Strategies for mining new secondary metabolites from fungi: from Classical Approaches to Genomics-Based Mining
Keywords:
Fungal secondary metabolites, Genome mining, Biosynthetic gene clusters (BGCs), Dereplication, Culture condition optimization, Natural product discoveryAbstract
Fungi are prolific producers of structurally diverse secondary metabolites, which play significant ecological and pharmacological roles. However, the rate of discovering new fungal natural products has slowed in recent decades, highlighting the need for innovative approaches to unlock their biosynthetic potential. Recent advances in genome sequencing and bioinformatics have revealed the complexity of fungal biosynthetic gene clusters, enabling the development of strategies to activate silent pathways and improve the efficiency of compound identification. This review synthesizes current methodologies for mining novel fungal metabolites, including classical approaches that modify culture conditions, genomics-based genome mining, and dereplication techniques to efficiently distinguish known from unknown compounds. We further highlight integrated, multi-strategy frameworks that maximize discovery efficiency and discuss emerging directions such as multi-omics integration and machine learning-assisted pathway prediction. By providing a comprehensive and forward-looking overview, this work aims to guide the effective exploitation of fungal resources in the search for new natural products.
References
Abraham E (1979) A glimpse of the early history of the cephalosporins. Reviews of Infectious Diseases:99–105.
https://doi.org/10.1093/clinids/1.1.99
Ahuja M, Chiang YM, Chang SL, Praseuth MB, Entwistle R, Sanchez JF, Lo HC, Yeh HH, Oakley BR, Wang CCC (2012) Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. Journal of the American Chemical Society 134:8212–8221.
https://doi.org/10.1021/ja3016395
Amaike S, Keller NP (2011) Aspergillus flavus. Annual Review of Phytopathology 49:107–133.
https://doi.org/10.1146/annurev-phyto-072910-095221
Arora S, Hu W, Kothari PK (2018) An analysis of the t-SNE algorithm for data visualization. In: Conf Learn Theory, Proc Mach Learn Res 75:1455–1462.
https://proceedings.mlr.press/v75/arora18a.html
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. Organic Letters 14:513–515.
https://doi.org/10.1021/ol203097b
Asai T, Otsuki S, Sakurai H, Yamashita K, Ozeki T, Oshima Y (2013a) Benzophenones from an endophytic fungus, Graphiopsis chlorocephala, from Paeonia lactiflora cultivated in the presence of an NAD⁺-dependent HDAC inhibitor. Organic Letters 15:2058–2061.
https://doi.org/10.1021/ol400781b
Asai T, Yamamoto T, Shirata N, Taniguchi T, Monde K, Fujii I, Gomi K, Oshima Y (2013b). Structurally diverse chaetophenol productions induced by chemically mediated epigenetic manipulation of fungal gene expression. Organic Letters 15:3346–3349.
https://doi.org/10.1021/ol401386w
Bai M, Zhang YY, Dong SH, Ren H, Chen JJ, Yao GD, Liu QB, Lin B, Huang XX, Song SJ (2020) Targeted isolation of cytotoxic germacranolide sesquiterpenes from Elephantopus scaber L. using small molecule accurate recognition technology. Bioorganic Chemistry 104:104314.
https://doi.org/10.1016/j.bioorg.2020.104314
Bai Y, Gao M, Wen LL, He C, Chen Y, Liu C, Fu X, Huang S (2018) Applications of microfluidics in quantitative biology. Biotechnology Journal 13:1700170.
https://doi.org/10.1002/biot.201700170
Bakiri A, Hubert J, Reynaud R, Lanthony S, Harakat D, Renault JH, Nuzillard JM (2017) Computer-aided 13C NMR chemical profiling of crude natural extracts without fractionation. Journal of Natural Products 80:1387–1396.
https://doi.org/10.1021/acs.jnatprod.6b01063
Balkovec JM, Hughes DL, Masurekar PS, Sable CA, Schwartz RE, Singh SB (2014) Discovery and development of first-in-class antifungal caspofungin (CANCIDAS®)—A case study. Natural Product Reports 31:15–34.
https://doi.org/10.1039/C3NP70070D
Bartholomew HP, Bradshaw M, Jurick WM II, Fonseca JM (2021) The good, the bad, and the ugly: mycotoxin production during postharvest decay and their influence on tritrophic host–pathogen–microbe interactions. Frontiers in Microbiology 12:611881.
https://doi.org/10.3389/fmicb.2021.611881
Baskiyar S, Ren C, Heck KL, Hall AM, Gulfam M, Packer S, Seals CD, Calderón AI (2022) Bioactive natural products identification using automation of molecular networking software. Journal of Chemical Information and Modeling 62:6378–6385.
https://doi.org/10.1021/acs.jcim.2c00307
Berger T, Alenfelder J, Steinmüller S, Heimann D, Gohain N, Petras D, Wang M, Berger R, Kostenis E, Reher R (2024) A MassQL-integrated molecular networking approach for the discovery and substructure annotation of bioactive cyclic peptides. Journal of Natural Products 87:692–704.
https://doi.org/10.1021/acs.jnatprod.3c00750
Bertrand S, Bohni N, Schnee S, Schumpp O, Gindro K, Wolfender JL (2014) Metabolite induction via microorganism co-culture: a potential way to enhance chemical diversity for drug discovery. Biotechnology Advances 32:1180–1204.
https://doi.org/10.1016/j.biotechadv.2014.03.001
Bethe B (1994) Ausarbeitung von Methoden und Konzepten zum Auffinden und Bewerten von Biosyntheseleistungen im Sekundarstoffwechsel sowie Isolierung und Strukturaufklärung der Sekundarstoffe des Streptomyceten Stammes Go 40/41. PhD thesis, Universität Göttingen.
