Abstract
Scientists are making efforts to search for new metabolites as they are essential lead molecules for the drug discovery, much required due to the evolution of multi drug resistance and new diseases. Moreover, higher production of known drugs is required because of the ever growing population. Microorganisms offer a vast collection of chemically distinct compounds that exhibit various biological functions. They play a crucial role in safeguarding crops, agriculture, and combating several infectious ailments and cancer. Research on fungi have grabbed a lot of attention after the discovery of penicillin, most of the compounds produced by fungi under normal cultivation conditions are discovered and now rarely new compounds are discovered. Treatment of fungi with the epigenetic modifiers has been becoming very popular since the last few years to boost the discovery of new molecules and enhance the production of already known molecules. Epigenetic literally means above genetics that actually does not alter the genome but alter its expression by altering the state of chromatin from heterochromatin to euchromatin. Chromatin in heterochromatin state usually doesn’t express because it is closely packed by histones in this state. Epigenetic modifiers loosen the packing of chromatin by inhibiting DNA methylation and histone deacetylation and thus permit the expression of genes that usually remain dormant. This study delves into the possibility of utilizing epigenetic modifying agents to generate pharmacologically significant secondary metabolites from fungi.
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Alam B, Lǐ J, Gě Q, Khan MA, Gōng J, Mehmood S, Gǒng W (2021) Endophytic fungi: from symbiosis to secondary metabolite communications or vice versa? Front Plant Sci 12:3060. https://doi.org/10.3389/fpls.2021.791033
Anjum K, Xuewei Y (2022) Epigenetic strategies to discover novel fungal secondary metabolites. J ISSN 2766:2276. https://doi.org/10.37871/jbres1430
Asai T, Yamamoto T, Oshima Y (2011) Histone deacetylase inhibitor induced the production of three novel prenylated tryptophan analogs in the entomopathogenic fungus, Torrubiella luteorostrata. Tetrahedron Lett 52:7042–7045. https://doi.org/10.1016/j.tetlet.2011.10.020
Asai T, Chung YM, Sakurai H, Ozeki T, Chang FR, Wu YC, Oshima Y (2012a) Highly oxidized ergosterols and isariotin analogs from an entomopathogenic fungus, Gibellula formosana, cultivated in the presence of epigenetic modifying agents. Tetrahedron 68:5817–5823. https://doi.org/10.1016/j.tet.2012.05.020
Asai T, Chung YM, Sakurai H, Ozeki T, Chang FR, Yamashita K, Oshima Y (2012) Tenuipyrone, a novel skeletal polyketide from the entomopathogenic fungus, Isaria tenuipes, cultivated in the presence of epigenetic modifiers. Org Lett 14:513–515. https://doi.org/10.1021/ol203097b
Asai T, Yamamoto T, Chung YM, Chang FR, Wu YC, Yamashita K, Oshima Y (2012) Aromatic polyketide glycosides from an entomopathogenic fungus, Cordyceps indigotica. Tetrahedron Lett 53:277–280. https://doi.org/10.1016/j.tetlet.2011.10.013
Bach SV, Hegde AN (2016) The proteasome and epigenetics: zooming in on histone modifications. Biomol Concepts 7(4):215–27. https://doi.org/10.1515/bmc-2016-0016
Bassett SA, Barnett MP (2014) The role of dietary histone deacetylases (HDACs) inhibitors in health and disease. Nutrients 6(10):4273–4301. https://doi.org/10.3390/nu6104273
Beau J, Mahid N, Burda WN, Harrington L, Shaw LN, Mutka T, Baker BJ (2012) Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii. Mar Drugs 10:762–774. https://doi.org/10.3390/md10040762
