Abstract
Endophytes are barely untapped as vital sources in the medicine. They are microorganisms which mostly exist in plants. As they are exploited, it is accepted that endophytes can produce active metabolites that possess same function as their hosts such as taxol, podophyllotoxin, hypericin, and azadirachtin. These metabolites have been promising potential usefulness in safety and human health concerns. We are supposed to adopt measures to raise production for the low yield of metabolites. This paper summarizes the latest advances in various bioprocess optimization strategies. These techniques can overcome the limitations associated with rare pharmaceutical metabolite-producing endophytic fungi. These strategies include strain improvement, genome shuffling, medium optimization, fermentation conditions optimization, addition of specific factor, addition of solid sorbent, and co-culturing. It will enable endophytes to produce high and sustainable production of rare pharmaceutical metabolites.
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References
Bajwa PK, Pinel D, Martin VJ, Trevors JT, Lee H (2010) Strain improvement of the pentose-fermenting yeast Pichia stipitis by genome shuffling. J Microbiol Methods 81:179–186. https://doi.org/10.1016/j.mimet.2010.03.009
Bhagat J, Kaur A, Kaur R, Yadav AK, Sharma V, Chadha BS (2016) Cholinesterase inhibitor (Altenuene) from an endophytic fungus Alternaria alternata: optimization, purification and characterization. J Appl Microbiol 121:1015–1025. https://doi.org/10.1111/jam.13192
Bian G, Yuan Y, Tao H, Shi X, Zhong X, Han Y, Fu S, Fang C, Deng Z, Liu T (2017) Production of taxadiene by engineering of mevalonate pathway in Escherichia coli and endophytic fungus Alternaria alternata TPF6. Biotechnol J 12:1600697. https://doi.org/10.1002/biot.201600697
Bigelis R, He H, Yang H, Chang L-P, Greenstein M (2006) Production of fungal antibiotics using polymeric solid supports in solid-state and liquid fermentation. J Ind Microbiol Biotechnol 33:815–826. https://doi.org/10.1007/s10295-006-0126-z
Chaichanan J, Wiyakrutta S, Pongtharangkul T, Isarangkul D, Meevootisom V (2014) Optimization of zofimarin production by an endophytic fungus, Xylaria sp. Acra L38. Braz J Microbiol 45:287–293
Cheng DH, Ren H, Tang XC (1996) Huperzine A, a novel promising acetylcholinesterase inhibitor. Neuroraport 8:97–101
Cho EJ, Oh JY, Chang HY, Yun JW (2006) Production of exopolysaccharides by submerged mycelial culture of a mushroom Tremella fuciformis. J Biotechnol 127:129–140. https://doi.org/10.1016/j.jbiotec.2006.06.013
Ebel J, Cosio EG (1994) Elicitors of plant defense responses. Int’l Rev Cytol 148:1–36. https://doi.org/10.1016/S0074-7696(08)62404-3
El-Gendy MM, Al-Zahrani SH, El-Bondkly AM (2017) Construction of potent recombinant strain through intergeneric protoplast fusion in endophytic fungi for anticancerous enzymes production using rice straw. Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-017-2429-0
Findlay JA, Buthelezi S, Li GQ, Seveck M, Miller JD (1997) Insect toxins from an endophytic fungus from wintergreen. J Nat Prod 60:1214–1215. https://doi.org/10.1021/np970222j
Franco-Lara E, Link H, Weuster-Botz D (2006) Evaluation of artificial neural networks for modelling and optimization of medium composition with a genetic algorithm. Process Biochem 41:2200–2206. https://doi.org/10.1016/j.procbio.2006.06.024