Bian G, Hou A, Yuan Y, Hu B, Cheng S, Ye Z, Di Y, Deng Z, Liu T (2018) Metabolic engineering-based rapid characterization of a sesquiterpene cyclase and the skeletons of fusariumdiene and fusagramineol from Fusarium graminearum. Organic Letters 20:1626–1629.
https://doi.org/10.1021/acs.orglett.8b00366
Bind S, Bind S, Sharma A, Chaturvedi P (2022) Epigenetic modification: A key tool for secondary metabolite production in microorganisms. Frontiers in Microbiology 13:784109.
https://doi.org/10.3389/fmicb.2022.784109
Blin K, Shaw S, Augustijn HE, Reitz ZL, Biermann F, Alanjary M, Fetter A, Terlouw BR, Metcalf WW, Helfrich EJN et al (2023) antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation. Nucleic Acids Research 51:W46–W50.
https://doi.org/10.1093/nar/gkad344
Blumenthal T (2004) Operons in eukaryotes. Briefings in Functional Genomics 3:199–211.
https://doi.org/10.1093/bfgp/3.3.199
Bo G (2000) Giuseppe Brotzu and the discovery of cephalosporins. Clinical Microbiology and Infection 6:6–8.
https://doi.org/10.1111/j.1469-0691.2000.tb02032.x
Bode HB, Bethe B, Höfs R, Zeeck A (2002) Big effects from small changes: possible ways to explore nature's chemical diversity. ChemBioChem 3:619–627.
https://doi.org/10.1002/1439-7633(20020703)3:7<619::AID-CBIC619>3.0.CO;2-9
Bruguière A, Derbré S, Bréard D, Tomi F, Nuzillard JM, Richomme P (2021) 13C NMR dereplication using MixONat software: a practical guide to decipher natural products mixtures. Planta Medica 87:1061–1068.
https://doi.org/10.1055/a-1470-0446
Bruguière A Derbré S Coste C Le Bot M Siegler B Leong ST Sulaiman SN Awang K Richomme P (2018) 13C-NMR dereplication of Garcinia extracts: Predicted chemical shifts as reliable databases. Fitoterapia 131:59–64.
https://doi.org/10.1016/j.fitote.2018.09.010
Bruguière A, Derbré S, Dietsch J, Leguy J, Rahier V, Pottier Q, Bréard D, Suor-Cherer S, Viault G, Le Ray AM et al (2020) MixONat, a software for the dereplication of mixtures based on 13C NMR spectroscopy. Analytical Chemistry 92:8793–8801.
https://doi.org/10.1021/acs.analchem.0c00193
Burmeister A, Grünberger A (2020) Microfluidic cultivation and analysis tools for interaction studies of microbial co-cultures. Current Opinion in Biotechnology 62:106–115.
https://doi.org/10.1016/j.copbio.2019.09.001
Cao L, Guler M, Tagirdzhanov A, Lee YY, Gurevich A, Mohimani H (2021) MolDiscovery: learning mass spectrometry fragmentation of small molecules. Nature Communications 12:3718.
https://www.nature.com/articles/s41467-021-23986-0
Chen L, Wu H, Liu H, Li E, Ren J, Wang W, Wang S, Yin WB (2019) Genetic dereplication of Trichoderma hypoxylon reveals two novel polycyclic lactones. Bioorganic Chemistry 91:103185.
https://doi.org/10.1016/j.bioorg.2019.103185
Chen Y, Yang W, Zou G, Wang G, Kang W, Yuan J, She Z (2022) Cytotoxic bromine- and iodine-containing cytochalasins produced by the mangrove endophytic fungus Phomopsis sp. QYM-13 using the OSMAC approach. Journal of Natural Products 85:1229–1238.
https://doi.org/10.1021/acs.jnatprod.1c01115
Chiang YM, Ahuja M, Oakley CE, Entwistle R, Asokan A, Zutz C, Wang CCC, Oakley BR (2016) Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew Chem Int Ed 55:1662–1665.
https://doi.org/10.1002/anie.201507097
Chung YM, El-Shazly M, Chuang DW, Hwang TL, Asai T, Oshima Y, Ashour ML, Wu YC, Chang FR (2013) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces the production of anti-inflammatory cyclodepsipeptides from Beauveria felina. Journal of Natural Products 76:1260–1266.
https://doi.org/10.1021/np400143j
Clendinen CS, Lee-McMullen B, Williams CM, Stupp GS, Vandenborne K, Hahn DA, Walter GA, Edison AS (2014) ¹³C NMR metabolomics: applications at natural abundance. Analytical Chemistry 86:9242–9250.
https://doi.org/10.1021/ac502346h
D’Ambrosio S, Ventrone M, Alfano A, Schiraldi C, Cimini D (2021) Microbioreactor (micro-Matrix) potential in aerobic and anaerobic conditions with different industrially relevant microbial strains. Biotechnology Progress 37:e3184.
https://doi.org/10.1002/btpr.3184
Diaz-Allen C (2022) Developing a 1D-TOCSY NMR-based dereplication technique to facilitate the isolation of new, cytotoxic compounds from natural products. PhD thesis, The Ohio State University.
Diaz-Allen C, Spjut RW, Kinghorn AD, Rakotondraibe HL (2021) Prioritizing natural product compounds using 1D-TOCSY NMR spectroscopy. Trends in Organic Chemistry 22:99–114.
