to provide an insight into the pharmacologically useful bioactive secondary metabolites produced by endophytic microorganisms.

The bioactive metabolite production is linked with its host organism and its environmental niche (Mittermeier et al. 1999) . It is essential to comprehend the strategies and rationale to provide the finest opportunities to isolate new endophytes as well as ones producing new bioactive compounds or products. Therefore, the vast diversity of plant communities in the earth makes the researcher adopt creative and imaginative strategies for the selection and processing of endophytes exhibiting desired bioactivity. Studies have shown that microorganisms and their biotopes which are persistently subjected to metabolic and ecological interactions tend to produce even more biologically active secondary metabolites (Schulz et al. 2002) . Usually, the selection of plants for the isolation of endophytes is based on four selection strategies described in Fig. 5 .1.

Structurally unique and novel natural compounds from endophytes facilitated the pharmacological application of such compounds and the discovery of novel drugs. Endophytes associated with plants have been reported to synthesize structurally distinct and diverse classes of secondary metabolites. Natural compounds, their synthetic analogs, and synthetic compounds that mimic natural compounds in their biological activities embody most of the accepted or approved small molecule drugs (Newman and Cragg 2016; Patridge et al. 2016) . Natural compounds that are biologically active and structurally diverse pharmacophores play a major role in novel drug discovery (Xiao et al. 2016) . The biomolecules which are produced by the endophytes are meant for the ecological adaptations and coevolve with the host plant. The functional natural compounds derived from the endophytes are significant in the ecological perspective. For instance, Neotyphodium coenophialum, an endophytic fungus living in the Festuca arundinacea, produces toxic alkaloids that help the host to escape from herbivorous by causing "fescue toxicosis" (Lyons et al. 1986 ). From the pharmacological perspective, the alkaloid can be used as a therapeutic compound in several diseases. Several endophytes are known to produce an 

Endophyte research has provided many potential drugs with promising antimicrobial, antioxidant, virus inhibitory, antidiabetic, immunosuppressant activities, etc. The finding of these compounds gives hope to fighting incurable diseases, antimicrobial resistance, and other recent challenges related to medicine and human health.

The following section briefly discusses the natural compounds obtained from endophytic microorganisms ( Fig. 5 .2) and their potential relevance in the pharmaceutical industry for the development of medicines or supplements.

Antimicrobial products are low-molecular-weight compounds that are active against microbes at lower concentrations. Several micromolecules are reported to have antimicrobial activity against a vast range of diseases causing bacteria, fungi, viruses, and protozoans. A unique antimycotic peptide cryptocandin was isolated from a fungus Pezicula cinnamomea, associated with the hardwood Tripterigeum wilfordii found in Europe. The plant was used as a traditional medicine in Eurasia (Strobel and Daisy 2003) . This natural bioactive compound is related to pneumocandins and echinocandins, used to known as antimycotics (Singh et al. 2013) . Cryptocandin-related antimycotic compounds are also produced by Pezicula cinnamomea and are active against several pathogenic fungi in plants such as Botrytis cinerea and Sclerotinia sclerotiorum. The endophytic compound is being used as an antimycotic agent against skin and nails fungal diseases (Onishi et al. 2000; Miller et al. 1998) .

Pseudomonas viridiflava is a fluorescent bacteria associated with the internal tissues of many grass species. The bacteria produce ecomycins, natural lipopeptides with a molecular mass ranges from 1153 to 1181. The compounds are used against disease causing fungi Cryptococcus neoformans and Candida albicans (Miller et al. 1998) . Another plant-associated bacteria Pseudomonas spp. produce a novel lipopeptide family compound known as pseudomucins and is active against Candida albicans, Cryptococcus neoformans, and several plant-pathogenic fungi such as Ceratocystis ulmi and Mycosphaerella fijiensis (Ballio et al. 1994; Harrison et al. 1991 ).