Gao Y, Yin H, Sun Y, Zhang Z, Cui Y (2008) Mutagenesis of a berberine-producing endophytic fungus. J. Fungal Res. 4:6
Gong GL, Sun X, Liu XL, Hu W, Cao WR, Liu H, Liu WF, Li YZ (2007) Mutation and a high-throughput screening method for improving the production of epothilones of Sorangium. J Ind Microbiol Biotechnol 34:615–623. https://doi.org/10.1007/s10295-007-0236-2
Hida H, Yamada T, Yamada Y (2007) Genome shuffling of Streptomyces sp. U121 for improved production of hydroxycitric acid. Appl Microbiol Biotechnol 73:1387–1393. https://doi.org/10.1007/s00253-006-0613-1
Jin ZH, Xu B, Lin SZ, Jin QC, Cen PL (2009) Enhanced production of spinosad in Saccharopolyspora spinosa by genome shuffling. Appl Biochem Biotechnol 159:655–663. https://doi.org/10.1007/s12010-008-8500-0
Kern KA, Pergo EM, Kagami FL, Arraes LS, Sert MA, Ishii-Iwamoto EL (2009) The phytotoxic effect of exogenous ethanol on Euphorbia heterophylla L. Plant Physiol Biochem 47:1095–1101. https://doi.org/10.1016/j.plaphy.2009.07.002
Kharwar RN, Mishra A, Gond SK, Stierle A, Stierle D (2011) Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat Prod Rep 28:1208–1228. https://doi.org/10.1039/c1np00008j
Kusari S, Lamshöft M, Zühlke S, Spiteller M (2008) An endophytic fungus from Hypericum perforatum that produces hypericin. J Nat Prod 71:159–162. https://doi.org/10.1021/np070669k
Kusari S, Zühlke S, Kosuth J, Cellarova E, Spiteller M (2009) Light-independent metabolomics of endophytic Thielavia subthermophila provides insight into microbial hypericin biosynthesis. J Nat Prod 72:1825–1835. https://doi.org/10.1021/np9002977
Kusari S, Verma VC, Lamshöft M, Spiteller M (2012) An endophytic fungus from Azadirachta indica A. Juss. that produces azadirachtin. World J Microbiol Biotechnol 28:1287–1294. https://doi.org/10.1007/s11274-011-0876-2
Leslie Gunatilaka AA (2006) Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. J Nat Prod 69:509–526. https://doi.org/10.1021/np058128n
Li YC, Tao WY (2009) Paclitaxel production using co-culture of Taxus suspension cells and paclitaxel-producing endophytic fungi in a co-bioreactor. Appl Microbiol Biotechnol 83:233–239. https://doi.org/10.1007/s00253-009-1856-4
Li JY, Sidhu RS, Bollon A, Strobel GA (1998) Stimulation of taxol production in liquid cultures of Pestalotiopsis microspora. Mycol Res 102:461–464. https://doi.org/10.1017/S0953756297005078
Lin J, Shi BH, Shi QQ, He YX, Wang MZ (2007) Rapid improvement in lipase production of Penicillium expansum by genome shuffling. Chin J Biotechnol 23:672–676. https://doi.org/10.1016/S1872-2075(07)60044-2
Liu L, Wei YM, Zhou XW, Lin J, Sun XF, Tang KX (2013) Agrobacterium tumefaciens mediated genetic transformation of the Taxol-producing endophytic fungus Ozonium sp EFY21. Genet Mol Res 12:2913–2922. https://doi.org/10.4238/2013.August.12.7
Luo H, Liu H, Cao Y, Xu D, Mao Z, Mou Y, Meng J, Lai D, Liu Y, Zhou L (2014) Enhanced production of botrallin and TMC-264 with in situ macroporous resin adsorption in mycelial liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12. Molecules 19:14221–14234. https://doi.org/10.3390/molecules190914221
Ma C, Jiang D, Wei X (2011) Mutation breeding of Emericella foeniculicola TR21 for improved production of tanshinone IIA. Process Biochem 46:2059–2063. https://doi.org/10.1016/j.procbio.2011.07.012