Ding W, Tian D, Chen M, Xia Z, Tang X, Zhang S, Wei J, Li X, Yao X, Wu B et al (2023) Molecular networking-guided isolation of cyclopentapeptides from the hydrothermal vent sediment derived fungus Aspergillus pseudoviridinutans TW58-5 and their anti-inflammatory effects. Journal of Natural Products 86:1919–1930.
https://doi.org/10.1021/acs.jnatprod.3c00287
Ding Z, Wang X, Kong FD, Huang HM, Zhao YN, Liu M, Wang ZP, Han J (2020) Overexpression of global regulator Talae1 leads to the discovery of new antifungal polyketides from endophytic fungus Trichoderma afroharzianum. Frontiers in Microbiology 11:622785.
https://doi.org/10.3389/fmicb.2020.622785
Dong QY, Wang Y, Wang ZQ, Liu YF, Yu H (2022) Phylogeny and systematics of the genus Tolypocladium (Ophiocordycipitaceae, Hypocreales). Journal of Fungi 8:1158.
https://doi.org/10.3390/jof8111158
Duggan BM, Cullum R, Fenical W, Amador LA, Rodríguez AD, La Clair JJ (2020) Searching for small molecules with an atomic sort. Angewandte Chemie 132:1160–1164.
https://doi.org/10.1002/ange.201911862
Dührkop K, Fleischauer M, Ludwig M, Aksenov AA, Melnik AV, Meusel M, Dorrestein PC, Rousu J, Böcker S (2019) SIRIUS 4: a rapid tool for turning tandem mass spectra into metabolite structure information. Nature Methods 16:299–302.
https://doi.org/10.1038/s41592-019-0344-8
Dührkop K, Nothias LF, Fleischauer M, Reher R, Ludwig M, Hoffmann MA, Petras D, Gerwick WH, Rousu J, Dorrestein PC et al (2021) Systematic classification of unknown metabolites using high-resolution fragmentation mass spectra. Nature Biotechnology 39:462–471.
https://doi.org/10.1038/s41587-020-0740-8
Edison AS, Colonna M, Gouveia GJ, Holderman NR, Judge MT, Shen X, Zhang S (2020) NMR: unique strengths that enhance modern metabolomics research. Analytical Chemistry 93:478–499.
https://doi.org/10.1021/acs.analchem.0c04414
Egan JM, van Santen JA, Liu DY, Linington RG (2021) Development of an NMR-based platform for the direct structural annotation of complex natural products mixtures. Journal of Natural Products 84:1044–1055.
https://doi.org/10.1021/acs.jnatprod.0c01076
El-Elimat T, Figueroa M, Ehrmann BM, Cech NB, Pearce CJ, Oberlies NH (2013) High-resolution MS, MS/MS, and UV database of fungal secondary metabolites as a dereplication protocol for bioactive natural products. Journal of Natural Products 76:1709–1716.
https://doi.org/10.1021/np4004307
Ernst RR, Bodenhausen G, Wokaun A (1990) Principles of nuclear magnetic resonance in one and two dimensions. Oxford University Press, New York.
Espinosa-Ortiz EJ, Rene ER, Gerlach R (2022). Potential use of fungal-bacterial co-cultures for the removal of organic pollutants. Critical Reviews in Biotechnology 42:361–383.
https://doi.org/10.1080/07388551.2021.1940831
Fan A, Mi W, Liu Z, Zeng G, Zhang P, Hu Y, Fang W, Yin WB (2017). Deletion of a histone acetyltransferase leads to the pleiotropic activation of natural products in Metarhizium robertsii. Organic Letters 19:1686–1689.
https://doi.org/10.1021/acs.orglett.7b00476
Fan B, Dewapriya P, Li F, Blümel M, Tasdemir D (2020) Pyrenosetins A–C, new decalinoylspirotetramic acid derivatives isolated by bioactivity-based molecular networking from the seaweed-derived fungus Pyrenochaetopsis sp. FVE-001. Marine Drugs 18:47.
https://doi.org/10.3390/md18010047
Fan B, Grauso L, Li F, Scarpato S, Mangoni A, Tasdemir D (2022) Application of feature-based molecular networking for comparative metabolomics and targeted isolation of stereoisomers from algicolous fungi. Marine Drugs 20:210.
https://doi.org/10.3390/md20030210
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. Marine Drugs 20:616.
https://doi.org/10.3390/md20100616
Fischedick JT, Johnson SR, Ketchum RE, Croteau RB, Lange BM (2015) NMR spectroscopic search module for Spektraris, an online resource for plant natural product identification – taxane diterpenoids from Taxus × media cell suspension cultures as a case study. Phytochemistry 113:87–95.
https://doi.org/10.1016/j.phytochem.2014.11.020
Fleming A (1929) On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. British Journal of Experimental Pathology 10:226.
Flores-Bocanegra L, Al Subeh ZY, Egan JM, El-Elimat T, Raja HA, Burdette JE, Pearce CJ, Linington RG, Oberlies NH (2022) Dereplication of fungal metabolites by NMR-based compound networking using MADByTE. Journal of Natural Products 85:614–624.
https://doi.org/10.1021/acs.jnatprod.1c00841
Floss HG (2006) Combinatorial biosynthesis—potential and problems. Journal of Biotechnology 124:242–257.
https://doi.org/10.1016/j.jbiotec.2005.12.001
Freire VF, Gubiani JR, Spencer TM, Hajdu E, Ferreira AG, Ferreira DAS, de Castro Levatti EV, Burdette JE, Camargo CH, Tempone AG et al (2022) Feature-based molecular networking discovery of bromopyrrole alkaloids from the marine sponge Agelas dispar. Journal of Natural Products 85:1340–1350.
https://doi.org/10.1021/acs.jnatprod.2c00094
Fuchser J, Zeeck A (1997) Aspinolides and aspinonene/aspyrone co-metabolites, new pentaketides produced by Aspergillus ochraceus. Liebigs Annalen 1:87–95.
