Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds
Abstract
:1. Introduction
2. Fungal Endophytes
3. Classification of Fungal Endophytes
4. Isolation of Fungal Endophytes: Rationale for Plant Selection and Prioritization
5. Bioactive Secondary Metabolites from Endophytic Fungi
6. Enhancement of Secondary Metabolite Biosynthesis in Fungal Endophytes
6.1. One-Strain Many-Compound (OSMAC) Approach
6.2. Microbial Co-Culture Approach
6.3. Chemical Epigenetic Modification
6.4. Molecular-Based Approaches
7. Conclusions and Future Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Baral, B.; Akhgari, A.; Metsä-Ketelä, M. Activation of microbial secondary metabolic pathways: Avenues and challenges. Synth. Syst. Biotechnol. 2018, 3, 163–178. [Google Scholar] [CrossRef] [PubMed]
- Phillipson, J.D. Phytochemistry and medicinal plants. Phytochemistry 2001, 56, 237–243. [Google Scholar] [CrossRef]
- Nesme, J.; Simonet, P. The soil resistome: A critical review on antibiotic resistance origins, ecology and dissemination potential in telluric bacteria. Environ. Microbiol. 2015, 17, 913–930. [Google Scholar] [CrossRef] [PubMed]
- Donadio, S.; Monciardini, P.; Alduina, R.; Mazza, P.; Chiocchini, C.; Cavaletti, L.; Sosio, M.; Puglia, A.M. Microbial technologies for the discovery of novel bioactive metabolites. J. Biotechnol. 2002, 99, 187–198. [Google Scholar] [CrossRef]
- Gouda, S.; Das, G.; Sen, S.K.; Shin, H.S.; Patra, J.K. Endophytes: A treasure house of bioactive compounds of medicinal importance. Front. Microbiol. 2016, 7. [Google Scholar] [CrossRef] [Green Version]
- Debbab, A.; Aly, A.H.; Proksch, P. Bioactive secondary metabolites from endophytes and associated marine derived fungi. Fungal Divers. 2011, 49, 1–12. [Google Scholar] [CrossRef]
- Rai, N.; Kumari Keshri, P.; Verma, A.; Kamble, S.C.; Mishra, P.; Barik, S.; Kumar Singh, S.; Gautam, V. Plant associated fungal endophytes as a source of natural bioactive compounds. Mycology 2021, in press. [Google Scholar] [CrossRef]
- Preethi, K.; Manon Mani, V.; Lavanya, N. Endophytic fungi: A potential source of bioactive compounds for commercial and therapeutic applications. In Endophytes; Springer: Singapore, 2021; pp. 247–272. [Google Scholar]
- Dutta, D.; Puzari, K.C.; Gogoi, R.; Dutta, P. Endophytes: Exploitation as a tool in plant protection. Braz. Arch. Biol. Technol. 2014, 57, 621–629. [Google Scholar] [CrossRef]
- Chowdhary, K.; Kaushik, N.; Raimundo, M. Endophytic fungi and their metabolites isolated from Indian medicinal plant. Phytochem. Rev. 2012, 467–485. [Google Scholar] [CrossRef]
- Abhijeet Singh, Y.M. Understanding the biodiversity and biological applications of endophytic fungi: A Review. J. Microb. Biochem. Technol. 2014, S8, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Sun, X.; Guo, L.D. Endophytic fungal diversity: Review of traditional and molecular techniques. Mycology 2012, 3, 65–76. [Google Scholar] [CrossRef]
- Chávez, R.; Fierro, F.; García-Rico, R.O.; Vaca, I. Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites. Front. Microbiol. 2015, 6, 903. [Google Scholar] [CrossRef] [Green Version]
- Gamboa, M.A.; Laureano, S.; Bayman, P. Measuring diversity of endophytic fungi in leaf fragments: Does size matter? Mycopathologia 2003, 156, 41–45. [Google Scholar] [CrossRef] [PubMed]
- Petrini, O.; Sieber, T.N.; Toti, L.; Viret, O. Ecology, metabolite production, and substrate utilization in endophytic fungi. Nat. Toxins 1993, 1, 185–196. [Google Scholar] [CrossRef] [PubMed]
- Hardoim, P.R.; van Overbeek, L.S.; Berg, G.; Pirttilä, A.M.; Compant, S.; Campisano, A.; Döring, M.; Sessitsch, A. The hidden world within plants: Ecological and evolutionary considerations for defining functioning of microbial endophytes. Microbiol. Mol. Biol. Rev. 2015, 79, 293–320. [Google Scholar] [CrossRef] [Green Version]
- Kloepper, J.W.; McInroy, J.A.; Liu, K.; Hu, C.H. Symptoms of fern distortion syndrome resulting from inoculation with opportunistic endophytic fluorescent Pseudomonas spp. PLoS ONE 2013, 8, e58531. [Google Scholar] [CrossRef] [Green Version]
- Arnold, A.E.; Maynard, Z.; Gilbert, G.S.; Coley, P.D.; Kursar, T.A. Are tropical fungal endophytes hyperdiverse? Ecol. Lett. 2000, 3, 267–274. [Google Scholar] [CrossRef]
- Kim, C.K.; Eo, J.K.; Eom, A.H. Diversity and seasonal variation of endophytic fungi isolated from three conifers in Mt. Taehwa, Korea. Mycobiology 2013, 41, 82–85. [Google Scholar] [CrossRef] [Green Version]
- Meshram, V.; Gupta, M. Endophytic Fungi: A Quintessential Source of Potential Bioactive Compounds; Cambridge University Press: Cambridge, UK, 2019; ISBN 9781108607667. [Google Scholar]