An endophytic fungi Pestalotiopsis microspora isolated from different plant sources produce an array of bioactive compounds, viz. antifungal ambuic acid (endophytic rain forest fungi) , terrain (Harper et al. 2001 ), pestaloside Mangrove Liu et al. (2016) and pyrones: pestalopyrone and hydroxypestalopyrone (endophytic to Torreya taxifolia) (Lee et al. 1995b) , caryophyllene sesquiterpenes such as pestalotiopsins A and B (endophytic on Torreya brevifolia) (Pulici et al. 1996a ), 2-alphahydroxydimeninol and humulane (Pulici et al. 1996b ). These reports revealed that the same species but different strains associated with different plants can produce a variety of natural bioactive secondary metabolites. The ecological condition and the host plant together influence the variation in the production of secondary metabolites. One of the studies reported that antifungal jesterone and hydroxyjesterone were produced by the endophyte Pestalotiopsis jester obtained from the Sepic river area of Papua New Guinea (Hu et al. 2001) . Another study reported that endophytic Phomopsis sp. produce phomopsichalasin, an antibacterial metabolite act against Bacillus subtilis, Salmonella enteric serovar Gallinarum, and Staphylococcus aureus (Horn et al. 1995 ). An antifungal compound, CR377, isolated from the endophyte Fusarium sp. associated with the plant Selaginella pallescens, exhibited remarkable activity against Candida albicans. A natural compound Colletotric acid produced by Colletotrichum gloeosporioides, associated with the plant Artemisia mongolica, showed antimicrobial action against several bacteria as well as a fungus, Helminthsporium sativum. Another Colletotrichum sp., associated with the plant Artemisia annua, produced artemisinin, an important antimalarial drug (Lu et al. 2000) . Endophytic Streptomyces sp. strain NRRL 30562 from Kennedia nigriscans produced wide-spectrum antibiotics called munumbicins (Castillo et al. 2002) . These antibiotics have different biological activities based on their target organism, but generally, they exhibited antibacterial activity against Bacillus anthracis and multidrug-resistant Mycobacterium tuberculosis. Endophytic fungi isolated from Ginkgo biloba L. showed antimicrobial activity against gram-positive and gram-negative bacteria. Xylaria sp. YX-28, an endophyte isolated from Ginkgo biloba L., disclosed the presence of an antimicrobial compound 7-amino-4methylcoumarin (Liu et al. 2008b ). Another fungal species Penicillium cataractum SYPF 7131 from the plant produced antimicrobial compounds such as penicimenolidyu A, penicimenolidyu B, and rasfonin (Wu et al. 2018) . Zhao et al. (2010) reported that Pichia guilliermondii Ppf9 isolated from Polyphylla Var. Yunnanensis produced three steroids and one nordammarane triterpenoid, ergosta-5,7,22-trienol, 5α,8α-epidioxyergosta-6,22-dien-3β-ol, and ergosta-7,22-dien3β,5α,6β-triol and helvolic acid, which exhibited antimicrobial activity against Agrobacterium tumefaciens, Escherichia coli, Pseudomonas lachrymans, Bacillus subtilis, Xanthomonas vesicatoria, Ralstonia solanacearum, Staphylococcus aureus, and Staphylococcus haemolyticus. Phaopongthai et al. (2013) reported that Alternaria alternata associated with Terminalia chebula produced a vast variety of antimicrobial compounds such as Altenusin, isoochracinic acid, altenuic acid, and 2,5-dimethyl-7-hydroxychromone. The compounds such as epicolactone and epicoccolides A and B reported from the fungus Epicoccum sp. CAFTBO isolated from Theobroma cacao exhibited antifungal activity against Pythium ultimum and Rhizoctonia solani (Talontsi et al. 2013) . Chapla et al. (2014) demonstrated the new antimicrobial compound, 2-phenylethyl-1H-indol-3-yl-acetate, and seven known compounds such as uracil, cyclo-(S*-Pro-S*-Tyr), cyclo-(S*-Pro-S*-Val), 2 (2-aminophenyl)-acetic acid, 2(4-hydroxyphenyl)acetic acid, 4-hydroxybenzamide, and 2-(2-hydroxyphenyl)-acetic acid, from the fungus Colletotrichum gloeosporioides present in the leaves of Michelia champaca. Huang et al. (2015) characterized five novel guaiane sesquiterpenes from the endophytic fungus Xylaria sp. YM 311647 isolated from Azadirachta