Gacek A, Strauss J (2012) The chromatin code of fungal secondary metabolite gene clusters. Applied Microbiology and Biotechnology 95:1389–1404.
https://doi.org/10.1007/s00253-012-4208-8
Galappaththi MC, Patabendige NM, Premarathne BM, Hapuarachchi KK, Tibpromma S, Dai DQ, Suwannarach N, Rapior S, Karunarathna SC (2022) A review of Ganoderma triterpenoids and their bioactivities. Biomolecules 13:24.
https://doi.org/10.3390/biom13010024
Gaudêncio SP, Pereira F (2015) Dereplication: racing to speed up the natural products discovery process. Natural Product Reports 32:779–810.
https://doi.org/10.1039/C4NP00134F
Grienke U, Foster PA, Zwirchmayr J, Tahir A, Rollinger JM, Mikros E (2019) ¹H NMR-MS-based heterocovariance as a drug discovery tool for fishing bioactive compounds out of a complex mixture of structural analogues. Scientific Reports 9:11113.
https://doi.org/10.1038/s41598-019-47434-8
Guijas C, Montenegro-Burke JR, Domingo-Almenara X, Palermo A, Warth B, Hermann G, Koellensperger G, Huan T, Uritboonthai W, Aisporna AE et al (2018) METLIN: a technology platform for identifying knowns and unknowns. Analytical Chemistry 90:3156–3164.
https://doi.org/10.1021/acs.analchem.7b04424
Guo C, Dai H, Zhang M, Liao H, Zhang R, Chen B, Han J, Liu H (2022) Molecular networking assisted discovery and combinatorial biosynthesis of new antimicrobial pleuromutilins. European Journal of Medicinal Chemistry 243:114713.
https://doi.org/10.1016/j.ejmech.2022.114713
Guo DL, Qiu L, Feng D, He X, Li XH, Cao ZX, Gu YC, Mei L, Deng F, Deng Y (2020) Three new α-pyrone derivatives induced by chemical epigenetic manipulation of Penicillium herquei, an endophytic fungus isolated from Cordyceps sinensis. Natural Product Research 34:958–964.
https://doi.org/10.1080/14786419.2018.1544974
Guo W, Peng J, Zhu T, Gu Q, Keyzers RA, Li D (2013) Sorbicillamines A–E, nitrogen-containing sorbicillinoids from the deep-sea-derived fungus Penicillium sp. F23-2. Journal of Natural Products 76:2106–2112.
https://doi.org/10.1021/np4006647
Hannigan GD, Prihoda D, Palicka A, Soukup J, Klempir O, Rampula L, Durcak J, Wurst M, Kotowski J, Chang D et al (2019) A deep learning genome-mining strategy for biosynthetic gene cluster prediction. Nucleic Acids Research 47:e110.
https://doi.org/10.1093/nar/gkz654
He QF, Wu ZL, Li L, Sun W, Wang G, Jiang R, Hu L, Shi L, He R, Wang Y et al (2021) Discovery of neuritogenic Securinega alkaloids from Flueggea suffruticosa by a building blocks-based molecular network strategy. Angew Chem Int Ed 60:19609–19613.
https://doi.org/10.1002/anie.202103878
He Y, Wang B, Chen W, Cox RJ, He J, Chen F (2018) Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp. Biotechnology Advances 36:739–783.
https://doi.org/10.1016/j.biotechadv.2018.02.001
Hebra T, Elie N, Poyer S, Van Elslande E, Touboul D, Eparvier V (2021) Dereplication, annotation, and characterization of 74 potential antimicrobial metabolites from Penicillium sclerotiorum using t-SNE molecular networks. Metabolites 11:444.
https://doi.org/10.3390/metabo11070444
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 Chemical Biology 11:2117–2123.
https://doi.org/10.1021/acschembio.6b00398
Hou XM, Li YY, Shi YW, Fang YW, Chao R, Gu YC, Wang CY, Shao CL (2019a) Integrating molecular networking and ¹H NMR to target the isolation of chrysogeamides from a library of marine-derived Penicillium fungi. Journal of Organic Chemistry 84:1228–1237.
https://doi.org/10.1021/acs.joc.8b02614
Hou XM, Liang TM, Guo ZY, Wang CY, Shao CL (2019b) Discovery, absolute assignments, and total synthesis of asperversiamides A–C and their potent activity against Mycobacterium marinum. Chemical Communications 55:1104–1107.
https://doi.org/10.1039/C8CC09347D
Hu Y, Zhao X, Song Y, Jiang J, Long T, Cong M, Miao Y, Liu Y, Yang Z, Zhu Y et al (2024) Anti-inflammatory and neuroprotective α-pyrones from a marine-derived strain of the fungus Arthrinium arundinis and their heterologous expression. Journal of Natural Products 87:1975–1982.
https://doi.org/10.1021/acs.jnatprod.4c00393
Huang JH, Lv JM, Wang QZ, Zou J, Lu YJ, Wang QL, Chen DN, Yao XS, Gao H, Hu D (2019) Biosynthesis of an anti-tuberculosis sesterterpenoid asperterpenoid A. Organic & Biomolecular Chemistry 17:248–251.
https://doi.org/10.1039/C8OB02832J
Hubert J, Nuzillard JM, Purson S, Hamzaoui M, Borie N, Reynaud R, Renault JH (2014) Identification of natural metabolites in mixture: a pattern recognition strategy based on ¹³C NMR. Analytical Chemistry 86:2955–2962.
https://doi.org/10.1021/ac403223f
Hyde KD, Baldrian P, Chen Y, Thilini Chethana KW, De Hoog S, Doilom M, de Farias ARG, Gonçalves MFM, Gonkhom D, Gui H et al (2024) Current trends, limitations and future research in the fungi. Fungal Diversity 1–71.
https://doi.org/10.1007/s13225-023-00532-5
Jackman CM, Deans KW, Forney LJ, Lin XN (2019) Microdroplet co-cultivation and interaction characterization of human vaginal bacteria. Integrative Biology 11:69–78.