- Banerjee, D. Endophytic fungal diversity in tropical and subtropical plants. Res. J. Microbiol. 2011, 6, 54–62. [Google Scholar] [CrossRef] [Green Version]
- Materatski, P.; Varanda, C.; Carvalho, T.; Dias, A.B.; Campos, M.D.; Rei, F.; Félix, M.d.R. Spatial and temporal variation of fungal endophytic richness and diversity associated to the phyllosphere of olive cultivars. Fungal Biol. 2019, 123, 66–76. [Google Scholar] [CrossRef]
- Bamisile, B.S.; Dash, C.K.; Akutse, K.S.; Keppanan, R.; Wang, L. Fungal endophytes: Beyond herbivore management. Front. Microbiol. 2018, 9, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rodriguez, R.J.; White, J.F.; Arnold, A.E.; Redman, R.S. Fungal endophytes: Diversity and functional roles: Tansley review. New Phytol. 2009, 182, 314–330. [Google Scholar] [CrossRef] [PubMed]
- Uzma, F.; Mohan, C.D.; Hashem, A.; Konappa, N.M.; Rangappa, S.; Kamath, P.V.; Singh, B.P.; Mudili, V.; Gupta, V.K.; Siddaiah, C.N.; et al. Endophytic fungi-alternative sources of cytotoxic compounds: A review. Front. Pharmacol. 2018, 9, 1–37. [Google Scholar] [CrossRef]
- Kaul, S.; Gupta, S.; Ahmed, M.; Dhar, M.K. Endophytic fungi from medicinal plants: A treasure hunt for bioactive metabolites. Phytochem. Rev. 2012, 11, 487–505. [Google Scholar] [CrossRef]
- Demers, D.; Knestrick, M.; Fleeman, R.; Tawfik, R.; Azhari, A.; Souza, A.; Vesely, B.; Netherton, M.; Gupta, R.; Colon, B.; et al. Exploitation of mangrove endophytic fungi for infectious disease drug discovery. Mar. Drugs 2018, 16, 376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tanaka, A.; Takemoto, D.; Chujo, T.; Scott, B. Fungal endophytes of grasses. Curr. Opin. Plant Biol. 2012, 15, 462–468. [Google Scholar] [CrossRef] [PubMed]
- Daley, D.K.; Brown, K.J.; Badal, S. Fungal Metabolites. In Pharmacognosy: Fundamentals, Applications and Strategy; Elsevier Inc.: Amsterdam, The Netherlands, 2017; pp. 413–421. ISBN 9780128020999. [Google Scholar]
- Chadha, N.; Mishra, M.; Prasad, R.; Varma, A. Root endophytic fungi: Research update. J. Biol. Life Sci. 2014, 5, 135. [Google Scholar] [CrossRef]
- Jia, Q.; Qu, J.; Mu, H.; Sun, H.; Wu, C. Foliar endophytic fungi: Diversity in species and functions in forest ecosystems. Symbiosis 2020, 80, 103–132. [Google Scholar] [CrossRef]
- Terhonen, E.; Blumenstein, K.; Kovalchuk, A.; Asiegbu, F.O. Forest tree microbiomes and associated fungal endophytes: Functional roles and impact on forest health. Forests 2019, 10, 42. [Google Scholar] [CrossRef] [Green Version]
- Strobel, G.; Daisy, B. Bioprospecting for microbial endophytes and their natural products. Microbiol. Mol. Biol. Rev. 2003, 67, 491–502. [Google Scholar] [CrossRef] [Green Version]
- Shearer, C.A.; Descals, E.; Kohlmeyer, B.; Kohlmeyer, J.; Marvanová, L.; Padgett, D.; Porter, D.; Raja, H.A.; Schmit, J.P.; Thorton, H.A.; et al. Fungal biodiversity in aquatic habitats. Biodivers. Conserv. 2007, 16, 49–67. [Google Scholar] [CrossRef]
- Deshmukh, S.K.; Gupta, M.K.; Prakash, V.; Sudhakara Reddy, M. Mangrove-associated fungi: A novel source of potential anticancer compounds. J. Fungi 2018, 4, 101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rana, K.L.; Kour, D.; Kaur, T.; Devi, R.; Negi, C.; Yadav, A.N.; Singh, K.; Saxena, A.K. Endophytic fungi from medicinal plants: Biodiversity and biotechnological applications. In Microbial Endophytes; Kumar, A., Radhakrishnan, E.K., Eds.; Woodhead Publishing: Cambridge, UK, 2020; pp. 273–305. [Google Scholar]
- Tiwari, K. The future products: Endophytic fungal metabolites. J. Biodivers. Bioprospect. Dev. 2014, 2, 1–7. [Google Scholar] [CrossRef]
- Zhao, J.; Zhou, L.; Wang, J.; Shan, T.; Zhong, L.; Liu, X.; Gao, X. Endophytic fungi for producing bioactive compounds originally from their host plants. Curr. Res. Technol. Educ. Trop. Appl. Microbiol. Microb. Biotechnol. 2010, 1, 567–576. [Google Scholar]
- Venieraki, A.; Dimou, M.; Katinakis, P. Endophytic fungi residing in medicinal plants have the ability to produce the same or similar pharmacologically active secondary metabolites as their hosts. Hell. Plant Prot. J. 2017, 10, 51–66. [Google Scholar] [CrossRef] [Green Version]
- Demain, A.L.; Vaishnav, P. Natural products for cancer chemotherapy. Microb. Biotechnol. 2011, 4, 687–699. [Google Scholar] [CrossRef] [Green Version]
- Xiong, Z.Q.; Yang, Y.Y.; Zhao, N.; Wang, Y. Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglojap yew, Taxus x media. BMC Microbiol. 2013, 13, 71. [Google Scholar] [CrossRef] [Green Version]