Bind S, Bind S, Sharma AK, Chaturvedi P (2022) Epigenetic modification: a key tool for secondary metabolite production in microorganisms. Front Microbiol 13:230
Bouyahya A, Mechchate H, Oumeslakht L, Zeouk I, Aboulaghras S, Balahbib A, El Omari N (2022) The role of epigenetic modifications in human cancers and the use of natural compounds as epidrugs: mechanistic pathways and pharmaco dynamic actions. Biomolecules 12:367. https://doi.org/10.3390/biom12030367
Brady SF, Wagenaar MM, Singh MP, Janso JE, Clardy J (2000) Thecytosporones, new octaketide antibiotics isolated from an endophytic fungus. Org Lett 2(25):4043–4046. https://doi.org/10.1021/ol006680s
Brookes RL, Crichton S, Wolfe CD, Yi Q, Li L, Hankey GJ, Markus HS (2018) Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke 49:54–61. https://doi.org/10.1161/STROKEAHA.117.016674
Cappellacci L, Perinell DR, Maggi F, Grifantini M, PetrelliR, (2020) Recent progress in histone deacetylase inhibitors as anticancer agents. Curr Med Chem 27(2449):2493. https://doi.org/10.2174/0929867325666181016163110
Chen HJ, AwakawaT SJY, Wakimoto T, Abe I (2013) Epigenetic modifier-induced biosynthesis of novel fusaric acid derivatives in endophytic fungi from Datura stramonium L. Nat Prod Bioprospect 3:20–23. https://doi.org/10.1007/s13659-013-0010-2
Chung YM, Wei CK, Chuang DW, El-Shazly M, Hsieh CT, Asai T, Chang FR (2013) An epigenetic modifier enhances the production of anti-diabetic and anti-inflammatory sesquiterpenoids from Aspergillus sydowii. Bioorg Med Chem 21:3866–3872. https://doi.org/10.1016/j.bmc.2013.04.004
Du L, King JB, Cichewicz RH (2014) Chlorinated polyketide obtained from a Daldinia sp. treated with the epigenetic modifier suberoylanilide hydroxamic acid. J Nat Prod 77:2454–2458. https://doi.org/10.1021/np500522z
Dube PS, Legoabe LJ, Beteck RM (2023) Quinolone: a versatile therapeutic compound class. Mol Divers. https://doi.org/10.1007/s11030-022-10581-8
El-Elimat T, Raja HA, Graf TN, FaethSH CNB, Oberlies NH (2014) Flavonolignans from Aspergillus iizukae, a fungal endophyte of milk thistle (Silybum marianum). J Nat Prod 77:193–199. https://doi.org/10.1021/np400955q
Feng T, Wei C, Deng X, Chen D, Wen Z, Xu J (2022) Epigenetic manipulation induced production of immunosuppressive chromones and cytochalasins from the mangrove endophytic fungus Phomopsis asparagi DHS-48. Mar Drugs 20:616. https://doi.org/10.3390/md20100616
Gnyszka A, Jastrzębski Z, Flis S (2013) DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res 33(8):2989–96
Gupta S, Kulkarni MG, White JF, Van Staden J (2020) Epigenetic-based developments in the field of plant endophytic fungi. S Afr J Bot 134:394–400
Gurudatt PS, Priti V, Shweta S, Ramesha BT, Ravikanth G, Vasudeva R, Puri S (2010) Attenuation of camptothecin production and negative relation between hyphal biomass and camptothecin content in endophytic fungal strains isolated from Nothapodytes nimmoniana Grahm (Icacinaceae). Curr Sci 98:1006–1010
Henke MT, Soukup AA, Goering AW, McClure RA, Thomson RJ, Keller NP, Kelleher NL (2016) New aspercryptins, lipopeptide natural products, revealed by HDAC inhibition in Aspergillus nidulans. ACS Chem Biol 11:2117–2123. https://doi.org/10.1021/acschembio.6b00398
Henrikson JC, Hoover AR, Joyner PM, Cichewicz RH (2009) A chemical epigenetics approach for engineering the in situ biosynthesis of a cryptic natural product from Aspergillus niger. Org Biomol Chem 7:435–438. https://doi.org/10.1039/B819208A
Hu C, Liu X, Zeng Y, Liu J, Wu F (2021) DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenet 13(1):1–16. https://doi.org/10.1186/s13148-021-01154-x
Ibrahim SR, Abdallah HM, Mohamed GA, Deshmukh SK (2023) Exploring potential of Aspergillus sclerotiorum: secondary metabolites and biotechnological relevance. Mycol Prog 22:1–28. https://doi.org/10.1007/s11557-022-01856-3