https://doi.org/10.1093/intbio/zyz006
Jin LQ, Jin WR, Ma ZC, Shen Q, Cai X, Liu ZQ, Zheng YG (2019) Promoter engineering strategies for the overproduction of valuable metabolites in microbes. Applied Microbiology and Biotechnology 103:8725–8736.
https://doi.org/10.1007/s00253-019-10172-y
Johnston CW, Skinnider MA, Wyatt MA, Li X, Ranieri MRM, Yang L, Zechel DL, Ma B, Magarvey NA (2015) An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products. Nature Communications 6:8421.
https://doi.org/10.1038/ncomms9421
Kankanamge S, Khalil ZG, Sritharan T, Capon RJ (2023) Noonindoles G–L: indole diterpene glycosides from the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339. Journal of Natural Products 86:508–516.
https://doi.org/10.1021/acs.jnatprod.2c01024
Keller NP (2019) Fungal secondary metabolism: regulation, function, and drug discovery. Nature Reviews Microbiology 17:167–180.
https://doi.org/10.1038/s41579-018-0121-1
Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND (2010) SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genetics and Biology 47:736–741.
https://doi.org/10.1016/j.fgb.2010.06.003
Khlebodarova TM, Bogacheva NV, Zadorozhny AV, Bryanskaya AV, Vasilieva AR, Chesnokov DO, Pavlova EI, Peltek SE (2024) Komagataella phaffii as a platform for heterologous expression of enzymes used for industry. Microorganisms 12:346.
https://doi.org/10.3390/microorganisms12020346
Kleks G, Holland DC, Porter J, Carroll AR (2021) Natural products dereplication by diffusion ordered NMR spectroscopy (DOSY). Chemical Science 12:10930–10943.
https://doi.org/10.1039/D1SC02940A
Knowles SL, Raja HA, Roberts CD, Oberlies NH (2022) Fungal–fungal co-culture: a primer for generating chemical diversity. Natural Product Reports 39:1557–1573.
https://doi.org/10.1039/D1NP00070E
Kuhn S, Nuzillard JM (2023) Easy structural dereplication of natural products by means of predicted carbon-13 nuclear magnetic resonance spectroscopy data. Chemistry - Methods 3:e202200054.
https://doi.org/10.1002/cmtd.202200054
Lakhani J, Khunteta A, Chowdhary A, Harwani D (2020) In silico detection tools to identify fungal secondary metabolites and their biosynthetic gene clusters. In: Gupta VK, Rodriguez-Couto S, Sharma GD (eds) New and Future Developments in Microbial Biotechnology and Bioengineering: Recent Advances in Application of Fungi and Fungal Metabolites. Elsevier, Amsterdam, pp 23–35.
https://doi.org/10.1016/B978-0-12-821008-6.00003-7
Lei H, Zhao P (2019) Advances in research on mining fungal secondary metabolites. Science China Life Sciences 49:865–873.
https://doi.org/10.1360/SSV-2019-0091
Li CY, Chung YM, Wu YC, Hunyadi A, Wang CCC, Chang FR (2020) Natural products development under epigenetic modulation in fungi. Phytochemistry Reviews 19:1323–1340.
https://doi.org/10.1007/s11101-020-09684-7
Li HT, Zhou H, Duan RT, Li HY, Tang LH, Yang XQ, Yang YB, Ding ZT (2019) Inducing secondary metabolite production by co-culture of the endophytic fungus Phoma sp. and the symbiotic fungus Armillaria sp. Journal of Natural Products 82:1009–1013.
https://doi.org/10.1021/acs.jnatprod.8b00685
Li ZJ, Song CX, Yang JY, et al (2024) Clustering algorithm based on DINNSM and its application in gene expression data analysis. Technology and Health Care 32:229–239.
https://doi.org/10.3233/thc-248020
Li ZW, Fan CL, Sun B, Huang L, Wang Z, Huang X, Zhang S, Ye W, Wu Z, Zhang X (2024) Discovery of unusual ajmaline-macroline type bisindole alkaloids from Alstonia macrophylla by building blocks-based molecular networking. Chemistry - A European Journal 30:e202303519.
https://doi.org/10.1002/chem.202303519
Ligon BL (2004) Penicillin: its discovery and early development. Seminars in Pediatric Infectious Diseases 15:52–57.
https://doi.org/10.1053/j.spid.2004.02.001
Lin S, Huang J, Zeng H, Tong Q, Zhang X, Yang B, Ye Y, Wang J, Hu Z, Zhang Y (2022) Distachydrimanes A–F, phenylspirodrimane dimers and hybrids with cytotoxic activity from the coral-derived fungus Stachybotrys chartarum. Chinese Chemical Letters 33:4587–4594.
https://doi.org/10.1016/j.cclet.2022.03.064
Lin TS, Chen B, Chiang YM, Wang CCC (2019) Discovery and elucidation of the biosynthesis of aspernidgulenes: novel polyenes from Aspergillus nidulans by using serial promoter replacement. ChemBioChem 20:329–334.
https://doi.org/10.1002/cbic.201800486
Lin Z, Zhu T, Wei H, Zhang G, Wang H, Gu Q (2009) Spicochalasin A and new aspochalasins from the marine-derived fungus Spicaria elegans. European Journal of Organic Chemistry 2009:3045–3051.
https://doi.org/10.1002/ejoc.200801085
Lin ZJ, Zhu TJ, Chen L, Gu QQ (2010) Three new aspochalasin derivatives from the marine-derived fungus Spicaria elegans. Chinese Chemical Letters 21:824–826.
https://doi.org/10.1016/j.cclet.2010.02.019
Liu DS, Rong XG, Kang HH, Ma LY, Hamann MT, Liu WZ (2018) Raistrickiones A–E from a highly productive strain of Penicillium raistrickii generated through thermo change. Marine Drugs 16:213.