- Roopa, G.; Madhusudhan, M.C.; Sunil, K.C.R.; Lisa, N.; Calvin, R.; Poornima, R.; Zeinab, N.; Kini, K.R.; Prakash, H.S.; Geetha, N. Identification of Taxol-producing endophytic fungi isolated from Salacia oblonga through genomic mining approach. J. Genet. Eng. Biotechnol. 2015, 13, 119–127. [Google Scholar] [CrossRef] [Green Version]
- Seetharaman, P.; Gnanasekar, S.; Chandrasekaran, R.; Chandrakasan, G.; Kadarkarai, M.; Sivaperumal, S. Isolation and characterization of anticancer flavone chrysin (5,7-dihydroxy flavone)-producing endophytic fungi from Passiflora incarnata L. leaves. Ann. Microbiol. 2017, 67, 321–331. [Google Scholar] [CrossRef]
- Shweta, S.; Zuehlke, S.; Ramesha, B.T.; Priti, V.; Mohana Kumar, P.; Ravikanth, G.; Spiteller, M.; Vasudeva, R.; Uma Shaanker, R. Endophytic fungal strains of Fusarium solani, from Apodytes dimidiata E. Mey. ex Arn (Icacinaceae) produce camptothecin, 10-hydroxycamptothecin and 9-methoxycamptothecin. Phytochemistry 2010, 71, 117–122. [Google Scholar] [CrossRef]
- El-Hawary, S.S.; Mohammed, R.; Abouzid, S.F.; Bakeer, W.; Ebel, R.; Sayed, A.M.; Rateb, M.E. Solamargine production by a fungal endophyte of Solanum nigrum. J. Appl. Microbiol. 2016, 120, 900–911. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qiu, M.; Xie, R.S.; Shi, Y.; Zhang, H.; Chen, H.M. Isolation and identification of two flavonoid-producing endophytic fungi from Ginkgo biloba L. Ann. Microbiol. 2010, 60, 143–150. [Google Scholar] [CrossRef]
- Kusari, S.; Lamshöft, M.; Zühlke, S.; Spiteller, M. An endophytic fungus from Hypericum perforatum that produces hypericin. J. Nat. Prod. 2008, 71, 159–162. [Google Scholar] [CrossRef] [PubMed]
- Yuan, Z.; Tian, Y.; He, F.; Zhou, H. Endophytes from Ginkgo biloba and their secondary metabolites. Chin. Med. 2019, 14, 1–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Q.; Wei, X.; Wang, J. Phillyrin produced by Colletotrichum gloeosporioides, an endophytic fungus isolated from Forsythia suspensa. Fitoterapia 2012, 83, 1500–1505. [Google Scholar] [CrossRef] [PubMed]
- Chithra, S.; Jasim, B.; Anisha, C.; Mathew, J.; Radhakrishnan, E.K. LC-MS/MS based identification of piperine production by endophytic Mycosphaerella sp. PF13 from Piper nigrum. Appl. Biochem. Biotechnol. 2014, 173, 30–35. [Google Scholar] [CrossRef] [PubMed]
- Verma, V.C.; Lobkovsky, E.; Gange, A.C.; Singh, S.K.; Prakash, S. Piperine production by endophytic fungus Periconia sp. Isolated from Piper longum L. J. Antibiot. 2011, 64, 427–431. [Google Scholar] [CrossRef] [PubMed]
- Vigneshwari, A.; Rakk, D.; Németh, A.; Kocsubé, S.; Kiss, N.; Csupor, D.; Papp, T.; Škrbić, B.; Vágvölgyi, C.; Szekeres, A. Host metabolite producing endophytic fungi isolated from Hypericum perforatum. PLoS ONE 2019, 14, e0217060. [Google Scholar] [CrossRef]
- Su, J.Q.; Yang, M.H. Huperzine A Production by Paecilomyces tenuis YS-13, an endophytic fungus isolated from Huperzia serrata. Nat. Prod. Res. 2015, 29, 1035–1041. [Google Scholar] [CrossRef]
- Le, T.T.M.; Hoang, A.T.H.; Nguyen, N.P.; Le, T.T.B.; Trinh, H.T.T.; Vo, T.T.B.; Quyen, D. Van A novel huperzine A-producing endophytic fungus Fusarium sp. Rsp5.2 isolated from Huperzia serrate. Biotechnol. Lett. 2020, 42, 987–995. [Google Scholar] [CrossRef]
- Ibrahim, S.R.M.; Abdallah, H.M.; Elkhayat, E.S.; Al Musayeib, N.M.; Asfour, H.Z.; Zayed, M.F.; Mohamed, G.A. Fusaripeptide A: New antifungal and anti-malarial cyclodepsipeptide from the endophytic fungus Fusarium sp. J. Asian Nat. Prod. Res. 2018, 20, 75–85. [Google Scholar] [CrossRef] [PubMed]
- Kour, A.; Shawl, A.S.; Rehman, S.; Sultan, P.; Qazi, P.H.; Suden, P.; Khajuria, R.K.; Verma, V. Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva. World J. Microbiol. Biotechnol. 2008, 24, 1115–1121. [Google Scholar] [CrossRef]
- Kumar, A.; Patil, D.; Rajamohanan, P.R.; Ahmad, A. Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus. PLoS ONE 2013, 8, e71805. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.J.; Min, C.L.; Ge, M.; Zuo, R.H. An endophytic sanguinarine-producing fungus from Macleaya cordata, Fusarium proliferatum BLH51. Curr. Microbiol. 2014, 68, 336–341. [Google Scholar] [CrossRef]
- Kusari, S.; Zühlke, S.; Spiteller, M. An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues. J. Nat. Prod. 2009, 72, 2–7. [Google Scholar] [CrossRef] [PubMed]
- Miao, Z.; Wang, Y.; Yu, X.; Guo, B.; Tang, K. A new endophytic taxane production fungus from Taxus chinensis. Appl. Biochem. Microbiol. 2009, 45, 81–86. [Google Scholar] [CrossRef]
- Zhao, J.; Li, C.; Wang, W.; Zhao, C.; Luo, M.; Mu, F.; Fu, Y.; Zu, Y.; Yao, M. Hypocrea lixii, novel endophytic fungi producing anticancer agent cajanol, isolated from pigeon pea (Cajanus cajan [L.] Millsp.). J. Appl. Microbiol. 2013, 115, 102–113. [Google Scholar] [CrossRef]