Mahapatra S, Banerjee D (2013) Optimization of a bioactive exopolysaccharide production from endophytic Fusarium solani SD5. Carbohydr Polym 97:627–634. https://doi.org/10.1016/j.carbpol.2013.05.039
Ola A, Thomy D, Lai D, Brötz Oesterhelt H, Proksch P (2013) Inducing secondary metabolite production by the endophytic fungus Fusarium tricinctum through coculture with Bacillus subtilis. J Nat Prod 76:2094–2099. https://doi.org/10.1021/np400589h
Parekh S (2000) Strain improvement. In: J Lederberg (ed): Encyclopedia of microbiology, vol. 4, 2nd ed. Academic Press, San Diego, 428-443
Parekh S, Vinci VA, Strobel RJ (2000) Improvement of microbial strains and fermentation processes. Appl Microbiol Biotechnol 54:287–301. https://doi.org/10.1007/s002530000403
Parra R, Aldred D, Magan N (2005) Medium optimization for the production of the secondary metabolite squalestatin S1 by a Phoma sp. combining orthogonal design and response surface methodology. Enzym Microb. Technol 37:704–711. https://doi.org/10.1016/j.enzmictec.2005.04.009
Pu X, Qu X, Chen F, Bao J, Zhang G, Luo Y (2013) Camptothecin-producing endophytic fungus Trichoderma atroviride LY357: isolation, identification, and fermentation conditions optimization for camptothecin production. Appl Microbiol Biotechnol 97:9365–9375. https://doi.org/10.1007/s00253-013-5163-8
Puri SC, Verma V, Amna T, Qazi GN, Spiteller M (2005) An endophytic fungus from Nothapodytes foetida that produces camptothecin. J Nat Prod 68:1717–1719. https://doi.org/10.1021/np0502802
Puri SC, Nazir A, Chawla R, Arora R, Riyaz-ul-Hasan S, Amna T, Ahmed B, Verma V, Singh S, Sagar R, Sharma A, Kumar R, Sharma RK, Qazi GN (2006) The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans. J Biotechnol 122:494–510. https://doi.org/10.1016/j.jbiotec.2005.10.015
Rani K, Rana R, Datt S (2012) Review on latest overview of proteases. Int J Curr Life Sci. 2:12–18
Rocha MV, Romanini D, Nerli BB, Tubio G (2012) Pancreatic serine protease extraction by affinity partition using a free triazine dye. Int J Biol Macromol 50:303–309. https://doi.org/10.1016/j.ijbiomac.2011.12.013
Sivaramakrishnan S, Gangadharan D, Madhavan KN, Pandey A (2006) Solid culturing of Bacillus amyloliquefaciens for alpha amylase production. Food Technol Biotechnol 44:269–274
Soliman SS, Raizada MN (2013) Interactions between co-habitating fungi elicit synthesis of taxol from an endophytic fungus in host taxus plants. Frontiers Microbiol 4:3. https://doi.org/10.3389/fmicb.2013.00003
Somjaipeng S, Medina A, Magan N (2016) Environmental stress and elicitors enhance taxol production by endophytic strains of Paraconiothyrium variabile and Epicoccum nigrum. Enzyme Microb Technol 90:69–75. https://doi.org/10.1016/j.enzmictec.2016.05.002
Sommart U, Rukachaisirikul V, Sukpondma Y, Phongpaichit S, Towatana NH, Graidist P, Hajiwangoh Z, Sakayaroj J (2009) A cyclohexenone derivative from Diaporthaceous fungus PSU-H2. Arch Pharm Res 32:1227–1231. https://doi.org/10.1007/s12272-009-1907-5
Stierle A, Strobel G, Stierle D, Grothaus P, Bignami G (1995) The search for a taxol-producing microorganism among the endophytic fungi of the Pacific yew, Taxus brevifolia. J Nat Prod 58:1315–1324. https://doi.org/10.1021/np50123a002