indica. The compounds showed antimicrobial activity against fungal pathogens Candida albicans, Aspergillus niger, Pyricularia oryzae, Fusarium avenaceum, and Hormodendrum compactum. Silva et al. (2017) reported the antifungal activity of three new isoaigialones, along with aigialone from the fungus Phaeoacremonium sp. isolated from the leaves of Senna spectabilis. One of the studies reported that an endophytic fungus Aspergillus clavatonanicus strain MJ31 produced seven antibiotics such as miconazole, fluconazole, ampicillin, ketoconazole, streptomycin, rifampicin, and chloramphenicol, and several other volatile compounds (Mishra et al. 2017) . Penicillium commune, Penicillium canescens and Alternaria alternate were isolated from Olea europaea L. reported producing six volatile compounds, where 3-methyl-1-butanol and phenylethyl alcohol ascribed as potent antimicrobial agents (Malhadas et al. 2017) . Seltsamia galinsogisoli, an endophyte isolated from the plant Galinsoga parviflora, produced antimicrobial compounds Seltsamiayu and Galinsogisoliyu along with several other known secondary metabolites (Zhang et al. 2019) . Endophytic Penicillium skrjabinii associated with the host plant Pelargonium sidoides DC. produced a potent antimicrobial agent dibutyl phthalate which inhibited Staphylococcus aureus and Escherichia coli at lower concentrations (Aboobaker et al. 2019) . Fungal species belongs to the genus Lecanicillium isolated from Sandwithia guyanensis produced five stephensiolides compounds that demonstrated antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) (Mai et al. 2020) . Several endophytic actinomyces were found to produce antimicrobial compounds such as actinoallolides belong to the class of macrolides (Actinoallomurus fulvus MK10-036), trehangelins which comprise of two trehalose molecules and an angelic acid (Polymorphospora rubra K07-0510), and spoxazomicins, pyochelin class of antibiotics (Streptosporangium oxazolinicum K07-0460) (Nakashima et al. 2013; Inahashi et al. 2011; Inahashi et al. 2015 ). An endophytic actinomycete strain BCC72023 derived from rice (Oryza sativa L.) produced three macrolide classes of bioactive compounds such as efomycins M, G, and oxohygrolidin and two polyethers such as abierixin and 29-O-methylabierixin. All of these compounds displayed antimalarial activity against the Plasmodium falciparum, K-1 strain, and different strains of bacteria such as Mycobacterium tuberculosis, Bacillus cereus, Colletotrichum gloeosporioides, and Colletotrichum capsici (Supong et al. 2016) . Studies on potential antimicrobial compounds from endophytic actinomycetes are scarce and need to be addressed abundantly because of its vast diversity and the presence of several natural compounds (Matsumoto and Takahashi 2017) . Antiviral compounds were also reported from endophytic organisms; however, there had been limited reports on antiviral metabolites from endophytes. The endophytic fungus Cytonaema sp. was reported producing two antiviral compounds such as cytonic acids A and B. These compounds act against human cytomegalovirus by inhibiting proteases (Guo et al. 2000) . Hinnuloquinone is another active compound which inhibits human immunodeficiency virus type 1 protease (HIV-1), isolated from an endophytic fungus Nodulisporium hinnuleum associated with the leaves of Quercus coccifera (Singh et al. 2004) . Streptomyces tsusimaensis an endophyte reported producing the compound valinomycin which acts as an antiviral compound against the corona virus. Another study reported that the endophyte Xylaria sp. produced a natural compound such as dihydroxynaphthol (glucopyranoside) which inhibits the Herpes virus (Pittayakhajonwut et al. 2005) . Zhang et al. (2014b) reported that the endophytic fungus Emericella sp. isolated from Aegiceras corniculatum produced two isoindolone derivatives acted against influenza A (H1N1). An extensive literature survey showed that the potential studies on the discoveries of antiviral compounds from endophytes are rudimentary. The major constraint in antiviral compound finding is perhaps associated with the deficiency of proper screening methods.