- Gangadevi, V.; Murugan, M.; Muthumary, J. Taxol determination from Pestalotiopsis pauciseta, a fungal endophyte of a medicinal plant. Shengwu Gongcheng Xuebao/Chin. J. Biotechnol. 2008, 24, 1433–1438. [Google Scholar] [CrossRef]
- Eyberger, A.L.; Dondapati, R.; Porter, J.R. Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. J. Nat. Prod. 2006, 69, 1121–1124. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Zhai, X.; Shu, Z.; Dong, R.; Ming, Q.; Qin, L.; Zheng, C. Phoma glomerata D14: An endophytic fungus from Salvia miltiorrhiza that produces Salvianolic acid C. Curr. Microbiol. 2016, 73, 31–37. [Google Scholar] [CrossRef] [PubMed]
- Maehara, S.; Simanjuntak, P.; Maetani, Y.; Kitamura, C.; Ohashi, K.; Shibuya, H. Ability of endophytic filamentous fungi associated with Cinchona ledgeriana to produce Cinchona alkaloids. J. Nat. Med. 2013, 67, 421–423. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Sang, X.; Li, S.; Zhang, S.; Bai, L. Studies on a chlorogenic acid-producing endophytic fungi isolated from Eucommia ulmoides Oliver. J. Ind. Microbiol. Biotechnol. 2010, 37, 447–454. [Google Scholar] [CrossRef] [PubMed]
- Ming, Q.; Han, T.; Li, W.; Zhang, Q.; Zhang, H.; Zheng, C.; Huang, F.; Rahman, K.; Qin, L. Tanshinone IIA and tanshinone i production by Trichoderma atroviride D16, an endophytic fungus in Salvia miltiorrhiza. Phytomedicine 2012, 19, 330–333. [Google Scholar] [CrossRef] [PubMed]
- Tan, X.; Zhou, Y.; Zhou, X.; Xia, X.; Wei, Y.; He, L.; Tang, H.; Yu, L. Diversity and bioactive potential of culturable fungal endophytes of Dysosma versipellis; A rare medicinal plant endemic to China. Sci. Rep. 2018, 8, 1–9. [Google Scholar] [CrossRef] [Green Version]
- Hodkinson, T.R.; Doohan, F.M.; Saunders, M.J.; Murphy, B.R. Endophytes for a Growing World; Cambridge University Press: Cambridge, UK, 2019; pp. 3–22. [Google Scholar]
- Ancheeva, E.; Daletos, G.; Proksch, P. Bioactive secondary metabolites from endophytic fungi. Curr. Med. Chem. 2019, 26. [Google Scholar] [CrossRef]
- Deshmukh, K.S.; Verekar, S.A.; Bhave, S.V. Endophytic fungi: A reservoir of antibacterials. Front. Microbiol. 2014, 5, 715. [Google Scholar]
- Martinez-Klimova, E.; Rodríguez-Peña, K.; Sánchez, S. Endophytes as sources of antibiotics. Biochem. Pharmacol. 2017, 134, 1–17. [Google Scholar] [CrossRef] [PubMed]
- Deshmukh, S.K.; Gupta, M.K.; Prakash, V.; Saxena, S. Endophytic fungi: A source of potential antifungal compounds. J. Fungi 2018, 4, 77. [Google Scholar] [CrossRef] [Green Version]
- Alvin, A.; Miller, K.I.; Neilan, B.A. Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds. Microbiol. Res. 2014, 169, 483–495. [Google Scholar] [CrossRef]
- Chen, L.; Zhang, Q.-Y.; Jia, M.; Ming, Q.-L.; Yue, W.; Rahman, K.; Qin, L.-P.; Han, T. Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds. Crit. Rev. Microbiol. 2014, 42, 1–20. [Google Scholar] [CrossRef]
- Kharwar, R.N.; Mishra, A.; Gond, S.K.; Stierle, A.; Stierle, D. Anticancer compounds derived from fungal endophytes: Their importance and future challenges. Nat. Prod. Rep. 2011, 28, 1208–1228. [Google Scholar] [CrossRef]
- Toghueo, K.M.; Boyom, F.F. Endophytes from ethno-pharmacological plants: Sources of novel antioxidants- A systematic review. Biocatal. Agric. Biotechnol. 2019, 22, 101430. [Google Scholar] [CrossRef]
- Corrêa, R.C.G.; Rhoden, S.A.; Mota, T.R.; Azevedo, J.L.; Pamphile, J.A.; de Souza, C.G.M.; Polizeli, M.D.; Bracht, A.; Peralta, R.M. Endophytic fungi: Expanding the arsenal of industrial enzyme producers. J. Ind. Microbiol. Biotechnol. 2014, 41, 1467–1478. [Google Scholar] [CrossRef]
- Khan, A.L.; Shahzad, R.; Al-Harrasi, A.; Lee, I.-J. Endophytic microbes: A resource for producing extracellular enzymes. In Endophytes: Crop Productivity and Protection; Springer: Cham, Switzerland, 2017; pp. 95–110. [Google Scholar]
- Hoffmeister, D.; Keller, N.P. Natural products of filamentous fungi: Enzymes, genes, and their regulation. Nat. Prod. Rep. 2007, 24, 393–416. [Google Scholar] [CrossRef] [PubMed]
- Keller, N.P.; Turner, G.; Bennett, J.W. Fungal secondary metabolism—From biochemistry to genomics. Nat. Rev. Microbiol. 2005, 3, 937–947. [Google Scholar] [CrossRef] [PubMed]
- Khaldi, N.; Seifuddin, F.T.; Turner, G.; Haft, D.; Nierman, W.C.; Wolfe, K.H.; Fedorova, N.D. SMURF: Genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 2010, 47, 736–741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keller, N.P. Fungal secondary metabolism: Regulation, function and drug discovery. Nat. Rev. Microbiol. 2019, 17, 167–180. [Google Scholar] [CrossRef]