Kamat S, Kumar S, Philip S, Kumari M (2023) Secondary metabolites from marine fungi: current status and application. Microbial biomolecules. Academic Press, Cambridge, pp 181–209
Keller NP (2019) Fungal secondary metabolism: regulation, function and drug discovery. Nat Rev Microbiol 17(3):167–180. https://doi.org/10.1038/s41579-018-0121-1
Kinyamu HK, Bennett BD, Bushel PR, Archer TK (2020) Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem 295(5):1271–87. https://doi.org/10.1016/s0021-9258(17)49885-1
Kritsky MS, Filippovich SY, Afanasieva TP, Bachurina GP, Russo VEA (2001) Effect of inhibitors of enzymatic DNA methylation on the formation of reproductive structures and carotenoid production in Neurospora crassa. Appl Biochem Microbiol 37:243–247. https://doi.org/10.1023/A:1010268832075
Kumara PM, Soujanya KN, Ravikanth G, Vasudeva R, Ganeshaiah KN, Shaanker RU (2014) Rohitukine, a chromone alkaloid and a precursor of flavopiridol, is produced by endophytic fungi isolated from Dysoxylum binectariferum Hook. f and Amoora rohituka (Roxb). Wight & Arn. J Phymed 21:541–546. https://doi.org/10.1016/j.phymed.2013.09.019
Kusari S, Zühlke S, Spiteller M (2011) Effect of artificial reconstitution of the interaction between the plant Camptotheca acuminata and the fungal endophyte Fusarium solani on camptothecin biosynthesis. J Nat Prod 74:764–775. https://doi.org/10.1021/np1008398
Li JY, Sidhu RS, Ford EJ, Long DM, Hess WM, Strobel GA (1998) The induction of taxol production in the endophytic fungus—Periconia sp. from Torreya grandifolia. J Ind Microbiol Biot 20:259–264. https://doi.org/10.1038/sj.jim.2900521
Li J, Lv C, Sun W, Li Z, Han X, Li Y, Shen Y (2013) Cytosporone B, an inhibitor of the type III secretion system of Salmonella enterica serovar Typhimurium. Antimicrob Agents Chemother 57:2191–2198. https://doi.org/10.1128/AAC.02421-12
Li Y, Chang W, Zhang M, Li X, Jiao Y, Lou H (2015) Diorcinol D exerts fungicidal action against Candida albicans through cytoplasm membrane destruction and ROS accumulation. PLoS ONE 10:e0128693. https://doi.org/10.1371/journal.pone.0128693
Li CY, Chung YM, Wu YC, Hunyadi A, Wang CC, Chang FR (2020) Natural products development under epigenetic modulation in fungi. Phytochem Rev 19:1323–1340. https://doi.org/10.1007/s11101-020-09684-7
Li Z, Xiong K, Wen W, Li L, Xu D (2023) Functional endophytes regulating plant secondary metabolism: current status, prospects and applications. Int J Mol Sci 24:1153. https://doi.org/10.3390/ijms24021153
Magotra A, Kumar M, Kushwaha M, AwasthiP Raina C, Gupta AP, Chaubey A (2017) Epigenetic modifier induced enhancement of fumiquinazoline C production in Aspergillus fumigatus (GA-L7): an endophytic fungus from Grewiaasiatica L. AMB Express 7:1–10. https://doi.org/10.1186/s13568-017-0343-z
Makhwitine JP, Kumalo HM, Ndlovu SI, Mkhwanazi NP (2023) Epigenetic induction of secondary metabolites production in endophytic fungi Penicillium chrysogenum and GC-MS analysis of crude metabolites with Anti-HIV-1 activity. Microorganisms 11(6):1404
Mathews-Roth MM (1990) Plasma concentrations of carotenoids after large doses of beta-carotene. Am J Clin Nutr 52:500–501. https://doi.org/10.1093/ajcn/52.3.500
Mulrooey CA, O’Brien EM, Morgan BJ, Kozlowski MC (2012) Perylenequinones: isolation, synthesis, and biological activity. Eur J Org Chem 2012:3887. https://doi.org/10.1002/ejoc.201200184
Osmanova N, Schultze W, Ayoub N (2010) Azaphilones: a class of fungal metabolites with diverse biological activities. Phytochem Rev 9:315–342. https://doi.org/10.1007/s11101-010-9171-3