https://doi.org/10.3390/md16060213
Liu H, Pu YH, Ren JW, Li EW, Guo LX, Yin WB (2020) Genetic dereplication driven discovery of a tricinoloniol acid biosynthetic pathway in Trichoderma hypoxylon. Organic & Biomolecular Chemistry 18:5344–5348.
https://doi.org/10.1039/D0OB01202E
Liu L, Wang B, Duan G, Wang J, Pan Z, Ou M, Bai X, Wang P, Zhao D, Nan N et al (2023) Histone deacetylase UvHST2 is a global regulator of secondary metabolism in Ustilaginoidea virens. Journal of Agricultural and Food Chemistry 71:13124–13136.
https://doi.org/10.1021/acs.jafc.3c01782
Liu W, Zhai S, Zhang L, Chen Y, Liu Z, Ma W, Zhang T, Zhang W, Ma L, Zhang C et al (2024a) Expanding the chemical diversity of grisechelins via heterologous expression. Journal of Natural Products 87:371–380.
https://doi.org/10.1021/acs.jnatprod.3c01132
Liu WZ, Ma LY, Liu DS, Huang YL, Wang CH, Shi SS, Pan XH, Song XD, Zhu RX (2014) Peniciketals A–C, new spiroketals from saline soil derived Penicillium raistrichii. Organic Letters 16:90–93.
https://doi.org/10.1021/ol403076s
Liu Y, Ding L, Shi Y, Yan X, Wu B, He S (2022) Molecular networking-driven discovery of antibacterial perinadines, new tetracyclic alkaloids from the marine sponge-derived fungus Aspergillus sp. ACS Omega 7:9909–9916.
https://doi.org/10.1021/acsomega.2c00402
Liu Y, Li P, Qi C, Zha Z, Meng J, Liu C, Han J, Zhou Q, Luo Z, Wang J et al (2024b) Cryptic piperazine derivatives activated by knocking out the global regulator LaeA in Aspergillus flavipes. Bioorganic & Medicinal Chemistry 103:117685.
https://doi.org/10.1016/j.bmc.2024.117685
Lopez-Perez JL, Theron R, del Olmo E, Díaz D (2007) NAPROC-13: a database for the dereplication of natural product mixtures in bioassay-guided protocols. Bioinformatics 23:3256–3257.
https://doi.org/10.1093/bioinformatics/btm516
Lu P, Shi Y, Zhang J, Hong K, Xue Y, Liu L (2024) New prenylated indole-benzodiazepine-2,5-diones with α-glucosidase inhibitory activities from the mangrove-derived Aspergillus spinosus. International Journal of Biological Macromolecules 257:128808.
https://doi.org/10.1016/j.ijbiomac.2023.128808
Ludwig M, Fleischauer M, Dührkop K, Hoffmann MA, Böcker S (2020a) De novo molecular formula annotation and structure elucidation using SIRIUS 4. In: Li S (ed) Computational Methods and Data Analysis for Metabolomics. Methods Mol Biol. Humana, New York, pp 185–207.
https://doi.org/10.1007/978-1-0716-0239-3_11
Ludwig M, Nothias LF, Dührkop K, Koester I, Fleischauer M, Hoffmann MA, Petras D, Vargas F, Morsy M, Aluwihare L et al (2020b) Database-independent molecular formula annotation using Gibbs sampling through ZODIAC. Nature Machine Intelligence 2:629–641.
https://doi.org/10.1038/s42256-020-00234-6
Lyu HN, Liu HW, Keller NP, Yin WB (2020) Harnessing diverse transcriptional regulators for natural product discovery in fungi. Natural Product Reports 37:6–16.
https://doi.org/10.1039/C8NP00027A
Lyu JM, Cao ZQ, Huang JH, et al (2022) Research progress in strategies for activating fungal silent gene clusters. Progress in Pharmaceutical Sciences 46:173–183
Ma C, Zhang K, Zhang X, Liu G, Zhu T, Che Q, Li D, Zhang G (2021) Heterologous expression and metabolic engineering tools for improving terpenoids production. Current Opinion in Biotechnology 69:281–289.
https://doi.org/10.1016/j.copbio.2021.02.008
Mafezoli J, Xu YM, Hilário F, Freidhof B, Espinosa-Artiles P, dos Santos LC, de Oliveira MCF, Gunatilaka AAL (2018) Modulation of polyketide biosynthetic pathway of the endophytic fungus Anteaglonium sp. FL0768 by copper(II) and anacardic acid. Phytochemistry Letters 28:157–163.
https://doi.org/10.1016/j.phytol.2018.10.011
Marø CE (2020) Manipulating the epigenetic machinery of marine fungi through the application of epigenetic modifiers to induce the biosynthesis of novel secondary metabolites. MS thesis, UiT The Arctic University of Norway.
Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC et al (2015) Minimum information about a biosynthetic gene cluster. Nature Chemical Biology 11:625–631.
https://doi.org/10.1038/nchembio.1890
Meng LH, Liu Y, Li XM, Xu GM, Ji NY, Wang BG (2015) Citrifelins A and B, citrinin adducts with a tetracyclic framework from cocultures of marine-derived isolates of Penicillium citrinum and Beauveria felina. Journal of Natural Products 78:2301–2305.
https://doi.org/10.1021/acs.jnatprod.5b00450
Merhej J, Richard-Forget F, Barreau C (2011) The pH regulatory factor Pac1 regulates Tri gene expression and trichothecene production in Fusarium graminearum. Fungal Genetics and Biology 48:275–284.