- Rutledge, P.J.; Challis, G.L. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat. Rev. Microbiol. 2015, 13, 509–523. [Google Scholar] [CrossRef] [PubMed]
- Fisch, K.M.; Gillaspy, A.F.; Gipson, M.; Henrikson, J.C.; Hoover, A.R.; Jackson, L.; Najar, F.Z.; Wägele, H.; Cichewicz, R.H. Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J. Ind. Microbiol. Biotechnol. 2009, 36, 1199–1213. [Google Scholar] [CrossRef]
- Schüller, A.; Wolansky, L.; Berger, H.; Studt, L.; Gacek-Matthews, A.; Sulyok, M.; Strauss, J. A novel fungal gene regulation system based on inducible VPR-dCas9 and nucleosome map-guided sgRNA positioning. Appl. Microbiol. Biotechnol. 2020, 104, 9801–9822. [Google Scholar] [CrossRef] [PubMed]
- Bode, H.B.; Bethe, B.; Höfs, R.; Zeeck, A. Big effects from small changes: Possible ways to explore nature’s chemical diversity. ChemBioChem 2002, 3, 619–627. [Google Scholar] [CrossRef]
- Reen, F.J.; Romano, S.; Dobson, A.D.W.; O’Gara, F. The sound of silence: Activating silent biosynthetic gene clusters in marine microorganisms. Mar. Drugs 2015, 13, 4754–4783. [Google Scholar] [CrossRef] [Green Version]
- Ahsan, T.; Chen, J.; Wu, Y.; Irfan, M.; Shafi, J. Screening, identification, optimization of fermentation conditions, and extraction of secondary metabolites for the biocontrol of Rhizoctonia solani AG-3. Biotechnol. Biotechnol. Equip. 2017, 31, 91–98. [Google Scholar] [CrossRef] [Green Version]
- Ding, G.; Zheng, Z.; Liu, S.; Zhang, H.; Guo, L.; Che, Y. Photinides A-F, cytotoxic benzofuranone-derived γ-lactones from the plant endophytic fungus Pestalotiopsis photiniae. J. Nat. Prod. 2009, 72, 942–945. [Google Scholar] [CrossRef]
- Ding, G.; Qi, Y.; Liu, S.; Guo, L.; Chen, X. Photipyrones A and B, new pyrone derivatives from the plant endophytic fungus Pestalotiopsis photiniae. J. Antibiot. 2012, 65, 271–273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ariantari, N.P.; Daletos, G.; Mándi, A.; Kurtán, T.; Müller, W.E.G.; Lin, W.; Ancheeva, E.; Proksch, P. Expanding the chemical diversity of an endophytic fungus: Bulgaria inquinans, an ascomycete associated with mistletoe, through an OSMAC approach. RSC Adv. 2019, 9, 25119–25132. [Google Scholar] [CrossRef] [Green Version]
- Hewage, R.T.; Aree, T.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. One strain-many compounds (OSMAC) method for production of polyketides, azaphilones, and an isochromanone using the endophytic fungus Dothideomycete sp. Phytochemistry 2014, 108, 87–94. [Google Scholar] [CrossRef] [PubMed]
- Supratman, U.; Suzuki, T.; Nakamura, T.; Yokoyama, Y.; Harneti, D.; Maharani, R.; Salam, S.; Abdullah, F.F.; Koseki, T.; Shiono, Y. New metabolites produced by endophyte Clonostachys rosea B5—2. Nat. Prod. Res. 2019, 35, 1525–1531. [Google Scholar] [CrossRef]
- Paranagama, P.A.; Wijeratne, E.M.K.; Gunatilaka, A.A.L. Uncovering biosynthetic potential of plant-associated fungi: Effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii. J. Nat. Prod. 2007, 70, 1939–1945. [Google Scholar] [CrossRef]
- Daletos, G.; Ebrahim, W.; Ancheeva, E.; El-neketi, M. Microbial coculture and OSMAC approach as strategies to induce cryptic fungal biogenetic gene clusters. Chem. Biol. Nat. Prod. 2017, 233–284. [Google Scholar] [CrossRef]
- Bayram, Ö.; Krappmann, S.; Ni, M.; Jin, W.B.; Helmstaedt, K.; Valerius, O.; Braus-Stromeyer, S.; Kwon, N.J.; Keller, N.P.; Yu, J.H.; et al. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 2008, 320, 1504–1506. [Google Scholar] [CrossRef]
- Pruß, S.; Fetzner, R.; Seither, K.; Herr, A.; Pfeiffer, E.; Metzler, M.; Lawrence, C.B.; Fischer, R. Role of the Alternaria alternata blue-light receptor LreA (White-Collar 1) in spore formation and secondary metabolism. Appl. Environ. Microbiol. 2014, 80, 2582–2591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hautbergue, T.; Jamin, E.L.; Debrauwer, L.; Puel, O.; Oswald, I.P. From genomics to metabolomics, moving toward an integrated strategy for the discovery of fungal secondary metabolites. Nat. Prod. Rep. 2018, 35, 147–173. [Google Scholar] [CrossRef]
- Pan, R.; Bai, X.; Chen, J.; Zhang, H.; Wang, H. Exploring structural diversity of microbe secondary metabolites using OSMAC strategy: A literature review. Front. Microbiol. 2019, 10, 1–20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stroe, M.; Netzker, T.; Scherlach, K.; Krüger, T.; Hertweck, C.; Valiante, V.; Brakhage, A.A. Targeted induction of a silent fungal gene cluster encoding the bacteria-specific germination inhibitor fumigermin. Elife 2020, 9, e52541. [Google Scholar] [CrossRef] [PubMed]