Patnaik E, Madu C, Lu Y (2023) Epigenetic modulators as therapeutic agents in cancer. Int J Mol Sci 24(19):14964. https://doi.org/10.3390/ijms241914964
Pillay LC, Nekati L, Makhwitine PJ, Ndlovu SI (2022) Epigenetic activation of silent biosynthetic gene clusters in endophytic fungi using small molecular modifiers. Front Microbiol 13:815008. https://doi.org/10.3389/fmicb.2022.815008
Priti V, Ramesha BT, Singh S, Ravikanth G, Ganeshaiah KN, Suryanarayanan TS, Uma Shaanker R (2009) How promising are endophytic fungi as alternative sources of plant secondary metabolites? Curr Sci 97:477–478
Ramesha KP, Chandra Mohana N, Chandra Nayaka S, Satish S (2021) Epigenetic modifiers revamp secondary metabolite production in endophytic Nigrospora sphaerica. Front Microbiol 12:730355. https://doi.org/10.3389/fmicb.2021.730355
Santi DV, Norment A, Garrett CE (1984) Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci 81(22):6993–7. https://doi.org/10.1073/pnas.81.22.699
Scherlach K, Hertweck C (2009) Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem 7:1753–1760. https://doi.org/10.1039/B821578B
Sharma V, Singamaneni V, Sharma N, Kumar A, Arora D, Kushwaha M, Gupta P (2018) Valproic acid induces three novel cytotoxic secondary metabolites in Diaporthe sp., an endophytic fungus from Datura inoxia Mill. Bioorg Med Chem Lett 28:2217–2221. https://doi.org/10.1016/j.bmcl.2018.04.018
Shwab EK, Bok JW, Tribus M, Galehr J, Graessle S, Keller NP (2007) Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot Cell 6:1656–1664. https://doi.org/10.1128/EC.00186-07
Shweta S, Gurumurthy BR, Ravikanth G, Ramanan US, Shivanna MB (2013) Endophytic fungi from Miquelia dentata Bedd., produce the anti-cancer alkaloid, camptothecine. Phytomedicine 20:337–342. https://doi.org/10.1016/j.phymed.2012.11.015
Stahl W, Sies H (1996) Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 336:1–9. https://doi.org/10.1006/abbi.1996.0525
Stierle A, Strobel G, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260:214–216. https://doi.org/10.1126/science.809706
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
Tiwari P, Bae H (2022) Endophytic fungi: key insights, emerging prospects, and challenges in natural product drug discovery. Microorganisms 10:360. https://doi.org/10.3390/microorganisms10020360
Toghueo RMK, Sahal D, Boyom FF (2020) Recent advances in inducing endophytic fungal specialized metabolites using small molecule elicitors including epigenetic modifiers. Phytochemistry 174:112338. https://doi.org/10.1016/j.phytochem.2020.112338
Triastuti A, Vansteelandt M, Barakat F, TrinelM JP, Fabre N, Haddad M (2019) How histone deacetylase inhibitors alter the secondary metabolites of Botryosphaeria mamane, an endophytic fungus isolated from Bixa orellana. Chem Biodivers 16:e1800485. https://doi.org/10.1002/cbdv.201800485
Van den Berg H, Faulks R, Granado HF, Hirschberg J, Olmedilla B, Sandmann G, Stahl W (2000) The potential for the improvement of carotenoid levels in foods and the likely systemic effects. J Sci Food Agric 80:880–912
VanderMolen KM, Darveaux BA, Chen WL, Swanson SM, Pearce CJ, Oberlies NH (2014) Epigenetic manipulation of a filamentous fungus by the proteasome-inhibitor bortezomib induces the production of an additional secondary metabolite. RSC Adv 4:18329–18335. https://doi.org/10.1039/C4RA00274A
Vasanthakumari MM, Jadhav SS, Sachin N, Vinod G, Shweta S, Manjunatha BL, Shaanker RU (2015) Restoration of camptothecine production in attenuated endophytic fungus on re-inoculation into host plant and treatment with DNA methyltransferase inhibitor. World J Microbiol Biotechnol 31:1629–1639. https://doi.org/10.1007/s11274-015-1916-0