One of the studies reported that the endophytic fungus, Taxomyces andreanae, from the plant Taxus brevifolia produced an anticancer compound, paclitaxel (Dong et al. 2014) . It is a diterpenoid, exceedingly functionalized compound that prevents tubulin molecules from depolymerization during cell division (Schiff and Horwitz 1980) . Another report showed that the endophyte Pestalotiopsis microspora isolated from Taxus wallichiana produced paclitaxel . Moreover, numerous other Pestalotiopsis microspora isolated from bald cypress was also reported to produce paclitaxel . Another endophyte Pestalotiopsis guepini from Wollemia nobilis was also reported to produce paclitaxel (Strobel et al. 1997) . Furthermore, fungal endophytes Periconia sp. and Seimatoantlerium nepalense were reported to produce paclitaxel (Li et al. 1998; Bashyal et al. 1999) .

Torreyanic acid is another anticancer compound produced by the endophyte Pestalotiopsis microspora strain isolated from Taxus taxifolia. The compound induces apoptosis in cancer cell lines which are sensitive to protein kinase C agonists (Lee et al. 1996) . Cytochalasins is a potent anticancer agent reported from endophytic genera such as Xylaria, Phoma, Hypoxylon, and Chalara. Around 20 species of fungi have been reported to produce the alkaloid compound, cytochalasins (Wagenaar et al. 2000) . Entrophospora infrequens, an endophyte derived from Nothapodytes foetida, was reported to generate an effective antineoplastic agent camptothecin (Puri et al. 2005) . Furthermore, analogs of camptothecin such as topotecan and irinotecan were isolated from Fusarium solani associated with the host plant Camptotheca acuminate, and the two compounds were successfully developed as clinically useful anticancer agents (Kusari et al. 2009b) . Kang et al. (2014) also reported camptothecin from the endophytic fungi Alternaria alternata, Colletotrichum gloeosporioides, Fusarium nematophilum and Phomopsis vaccinia, all of them isolated from Cyanea acuminata.

A nonalkaloid lignin called podophyllotoxin was first discovered from Trametes hirsute with tremendous anticancer prospective (Puri et al. 2006) . Several other fungal species were reported to produce podophyllotoxin and other related teralin lignin. Aspergillus fumigatus derived from Juniperus communis (Kusari et al. 2009a) , Phialocephala fortinii from the host plant Podophyllum peltatum (Eyberger et al. 2006) and Fusarium oxysporum derived from the plant Juniperus recurva (Kour et al. 2008 ) are some of the examples of podophyllotoxin and its analog producing endophytic fungi. Another game changing compound vincristine was extracted from the endophyte Mycelia sterilia associated with the host plant Catharanthus roseus (Yang et al. 2004) . Vincristine is mostly applied as a chemotherapeutic agent in nephroblastoma and acute lymphoblastic leukemia.

Pestalotiopsis microspora, an endophyte derived from Terminalia morobensis, reported to produce two antioxidant and antimicrobial compounds, pestacin and isopestacin. The antioxidant activity of isopestacin by scavenging hydroxyl and superoxide free radicals was because of its structural resemblance to the flavonoids (Harper et al. 2003) . Pseudocercospora sp. ESL 02 derived from the host plant Elaeocarpus sylvestris produced two antioxidant compounds such as terreic acid and 6-methylsalicylic acid. The natural compounds from the endophyte also had remarkable activities reducing power and β-carotene bleaching activity (Prihantini and Tachibana 2017) . Two chemical compounds such as benzeneethanol and 1,4-diaza-2,5-dioxo-3-isobutyl bicycle [4.3.0] nonane identified in GC/MS from the endophyte Diaporthe schini showed remarkable antioxidant activity and suggested for pharmacological use (da Rosa et al. 2020) . Another compound cajaninstilbene acid is a potential antioxidant compound isolated from several fungi such as Fusarium solani ERP-07, Fusarium oxysporum ERP-10, and Fusarium proliferatum ERP-13 inhabiting in the host plant Cajanus cajan (L.) (Zhao et al. 2012) . The investigation of the fungus Eurotium cristatum EN-220 collected from the marine alga Sargassum thunbergii produced several bioactive compounds such as isovariecolorin I, dehydroechinulin, rubrumazine B, neoechinulin B, neoechinulin C, didehydroechinulin, alkaloid E-7, echinulin, and variecolorin H, all of them revealed antioxidant activity (Zhao et al. 2012) . The list of compounds from endophytes does not end here. The search for better antioxidant compounds has been increased recently because of the current demand for the treatment or combating of different diseases.