- Bertrand, S.; Bohni, N.; Schnee, S.; Schumpp, O.; Gindro, K.; Wolfender, J.L. Metabolite induction via microorganism co-culture: A potential way to enhance chemical diversity for drug discovery. Biotechnol. Adv. 2014, 32, 1180–1204. [Google Scholar] [CrossRef]
- Khare, E.; Mishra, J.; Arora, N.K. Multifaceted interactions between endophytes and plant: Developments and prospects. Front. Microbiol. 2018, 9, 15. [Google Scholar] [CrossRef]
- Kuo, T.H.; Yang, C.T.; Chang, H.Y.; Hsueh, Y.P.; Hsu, C.C. Nematode-trapping fungi produce diverse metabolites during predator–prey interaction. Metabolites 2020, 10, 117. [Google Scholar] [CrossRef] [Green Version]
- Marmann, A.; Aly, A.H.; Lin, W.; Wang, B.; Proksch, P. Co-cultivation—A powerful emerging tool for enhancing the chemical diversity of microorganisms. Mar. Drugs 2014, 12, 1043–1065. [Google Scholar] [CrossRef] [Green Version]
- Moody, S.C. Microbial co-culture: Harnessing intermicrobial signaling for the production of novel antimicrobials. Future Microbiol. 2014, 9, 575–578. [Google Scholar] [CrossRef] [Green Version]
- Ola, A.R.B.; Thomy, D.; Lai, D.; Brötz-Oesterhelt, H.; Proksch, P. Inducing secondary metabolite production by the endophytic fungus Fusarium tricinctum through coculture with Bacillus subtilis. J. Nat. Prod. 2013, 76, 2094–2099. [Google Scholar] [CrossRef] [PubMed]
- Akone, S.H.; Mándi, A.; Kurtán, T.; Hartmann, R.; Lin, W.; Daletos, G.; Proksch, P. Inducing secondary metabolite production by the endophytic fungus Chaetomium sp. through fungal–bacterial co-culture and epigenetic modification. Tetrahedron 2016, 72, 6340–6347. [Google Scholar] [CrossRef] [Green Version]
- Ebrahim, W.; El-Neketi, M.; Lewald, L.I.; Orfali, R.S.; Lin, W.; Rehberg, N.; Kalscheuer, R.; Daletos, G.; Proksch, P. Metabolites from the fungal endophyte Aspergillus austroafricanus in axenic culture and in fungal-bacterial mixed cultures. J. Nat. Prod. 2016, 79, 914–922. [Google Scholar] [CrossRef] [PubMed]
- König, C.C.; Scherlach, K.; Schroeckh, V.; Horn, F.; Nietzsche, S.; Brakhage, A.A.; Hertweck, C. Bacterium induces cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus. ChemBioChem 2013, 14, 938–942. [Google Scholar] [CrossRef]
- Soliman, S.S.M.; Raizada, M.N. Interactions between co-habitating fungi elicit synthesis of Taxol from an endophytic fungus in host Taxus plants. Front. Microbiol. 2013, 4, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, C.; Sarotti, A.M.; Yang, B.; Turkson, J.; Cao, S. A New N-methoxypyridone from the co-cultivation of hawaiian endophytic fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062. Molecules 2017, 22, 1166. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.P.; Lin, W.; Wray, V.; Lai, D.; Proksch, P. Induced production of depsipeptides by co-culturing Fusarium tricinctum and fusarium begoniae. Tetrahedron Lett. 2013, 54, 2492–2496. [Google Scholar] [CrossRef]
- Li, H.-T.; Zhou, H.; Duan, R.-T.; Li, H.-Y.; Tang, L.-H.; Yang, X.-Q.; Yang, Y.-B.; Ding, Z.-T. Inducing secondary metabolite production by co-culture of the endophytic fungus Phoma sp. and the symbiotic fungus Armillaria sp. J. Nat. Prod 2019, 82, 1009–1013. [Google Scholar] [CrossRef]
- Zhu, F.; Lin, Y. Marinamide, a novel alkaloid and its methyl ester produced by the application of mixed fermentation technique to two mangrove endophytic fungi from the South China Sea. Chin. Sci. Bull. 2006, 51, 1426–1430. [Google Scholar] [CrossRef]
- Zhu, F.; Chen, G.Y.; Wu, J.S.; Pan, J.H. Structure revision and cytotoxic activity of marinamide and its methyl ester, novel alkaloids produced by co-cultures of two marine-derived mangrove endophytic fungi. Nat. Prod. Res. 2013, 27, 1960–1964. [Google Scholar] [CrossRef]
- Rojas-Aedo, J.F.; Gil-Durán, C.; Goity, A.; Vaca, I.; Levicán, G.; Larrondo, L.F.; Chávez, R. The developmental regulator Pcz1 affects the production of secondary metabolites in the filamentous fungus Penicillium roqueforti. Microbiol. Res. 2018, 212–213, 67–74. [Google Scholar] [CrossRef]
- Brakhage, A.A. Regulation of fungal secondary metabolism. Nat. Rev. Microbiol. 2013, 11, 21–32. [Google Scholar] [CrossRef] [PubMed]
- García-Estrada, C.; Domínguez-Santos, R.; Kosalková, K.; Martín, J.-F. Transcription factors controlling primary and secondary metabolism in filamentous fungi: The β-Lactam paradigm. Fermentation 2018, 4, 47. [Google Scholar] [CrossRef] [Green Version]