Strobel G, Daisy B (2003) Bioprospecting for microbial endophytes and their natural products. Microbiol Mol Biol Rev 67:491–502. https://doi.org/10.1128/MMBR.67.4.491-502.2003
Strobel G, Daisy B, Castillo U, Harper J (2004) Natural products from endophytic microorganisms. J Nat Prod 67:257–268. https://doi.org/10.1021/np030397v
Thammajaruk N, Sriubolmas N, Israngkul D, Meevootisom V, Wiyakrutta S (2011) Optimization of culture conditions for mycoepoxydiene production by Phomopsis sp. Hant25. J Ind Microbiol Biotechnol 38:679–685. https://doi.org/10.1007/s10295-010-0813-7
Thompson CJ, Ward JM, Hopwood DA (1982) Cloning of antibiotic resistance and nutritional genes in streptomycetes. J Bacteriol 151:668–677
Ueda M, Kubo T, Miyatake K, Nakamura T (2007) Purification and characterization of fibrinolytic alkaline protease from Fusarium sp. BLB. Appl Microbiol Biotechnol 74:331–338. https://doi.org/10.1007/s00253-006-0621-1
Venugopalan A, Potunuru UR, Dixit M, Srivastava S (2016) Effect of fermentation parameters, elicitors and precursors on camptothecin production from the endophyte Fusarium solani. Bioresour Technol 206:104–111. https://doi.org/10.1016/j.biortech.2016.01.079
Vinale F, Nicoletti R, Borrelli F, Mangoni A, Parisi OA, Marra R, Lombardi N, Lacatena F, Grauso L, Finizio S (2017) Co-culture of plant beneficial microbes as source of bioactive metabolites. Sci Rep 7:14330. https://doi.org/10.1038/s41598-017-14569-5
Wang Y, Guo B, Miao Z, Tang K (2007) Transformation of taxol-producing endophytic fungi by restriction enzyme-mediated integration (REMI). FEMS Microbiol Lett 273:253–259. https://doi.org/10.1111/j.1574-6968.2007.00801.x
Wang X, Wang C, Sun YT, Sun CZ, Zhang Y, Wang XH, Zhao K (2015) Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells. Asian Pac J Cancer Prev 16:125–131. https://doi.org/10.7314/APJCP.2015.16.1.125
Wang M, Zhang W, Xu W, Shen Y, Du L (2016) Optimization of genome shuffling for high-yield production of the antitumor deacetylmycoepoxydiene in an endophytic fungus of mangrove plants. Appl Microbiol Biotechnol 100:7491–7498. https://doi.org/10.1007/s00253-016-7457-0
Wei YM, Zhou XW, Liu L, Lu J, Wang ZN, Yu G (2010) An efficient transformation system of taxol-producing endophytic fungus EFY-21 (Ozonium sp.). Afr J Biotechnol 9:1726–1733. https://doi.org/10.5897/AJB2010.000-3019
Wen Y, Wang Y, Liu X, Zhang W, Xiong X, Han Z, Liang X (2017) Camptothecin-based nanodrug delivery systems. Cancer Biol Med 14:363–370
Wetwitaklung P, Thavanapong N, Charoenteeraboon J (2009) Chemical constituents and antimicrobial activity of essential oil and extracts of heartwood of Aquilaria crassna obtained from water distillation and supercritical fluid carbon dioxide extraction. Silpakorn Univ Sci Tech J 3:25–33
Xu B, Wang MR, Xia Y, Yang K, Zhang CY (2006a) Improvement of the output of teicoplanin by genome shuffling. Chin J Antibiot 31:237–242. https://doi.org/10.1360/yc-006-1627
Xu F, Tao W, Cheng L, Guo L (2006b) Strain improvement and optimization of the media of taxol-producing fungus Fusarium maire. Biochem Eng J 31:67–73. https://doi.org/10.1016/j.bej.2006.05.024
Xu LJ, Liu YS, Zhou LG, Wu JY (2009) Enhanced beauvericin production with in situ adsorption in mycelial liquid culture of Fusarium redolens Dzf2. Process Biochem 44:1063–1067. https://doi.org/10.1016/j.procbio.2009.05.004