Verma A, Tiwari H, Singh S, Gupta P, Rai N, Kumar Singh S, Gautam V (2023) Epigenetic manipulation for secondary metabolite activation in endophytic fungi: current progress and future directions. Mycology. https://doi.org/10.1080/21501203.2023.2241486
Verza FA, Das U, Fachin AL, Dimmock JR, Marins M (2020) Roles of histone deacetylases and inhibitors in anticancer therapy. Cancers 12(6):1664. https://doi.org/10.3390/cancers12061664
Wang X, SenaFilho JG, Hoover AR, King JB, Ellis TK, Powell DR, Cichewicz RH (2010) Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J Nat Prod 73:942–948. https://doi.org/10.1021/np100142h
Wang G, Yuan Y, Li Z, Zhu J, She Z, Chen Y (2023) Cytosporones with anti-inflammatory activities from the mangrove endophytic fungus Phomopsis sp QYM-13. Mar Drugs 21(12):631. https://doi.org/10.3390/md21120631
Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH (2008) Epigenetic remodeling of the fungal secondary metabolome. Org Biomol Chem 6:1895–1897. https://doi.org/10.1039/B804701D
Wu N, Wu XW, Agama K, Pommier Y, Du J, Li D, An LK (2010) A novel DNA topoisomerase I inhibitor with different mechanism from camptothecin induces G2/M phase cell cycle arrest to K562 cells. Biochem 49:10131–10136. https://doi.org/10.1021/bi1009419
Xue M, Hou X, Fu J, Zhang J, Wang J, Zhao Z, Zhou L (2023) Recent advances in search of bioactive secondary metabolites from fungi triggered by chemical epigenetic modifiers. J Fungi 9:172. https://doi.org/10.3390/jof9020172
Yang SW, Chan TM, Terracciano J, Patel R, Patel M, Gullo V, Chu M (2006) A new hydrogenated azaphilone Sch 725680 from Aspergillus sp. J Antibiot 59:720–723. https://doi.org/10.1038/ja.2006.96
Yang XL, Huang L, Ruan XL (2014) 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 16(4):412–7. https://doi.org/10.1080/10286020.2014.881356
Yeh HH, Ahuja M, Chiang YM, Oakley CE, Moore S, Yoon O, Hajovsky H, Bok JW, Keller NP, Wang CC, Oakley BR (2016) Resistance gene-guided genome mining: serial promoter exchanges in Aspergillus nidulans reveal the biosynthetic pathway for fellutamide B, a proteasome inhibitor. ACS Chem Biol 11(8):2275–84. https://doi.org/10.1021/acschembio.6b00213
Zheng YY, Ma ZL, Wu JS, Shao CL, Yao GS, Wang CY (2022) Induction of secondary metabolite biosynthesis by deleting the histone deacetylase HdaA in the marine-derived fungus Aspergillus terreus RA2905. J Fungi 8:1024. https://doi.org/10.3390/jof8101024
Zimmermann J, Erdmann D, Lalande I, Grossenbacher R, Noorani M, Fürst P (2000) Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1. Oncogene 19:2913–2920. https://doi.org/10.1038/sj.onc.1203606
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The authors are thankful to the Indian Council of Medical Research (ICMR) and Council of Scientific and Industrial Research (CSIR), New Delhi for the financial assistance.
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This work was supported by the CSIR-Indian Institute of Integrative Medicine (MLP 21002).
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VS: Writing original draft, Formal analysis. SP: Draft manuscript preparation, Editing and Review. NS: Conceived and designed the analysis. VA: Drafted the article and revised. UG: Formal analysis and review. SJ: Conceptualization, Formal analysis, Final review, Editing and supervision.
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Sharma, V., Panjgotra, S., Sharma, N. et al. Epigenetic modifiers as inducer of bioactive secondary metabolites in fungi. Biotechnol Lett 46, 297–314 (2024). https://doi.org/10.1007/s10529-024-03478-z
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DOI: https://doi.org/10.1007/s10529-024-03478-z