Insulin mimicking nonpeptidial fungal compound L-783,281 was isolated from Pseudomassaria sp. from the rainforest of Democratic Republic of the Congo (Lenz 2000) . Unlike insulin, the compound would not destroy the digestive system and could be administered orally. Orally administered L-783 significantly lowered the blood glucose levels (Lenz 2000) . α-Glucosidase inhibitor, a potent antidiabetic agent, producing endophytic Actinomycetes sp. was isolated from Caesalpinia sappan (Irawan and Biologi 2009) , and Streptomyces sp. have also reported to harbor a significant antidiabetic potential compounds (Pujiyanto et al. 2012) . Penicillium sp. derived from Tabebuia argentea produced octadecanoics, a potent antidiabetic agent which inhibited all diabetic protein activity (Murugan et al. 2017) . Another endophytic fungi, Alternaria sp., derived from Salvadora persica produced cetene and 1,2-benzenedicarboxylic acid which showed promising antidiabetic activity (Elgorban et al. 2019) . These findings would lead to a new treatment for diabetes. Immunosuppressants are agents that are commonly used in graft rejection problems as well as in the treatment of autoimmune diseases. One of the studies conducted in the endophytic Fusarium subglutinans, obtained from Tripterygium wilfordii, produces the compound subglutinol A and B. These compounds are noncytotoxic diterpene pyrones and equipotent in the mixed lymphocyte assay and thymocyte proliferation assays (Lee et al. 1995a) . Another study revealed that the endophytic fungus Tolypocladium inflatum produced cyclosporine, a tremendously used immunosuppressant (Ramana Murthy et al. 1999) . Curtachalasins is a potent immunosuppressive agent derived from the endophytic fungus Xylaria cf. curta isolated from rice. Lipopolysaccharide (LPS)-driven B lymphocyte cell proliferation revealed that the compound Curtachalasins inhibited B-cell proliferation and selectively inhibited T-cell proliferation (Wang et al. 2019 ).

Without any question, endophytes continue as an eminent biodiversity and warehouse of new natural bioactive molecules with useful activities and give a base to novel drugs against untreatable diseases or conditions. The selection of endophyte does matter in terms of their bioactive molecule production. Ecological adaptations as well as challenging ecological niche encourage the endophyte as well as the host plant to produce a diverse array of natural compounds. New biotechnological advancements, metabolic technology, and advanced microbial culturing technology envisaged the isolation and identification of bioactive endophytes as well as their natural compound production. A better understanding of the mechanism of bioactive compounds production could give us to manipulate the organisms to produce an increased amount of natural bioactive compounds. However, studies in the area of endophyte bioactive metabolite production and their successful pharmacological applications need to be conducted. Finding new drugs from endophyte is undoubtedly dazzling.

Endophytic fungi isolated from Pelargonium sidoides DC: antimicrobial interaction and isolation of a bioactive compound

Novel bioactive lipodepsipeptides from Pseudomonas syringae: the pseudomycins

Seimatoantlerium nepalense, an endophytic taxol producing coelomycete from himalayan yew (Taxus wallachiana)

The guanacastepenes: a highly diverse family of secondary metabolites produced by an endophytic fungus

Asterogynins: secondary metabolites from a Costa Rican endophytic fungus

Munumbicins, wide-spectrum antibiotics produced by Streptomyces NRRL 30562, endophytic on Kennedia nigriscans

Antifungal compounds produced by Colletotrichum gloeosporioides, an endophytic fungus from Michelia champaca

Antioxidant compounds extracted from Diaporthe schini using supercritical CO2 plus cosolvent

Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase

Chaetoglobosin U, a cytochalasan alkaloid from endophytic Chaetomium globosum IFB-E019

A-D from a mangrove endophyte reveal an unparalleled plasticity in ansa-macrolide biosynthesis

Secovironolide, a novel furanosteroid scaffold with a five-membered B ring from the endophytic fungus Talaromyces wortmannii LGT-4