https://doi.org/10.1016/j.fgb.2010.11.008
Merwin NJ, Mousa WK, Dejong CA, Skinnider MA, Cannon MJ, Li H, Dial K, Gunabalasingam M, Johnston C, Magarvey NA (2020) DeepRiPP integrates multiomics data to automate discovery of novel ribosomally synthesized natural products. Proceedings of the National Academy of Sciences of the United States of America 117:371–380.
https://doi.org/10.1073/pnas.1901493116
Meunier M, Schinkovitz A, Derbré S (2024) Current and emerging tools and strategies for the identification of bioactive natural products in complex mixtures. Natural Product Reports 41:1766–1786.
https://doi.org/10.1039/D4NP00006D
Mohimani H, Gurevich A, Mikheenko A, Garg N, Nothias LF, Ninomiya A, Takada K, Dorrestein PC, Pevzner PA (2017) Dereplication of peptidic natural products through database search of mass spectra. Nature Chemical Biology 13:30–37.
https://doi.org/10.1038/nchembio.2219
Mohimani H, Gurevich A, Shlemov A, Mikheenko A, Korobeynikov A, Cao L, Shcherbin E, Nothias LF, Dorrestein PC, Pevzner PA (2018) Dereplication of microbial metabolites through database search of mass spectra. Nature Communications 9:4035.
https://doi.org/10.1038/s41467-018-06082-8
Moon H, Lee MK, Bok I, Bok JW, Keller NP, Yu JH (2023) Unraveling the gene regulatory networks of the global regulators VeA and LaeA in Aspergillus nidulans. Microbiology Spectrum 11:e00166-23.
https://doi.org/10.1128/spectrum.00166-23
Morehouse NJ, Clark TN, McMann EJ, van Santen JA, Haeckl FPJ, Gray CA, Linington RG (2023) Annotation of natural product compound families using molecular networking topology and structural similarity fingerprinting. Nature Communications 14:308.
https://doi.org/10.1038/s41467-022-35734-z
Morris KF, Johnson CS Jr (1992) Diffusion-ordered two-dimensional nuclear magnetic resonance spectroscopy. Journal of the American Chemical Society 114:3139–3141.
https://doi.org/10.1021/ja00034a071
Niego AGT, Rapior S, Thongklang N, Raspé O, Hyde KD, Mortimer P (2023) Reviewing the contributions of macrofungi to forest ecosystem processes and services. Fungal Biology Reviews 44:100294.
https://doi.org/10.1016/j.fbr.2022.11.002
Nishad JH, Singh A, Bharti R, Prajapati P, Sharma VK, Gupta VK, Kharwar RN (2021) Effect of the histone methyltransferase specific probe BRD4770 on metabolic profiling of the endophytic fungus Diaporthe longicolla. Frontiers in Microbiology 12:725463.
https://doi.org/10.3389/fmicb.2021.725463
Niu S, Liu D, Shao Z, Liu J, Fan A, Lin W (2021) Chemical epigenetic manipulation triggers the production of sesquiterpenes from the deep-sea derived Eutypella fungus. Phytochemistry 192:112978.
https://doi.org/10.1016/j.phytochem.2021.112978
Nothias LF, Nothias-Esposito M, Da Silva R, Wang M, Protsyuk I, Zhang Z, Sarvepalli A, Leyssen P, Touboul D, Costa J et al (2018) Bioactivity-based molecular networking for the discovery of drug leads in natural product bioassay-guided fractionation. Journal of Natural Products 81:758–767.
https://doi.org/10.1021/acs.jnatprod.7b00737
Nothias LF, Petras D, Schmid R, Dührkop K, Rainer J, Sarvepalli A, Protsyuk I, Ernst M, Tsugawa H, Fleischauer M et al (2020) Feature-based molecular networking in the GNPS analysis environment. Nature Methods 17:905–908.
https://doi.org/10.1038/s41592-020-0933-6
Nuzillard JM (2021) Taxonomy-focused natural product databases for carbon-13 NMR-based dereplication. Analytica 2:50–56.
https://doi.org/10.3390/analytica2030006
Oettl SK, Hubert J, Nuzillard JM, Stuppner H, Renault JH, Rollinger JM (2014) Dereplication of depsides from the lichen Pseudevernia furfuracea by centrifugal partition chromatography combined to 13C nuclear magnetic resonance pattern recognition. Analytica Chimica Acta 846:60–67.
https://doi.org/10.1016/j.aca.2014.07.009
Ogbe AA, Finnie JF, Van Staden J (2020) The role of endophytes in secondary metabolites accumulation in medicinal plants under abiotic stress. South African Journal of Botany 134:126–134.
https://doi.org/10.1016/j.sajb.2020.06.023
Oikawa H (2020) Reconstitution of biosynthetic machinery of fungal natural products in heterologous hosts. Bioscience, Biotechnology, and Biochemistry 84:433–444.
https://doi.org/10.1080/09168451.2019.1690976
Olivon F, Elie N, Grelier G, Roussi F, Litaudon M, Touboul D (2018) MetGem software for the generation of molecular networks based on the t-SNE algorithm. Analytical Chemistry 90:13900–13908.
https://doi.org/10.1021/acs.analchem.8b03099
Oppong-Danquah E, Blümel M, Scarpato S, Mangoni A, Tasdemir D (2022) Induction of isochromanones by co-cultivation of the marine fungus Cosmospora sp. and the phytopathogen Magnaporthe oryzae. International Journal of Molecular Sciences 23:782.
https://doi.org/10.3390/ijms23020782
Pan R, Bai X, Chen J, Zhang H, Wang H (2019) Exploring structural diversity of microbe secondary metabolites using OSMAC strategy: a literature review. Frontiers in Microbiology 10:294.
https://doi.org/10.3389/fmicb.2019.00294
Park J, Kerner A, Burns MA, Lin XN (2011) Microdroplet-enabled highly parallel co-cultivation of microbial communities. PLOS ONE 6:e17019.