Yamin W, Lu L, Xuanwei Z, Juan L, Xiaofen S, Kexuan T (2012) Engineering taxol biosynthetic pathway for improving taxol yield in taxol-producing endophytic fungus EFY-21 (Ozonium sp.). Afr J Biotechnol 11:9094–9101. https://doi.org/10.5897/AJB10.1896
Zaferanloo B, Virkar A, Mahon PJ, Palombo EA (2013) Endophytes from an Australian native plant are a promising source of industrially useful enzymes. World J Microbiol Biotechnol 29:335–345. https://doi.org/10.1007/s11274-012-1187-y
Zaferanloo B, Quang TD, Daumoo S, Ghorbani MM, Mahon PJ, Palombo EA (2014) Optimization of protease production by endophytic fungus, Alternaria alternata, isolated from an Australian native plant. World J Microbiol Biotechnol 30:1755–1762. https://doi.org/10.1007/s11274-014-1598-z
Zhang YX, Perry K, Vinci VA, Powell K, Stemmer WP, del Cardayré SB (2002) Genome shuffling leads to rapid phenotypic improvement in bacteria. Nature 415:644–646. https://doi.org/10.1038/415644a
Zhang HW, Song YC, Tan RX (2006) Biology and chemistry of endophytes. Nat Prod Rep 23:753–771. https://doi.org/10.1039/b609472b
Zhang P, Liu TT, Zhou PP, Li ST, Yu LJ (2011) Agrobacterium tumefaciens-mediated transformation of a Taxol-producing endophytic fungus, Cladosporium cladosporioides MD2. Curr Microbiol 62:1315–1320. https://doi.org/10.1007/s00284-010-9864-2
Zhao K, Ping WX, Zhang LN, Liu J, Lin Y, Jin T, Zhou D (2008) Screening and breeding of high taxol producing fungi by genome shuffling. Sci China Ser C Life Sci 51:222–231. https://doi.org/10.1007/s11427-008-0037-5
Zhao J, Li Y, Shan T, Mou Y, Zhou L (2011) Enhancement of diepoxin ζ production with in situ resin adsorption in mycelial liquid culture of the endophytic fungus Berkleasmium sp. Dzf12 from Dioscorea zingiberensis. World J Microbiol Biotechnol 27:2753–2758. https://doi.org/10.1007/s11274-011-0750-2
Zhao XM, Wang ZQ, Shu SH, Wang WJ, Xu HJ, Ahn YJ, Wang M, Hu X (2013) Ethanol and methanol can improve huperzine a production from endophytic Colletotrichum gloeosporioides ES026. PLoS ONE 8:e61777. https://doi.org/10.1371/journal.pone.0061777
Zhou DP, Ping WX, Sun JQ, Zhou XH, Liu XL, Yang DZ, Zhang JP, Zheng XQ (2001a) Isolation of taxol producing fungi. J Microbiol 21(18–19):32
Zhou DP, Sun JQ, Yu HY, Ping WX, Zheng XQ (2001b) Nodulisporium, a genus new to China. Mycosystema 20:277–278
Zhu SS, Zhang YS, Sheng XH, Xu M, Wu SS, Shen YM, Huang YJ, Wang Y, Shi YQ (2015) Deacetyl-mycoepoxydiene, isolated from plant endophytic fungi Phomopsis sp. demonstrates anti-microtubule activity in MCF-7 cells. Biomed Pharmacother 69:82–89. https://doi.org/10.1016/j.biopha.2014.11.020
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This work was supported by Project of Shandong Province Key Research and Development Program (2017YYSP030). The authors would also like to thank the anonymous reviewers for their helpful comments and suggestions that greatly improved the manuscript.
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Xu, F., Wang, S., Li, Y. et al. Yield enhancement strategies of rare pharmaceutical metabolites from endophytes. Biotechnol Lett 40, 797–807 (2018). https://doi.org/10.1007/s10529-018-2531-6
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DOI: https://doi.org/10.1007/s10529-018-2531-6