Taxomyces andreanae, a proposed new taxon for a bulbilliferous hyphomycete associated with Pacific yew (Taxus brevifolia)

Natural products of Alternaria sp., an endophytic fungus isolated from Salvadora persica from Saudi Arabia

Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin

Cytonic acids A and B: novel tridepside inhibitors of hCMV protease from the endophytic fungus Cytonaema species

Characterization of stereochemistry and molecular conformation using solid-state NMR tensors

Pestacin: a 1,3-dihydro isobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimycotic activities

Pseudomycins, a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity

Phomopsichalasin, a novel antimicrobial agent from an endophytic Phomopsis sp

Exploring chemical diversity of epoxyquinoid natural products: synthesis and biological activity of (À)-Jesterone and related molecules

Five new guaiane sesquiterpenes from the endophytic fungus Xylaria sp. YM 311647 of Azadirachta indica

A-C, novel antitrypanosomal alkaloids produced by an endophytic actinomycete, Streptosporangium oxazolinicum K07-0460 T

Actinoallolides A-E, new anti-trypanosomal macrolides, produced by an endophytic actinomycete, actinoallomurus fulvus MK10-036

Isolasi aktinomiset endofit tanaman obat yang berpotensi sebagai antidiabetes melalui kajian aktivitas

Chaetominine, a cytotoxic alkaloid produced by endophytic Chaetomium sp. IFB-E015

Medicinal plant endophytes produce analogous bioactive compounds morphological and molecular characterization of pathogenic Colletotrichum and Fusarium species and in vitro evaluation of antifungal activity of local plants extracts for potential biocontrol

HPLC-SPE-NMR identification of a novel metabolite containing the benzo[c]oxepin skeleton from the endophytic fungus pestalotiopsis virgatula culture

Anticancer compounds derived from fungal endophytes: their importance and future challenges

Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva

Xanthones and oxepino[2, 3-b]chromones from three endophytic fungi

Aspergillus fumigatus Fresenius, an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro-drug deoxypodophyllotoxin

An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues

Subglutinols a and b: immunosuppressive compounds from the endophytic fungus Fusarium subglutinans

The relationship between an endangered north American tree and an endophytic fungus

Torreyanic acid: a selectively cytotoxic quinone dimer from the endophytic fungus Pestalotiopsis microspora

Discovery of a small molecule insulin mimetic with antidiabetic activity in mice

Three unusual indole diketopiperazine alkaloids from a terrestrial-derived endophytic fungus, Aspergillus sp

The induction of taxol production in the endophytic fungus-Periconia sp from Torreya grandifolia

Ambuic acid, a highly functionalized cyclohexenone with antifungal activity from Pestalotiopsis spp. and Monochaetia sp

Lycopodiellactone, an unusual δ-lactoneisochromanone from a Hawaiian plant-associated fungus Paraphaeosphaeria neglecta FT462

Chloropupukeananin, the first chlorinated pupukeanane derivative, and its precursors from Pestalotiopsis fici

Antimicrobial activity of an endophytic Xylaria sp.YX-28 and identification of its

Structures and absolute configurations of penicillactones A-C from an endophytic microorganism, Penicillium dangeardii pitt

Aspterpenacids A and B, two Sesterterpenoids from a mangrove endophytic fungus Aspergillus terreus H010

Isofusidienols: novel chromone-3-oxepines produced by the endophytic fungus Chalara sp

New bioactive metabolites produced by Colletotrichum sp., an endophytic fungus in Artemisia annua

Occurrence of peptide and clavine ergot alkaloids in tall fescue grass

Identification of antimicrobial compounds from sandwithia guyanensis-associated endophyte using molecular network approach

Antimicrobial activity of endophytic fungi from olive tree leaves

Endophytic actinomycetes: promising source of novel bioactive compounds

Three diketopiperazine alkaloids with spirocyclic skeletons and one bisthiodiketopiperazine derivative from the mangrove-derived endophytic fungus Penicillium brocae MA-231

Absolute configurations of unique harziane diterpenes from Trichoderma species

Ecomycins, unique antimycotics from Pseudomonas viridiflava

Determination and production of antimicrobial compounds by Aspergillus clavatonanicus strain MJ31, an endophytic fungus from Mirabilis jalapa L. using UPLC-ESI-MS/MS and TD-GC-MS analysis