- Cichewicz, R.H. Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat. Prod. Rep. 2010, 27, 11–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, X.L.; Huang, L.; Ruan, X.L. Epigenetic modifiers alter the secondary metabolite composition of a plant endophytic fungus, Pestalotiopsis crassiuscula obtained from the leaves of Fragaria chiloensis. J. Asian Nat. Prod. Res. 2014, 16, 412–417. [Google Scholar] [CrossRef] [PubMed]
- Magotra, A.; Kumar, M.; Kushwaha, M.; Awasthi, P.; Raina, C.; Gupta, A.P.; Shah, B.A.; Gandhi, S.G.; Chaubey, A. Epigenetic modifier induced enhancement of fumiquinazoline C production in Aspergillus fumigatus (GA-L7): An endophytic fungus from Grewia asiatica L. AMB Express 2017, 7, 1–10. [Google Scholar] [CrossRef]
- González-Menéndez, V.; Pérez-Bonilla, M.; Pérez-Victoria, I.; Martín, J.; Muñoz, F.; Reyes, F.; Tormo, J.R.; Genilloud, O. Multicomponent analysis of the differential induction of secondary metabolite profiles in fungal endophytes. Molecules 2016, 21, 234. [Google Scholar] [CrossRef] [Green Version]
- Beau, J.; Mahid, N.; Burda, W.N.; Harrington, L.; Shaw, L.N.; Mutka, T.; Kyle, D.E.; Barisic, B.; Van Olphen, A.; Baker, B.J. Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii. Mar. Drugs 2012, 10, 762–774. [Google Scholar] [CrossRef] [PubMed]
- Li, G.; Kusari, S.; Golz, C.; Laatsch, H.; Strohmann, C.; Spiteller, M. Epigenetic modulation of endophytic Eupenicillium sp. LG41 by a histone deacetylase inhibitor for production of decalin-containing compounds. J. Nat. Prod. 2017, 80, 983–988. [Google Scholar] [CrossRef] [PubMed]
- Sun, J.; Awakawa, T.; Noguchi, H.; Abe, I. Induced production of mycotoxins in an endophytic fungus from the medicinal plant Datura stramonium L. Bioorgan. Med. Chem. Lett. 2012, 22, 6397–6400. [Google Scholar] [CrossRef]
- González-Menéndez, V.; Crespo, G.; Toro, C.; Martín, J.; De Pedro, N.; Tormo, J.R.; Genilloud, O. Extending the metabolite diversity of the endophyte Dimorphosporicola tragani. Metabolites 2019, 9, 197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brakhage, A.A.; Schuemann, J.; Bergmann, S.; Scherlach, K.; Schroeckh, V.; Hertweck, C. Activation of fungal silent gene clusters: A new avenue to drug discovery. In Natural Compounds as Drugs; Birkhäuser: Basel, Switzlerland, 2008; pp. 1–12. [Google Scholar]
- Wiemann, P.; Keller, N.P. Strategies for mining fungal natural products. J. Ind. Microbiol. Biotechnol. 2014, 41, 301–313. [Google Scholar] [CrossRef]
- Knox, P.B.; Keller, P.N. Key players in the regulation of fungal secondary metabolism. In Biosynthesis and Molecular Genetics of Fungal Secondary; Zeilinger, S., Martín, J.F., García-Estrada, C., Eds.; Springer: New York, NY, USA, 2015; pp. 13–28. [Google Scholar]
- Macheleidt, J.; Mattern, D.J.; Fischer, J.; Netzker, T.; Weber, J.; Schroeckh, V.; Valiante, V.; Brakhage, A.A. Regulation and role of fungal secondary metabolites. Annu. Rev. Genet. 2016, 50, 371–392. [Google Scholar] [CrossRef]
- Zeilinger, S.; Martín, J.F.; García-Estrada, C. Fungal secondary metabolites in the “OMICS” era. In Biosynthesis and Molecular Genetics of Fungal Secondary; Zeilinger, S., Martín, J.F., García-Estrada, C., Eds.; Springer: New York, NY, USA, 2015; pp. 1–12. [Google Scholar]
- Bergmann, S.; Schümann, J.; Scherlach, K.; Lange, C.; Brakhage, A.A.; Hertweck, C. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 2007, 3, 213–217. [Google Scholar] [CrossRef]
- Zabala, A.O.; Xu, W.; Chooi, Y.H.; Tang, Y. Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation. Chem. Biol. 2012, 19, 1049–1059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Derntl, C.; Kluger, B.; Bueschl, C.; Schuhmacher, R.; Mach, R.L.; Mach-Aigner, A.R. Transcription factor Xpp1 is a switch between primary and secondary fungal metabolism. Proc. Natl. Acad. Sci. USA 2017, 114, E560–E569. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, G.; Zhou, H.; Zhang, P.; Wang, X.; Li, W.; Zhang, W.; Liu, X.; Liu, H.W.; Keller, N.P.; An, Z.; et al. Polyketide production of Pestaloficiols and Macrodiolide Ficiolides revealed by manipulations of epigenetic regulators in an endophytic fungus. Org. Lett. 2016, 18, 1832–1835. [Google Scholar] [CrossRef] [PubMed]
- Skellam, E. Strategies for engineering natural product biosynthesis in fungi. Trends Biotechnol. 2019, 37, 416–427. [Google Scholar] [CrossRef] [Green Version]
- Chiang, Y.M.; Oakley, C.E.; Ahuja, M.; Entwistle, R.; Schultz, A.; Chang, S.L.; Sung, C.T.; Wang, C.C.C.; Oakley, B.R. An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J. Am. Chem. Soc. 2013, 135, 7720–7731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oakley, C.E.; Ahuja, M.; Sun, W.W.; Entwistle, R.; Akashi, T.; Yaegashi, J.; Guo, C.J.; Cerqueira, G.C.; Russo Wortman, J.; Wang, C.C.C.; et al. Discovery of McrA, a master regulator of Aspergillus secondary metabolism. Mol. Microbiol. 2017, 103, 347–365. [Google Scholar] [CrossRef] [Green Version]