Robles Gil P (1999) Hotspots: earth's biologically richest and most endangered terrestrial ecoregions

Anti-diabetic activity of endophytic Fungi, Penicillium species of Tabebuia argentea; in silico and experimental analysis

Trehangelins A, B and C, novel photo-oxidative hemolysis inhibitors produced by an endophytic actinomycete, Polymorphospora rubra K07-0510

Natural products as sources of new drugs from 1981 to 2014

Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors

An analysis of FDA-approved drugs: natural products and their derivatives

Azolesynergistic anti-candidal activity of altenusin, a biphenyl metabolite of the endophytic fungus Alternaria alternata isolated from Terminalia chebula Retz

An anti-herpes simplex virus-type 1 agent from Xylaria mellisii (BCC 1005)

Antioxidant compounds produced by Pseudocercospora sp. ESL 02, an endophytic fungus isolated from Elaeocarpus sylvestris

Alpha-glucosidase inhibitor activity and characterization of endophytic actinomycetes isolated from some Indonesian diabetic medicinal plants

Pestalotiopsins A and B: new caryophyllenes from an endophytic fungus of Taxus brevifolia

A new isodrimeninol from Pestalotiopsis sp

An endophytic fungus from Nothapodytes foetida that produces camptothecin

The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans

Cyclosporin-A production by Tolypocladium inflatum using solid state fermentation

Solanioic acid, an antibacterial degraded steroid produced in culture by the fungus Rhizoctonia solani isolated from tubers of the medicinal plant Cyperus rotundus

Taxol stabilizes microtubules in mouse fibroblast cells

Endophytic fungi: a source of novel biologically active secondary metabolites

Lactone derivatives produced by a Phaeoacremonium sp., an endophytic fungus from Senna spectabilis

Hinnuliquinone, a C2-symmetric dimeric non-peptide fungal metabolite inhibitor of HIV-1 protease

Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins

Bioprospecting for microbial endophytes and their natural products

Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana

Pestalotiopsis guepinii, a taxol-producing endophyte of the wollemi pine, Wollemia nobilis

Antimicrobial compounds from endophytic Streptomyces sp. BCC72023 isolated from rice

Epicoccolides: antimicrobial and antifungal polyketides from an endophytic fungus Epicoccum sp. associated with Theobroma cacao

Antidiabetic activity of endophytic fungi isolated from Ficus religiosa

Spiro-Mamakone A: a unique relative of the spirobisnaphthalene class of compounds

Three new cytochalasins produced by an endophytic fungus in the genus Rhinocladiella

Curtachalasins, immunosuppressive agents from the endophytic fungus: Xylaria cf. curta

An endophytic Fungi of Ginkgo biloba L. produces antimicrobial metabolites as potential inhibitors of FtsZ of Staphylococcus aureus

Strategies for the optimization of natural leads to anticancer drugs or drug candidates

A branched extender unit shared between two orthogonal polyketide pathways in an endophyte

Preliminary study of a vincristine-producing endophytic fungus isolated from leaves of Catharanthus roseus

Neosartoryadins A and B, fumiquinazoline alkaloids from a mangrove-derived fungus Neosartorya udagawae HDN13-313

New mono-and dimeric members of the secalonic acid family: Blennolides A-G isolated from the fungus Blennoria sp

Characterization, synthesis and self-aggregation of (À)-alternarlactam: a new fungal cytotoxin with cyclopentenone and isoquinolinone scaffolds

Periconianone A, a new 6/6/6 carbocyclic sesquiterpenoid from endophytic fungus Periconia sp. with neural anti-inflammatory activity

Antimicrobial metabolites from the endophytic fungus aspergillus sp. of eucommia ulmoides

New antimicrobial compounds produced by Seltsamia galinsogisoli sp. nov., isolated from Galinsoga parviflora as potential inhibitors of FtsZ

Antimicrobial metabolites from the endophytic fungus pichia guilliermondii isolated from Paris polyphylla var. yunnanensis

Endophytic fungi from pigeon pea [Cajanus cajan (L.) Millsp.] produce antioxidant cajaninstilbene acid