- Bok, J.W.; Keller, N.P. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 2004, 3, 527–535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Endophytic Fungi | Host Plant | Bioactive Compound | Structure | Bioactivity | Reference |
---|---|---|---|---|---|
Altenaria alternata | Passiflora incarnata | Chrysin | Antibacterial, anti-inflammatory, anticancer effects | [43] | |
Alternaria alternata, Phomopsis sp. and Fomitopsis sp. | Miquelia dentata | Camptothecine | Anticancer agent | [44] | |
Aspergillus flavus | Solanum nigrum | Solamargine | Anticancer activity | [45] | |
Aspergillus nidulans, and Aspergillus oryzae | Ginkgo biloba | Quercetin | Anti-inflammatory | [46] | |
Chaetomium globosum | Hypericum perforatum | Hypericin | Anti-inflammatory effects, antimicrobialand antioxidant activities | [47] | |
Chaetomium globosum | Hypericum perforatum | Emodin | Anti-inflammatory effects, antimicrobialand antioxidant activities, | [47] | |
Chaetomium globosum | Ginkgo biloba | Quercetin | Anti-inflammatory and antiallergic effects | [48] | |
Colletotrichum gloeosporioides | Forsythia suspensa | Phillyrin | Antioxidant, anti-infl ammatory, anti-hyperlipidemia and antipyretic activities | [49] | |
Colletotrichum gloeosporioides and Periconia sp. | Piper longum and Piper nigrum | Piperine | Antibacterial, antifungal, anti-inflammatory and and antioxidant | [50,51] | |
Epicoccum nigrum | Hypericum perforatum | Emodin | Antimicrobial, anti-inflammatory and antioxidant | [52] | |
Fusarium sp. and Paecilomyces tenuis | Huperzia serrata | Huperzine A | Treatment of Alzheimer’s disease | [53,54] | |
Fusarium sp. | Mentha longifolia | Fusaripeptide A | Antifungal, antimalarial and cytotoxicity | [55] | |
Fusarium oxysporum | Sabina recurva | Podophyllotoxin | Anticancer agent | [56] | |
Fusarium oxysporum | Catharanthus roseus | Vinblastine | Anticancer/antitumor agent | [57] | |
Fusarium oxysporum | Catharanthus roseus | Vincristine | Anticancer/antitumor agent | [57] | |
Fusarium proliferatum | Macleaya cordata | Sanguinarine | antibacterial, antihelmintic, antitumor | [58] | |
Fusarium solani | Camptotheca acuminate and Apodytes dimidiata | Camptothecine | Antineoplastic | [44,59] | |
Fusarium solani, Metarhizium anisopliae and Mucor rouxianus | Taxus chinensis | Paclitaxel | Anticancer/antitumor agent | [60] | |
Hypocrea lixii | Cajanus cajan | Cajanol | Antiplasmodial, antimicrobial, anticancer agent | [61] | |
Pestalotiopsis pauciseta | Cardiospermum helicacabum | Paclitaxel | Anticancer/antitumor agent | [62] | |
Pestalotiopsis terminaliae | Terminalia arjuna | Paclitaxel | Anticancer/antitumor agent | [60] | |
Phialocephala fortinii | Podophyllum peltatum | Podophyllotoxin | Anticancer, antiviral, antioxidant, antibacterial and anti-rheumatic activities | [63] | |
Phoma glomerata | Salvia miltiorrhiza | Salvianolic acid C | Cardiovascular/ cerebrovascular | [64] | |
Phomopsis sp. and Diaporthe sp. | Cinchona ledgeriana | Quinine | Antipyretic and antimalarial | [65] | |
Phomopsis sp. and Diaporthe sp. | Cinchona ledgeriana | Quinidine | Antipyretic and antimalarial | [65] | |
Phomopsis sp. and Diaporthe sp. | Cinchona ledgeriana | Cinchonidine | Antipyretic and antimalarial | [65] | |
Phomopsis sp. and Diaporthe sp. | Cinchona ledgeriana | Cinchonine | Antipyretic and antimalarial | [65] | |
Sordariomycetes sp. | Eucommia ulmoides | Chlorogenic acid | Antimicrobial and antitumor | [66] | |
Trichoderma atroviride | Salvia miltiorrhiza | Tanshinone I | Antibacterial and anti-inflammatory | [67] | |
Trichoderma atroviride | Salvia miltiorrhiza | Tanshinone IIA | Antibacterial and anti-inflammatory | [67] | |
Thielavia subthermophila | Hypericum perforatum | Emodin | Antimicrobial, anti-inflammatory and antioxidant | [59] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Gakuubi, M.M.; Munusamy, M.; Liang, Z.-X.; Ng, S.B. Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds. J. Fungi 2021, 7, 786. https://doi.org/10.3390/jof7100786
Gakuubi MM, Munusamy M, Liang Z-X, Ng SB. Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds. Journal of Fungi. 2021; 7(10):786. https://doi.org/10.3390/jof7100786
Chicago/Turabian StyleGakuubi, Martin Muthee, Madhaiyan Munusamy, Zhao-Xun Liang, and Siew Bee Ng. 2021. "Fungal Endophytes: A Promising Frontier for Discovery of Novel Bioactive Compounds" Journal of Fungi 7, no. 10: 786. https://doi.org/10.3390/jof7100786