https://doi.org/10.1371/journal.pone.0017019
Peng XY, Wu JT, Shao CL, Li ZY, Chen M, Wang CY (2021) Co-culture: stimulate the metabolic potential and explore the molecular diversity of natural products from microorganisms. Marine Life Science & Technology 3:363–374.
https://doi.org/10.1007/s42995-020-00077-5
Pfannenstiel BT, Keller NP (2019) On top of biosynthetic gene clusters: how epigenetic machinery influences secondary metabolism in fungi. Biotechnology Advances 37:107345.
https://doi.org/10.1016/j.biotechadv.2019.02.001
Phelan VV, Liu WT, Pogliano K, Dorrestein PC (2012) Microbial metabolic exchange—the chemotype-to-phenotype link. Nature Chemical Biology 8:26–35.
https://doi.org/10.1038/nchembio.739
Prakash S, Kumari H, Minakshi, Kumar A (2024) Epigenetic regulation of fungal secondary metabolites for the enhancement of therapeutically active compounds. In: Deshmukh SK, Takahashi JA, Saxena S (eds) Fungi bioactive metabolites. Springer, Singapore, pp 605–632.
https://doi.org/10.1007/978-981-99-5696-8_19
Pretsch E, Bühlmann P, Badertscher M (2020) Structure determination of organic compounds: tables of spectral data, 5th ed. Springer, Berlin Heidelberg.
https://doi.org/10.1007/978-3-662-62439-5
Qian Z, Bruhn T, D’Agostino PM, Herrmann A, Haslbeck M, Antal N, Fiedler HP, Brack-Werner R, Gulder TAM (2020) Discovery of the streptoketides by direct cloning and rapid heterologous expression of a cryptic PKS II gene cluster from Streptomyces sp. Tü 6314. Journal of Organic Chemistry 85:664–673.
https://doi.org/10.1021/acs.joc.9b02741
Qin GF, Zhang X, Zhu F, Huo ZQ, Yao QQ, Feng Q, Liu Z, Zhang GM, Yao JC, Liang HB (2022a) MS/MS-based molecular networking: an efficient approach for natural products dereplication. Molecules 28:157.
https://doi.org/10.3390/molecules28010157
Qin M, Li Y, Cai L, Yin X, He Z, Kang J (2022b) Overexpression of the global regulator FnVeA upregulates antitumor substances in endophytic Fusarium nematophilum. Canadian Journal of Microbiology 68:531–541.
https://doi.org/10.1139/cjm-2022-0067
Qin Y, Zou L, Lei X, Su J, Yang R, Xie W, Li W, Chen G (2023) OSMAC strategy integrated with molecular networking discovery peniciacetals A−I, nine new meroterpenoids from the mangrove-derived fungus Penicillium sp. HLLG-122. Bioorganic Chemistry 130:106271.
https://doi.org/10.1016/j.bioorg.2022.106271
Ran H, Yin W (2023) Research progress in discovery of novel natural products driven by microbial interactions. Progress in Pharmaceutical Sciences 47:260–272.
Reher R, Kim HW, Zhang C, Mao HH, Wang M, Nothias LF, Caraballo-Rodriguez AM, Glukhov E, Teke B, Leao T et al (2020) A convolutional neural network-based approach for the rapid annotation of molecularly diverse natural products. Journal of the American Chemical Society 142:4114–4120.
https://doi.org/10.1021/jacs.9b13786
Rokas A, Mead ME, Steenwyk JL, Raja HA, Oberlies NH (2020) Biosynthetic gene clusters and the evolution of fungal chemodiversity. Natural Product Reports 37:868–878.
https://doi.org/10.1039/C9NP00045C
Rutledge PJ, Challis GL (2015) Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nature Reviews Microbiology 13:509–523.
https://doi.org/10.1038/nrmicro3496
Sahayasheela VJ, Lankadasari MB, Dan VM, Dastager SG, Pandian GN, Sugiyama H (2022) Artificial intelligence in microbial natural product drug discovery: current and emerging role. Natural Product Reports 39:2215–2230.
https://doi.org/10.1039/D2NP00035K
Salim AA, Khalil ZG, Elbanna AH, Wu T, Capon RJ (2021) Methods in microbial biodiscovery. Marine Drugs 19:503.
https://doi.org/10.3390/md19090503
Satyanarayana U (2013) Biochemistry, 4th ed. Elsevier Health Sci, Amsterdam.
Schiewe HJ, Zeeck A (1999) Cineromycins, γ-butyrolactones and ansamycins by analysis of the secondary metabolite pattern created by a single strain of Streptomyces. The Journal of Antibiotics 52:635–642.
https://doi.org/10.7164/antibiotics.52.635
Schmid R, Petras D, Nothias LF, Wang M, Aron AT, Jagels A, Tsugawa H, Rainer J, Garcia-Aloy M, Dührkop K et al (2021) Ion identity molecular networking for mass spectrometry-based metabolomics in the GNPS environment. Nature Communications 12:3832.
https://doi.org/10.1038/s41467-021-23953-9
Selegato DM, Freire RT, Tannús A, Castro-Gamboa I (2016) New dereplication method applied to NMR-based metabolomics on different Fusarium species isolated from rhizosphere of Senna spectabilis. Journal of the Brazilian Chemical Society 27:1421–1431.
https://doi.org/10.5935/0103-5053.20160139
Selegato DM, Zanatta AC, Pilon AC, Veloso JH, Castro-Gamboa I (2023) Application of feature-based molecular networking and MassQL for the MS/MS fragmentation study of depsipeptides. Frontiers in Molecular Biosciences 10:1238475.
https://doi.org/10.3389/fmolb.2023.1238475
Shang Z, Salim AA, Capon RJ (2017) Chaunopyran A: co-cultivation of marine mollusk-derived fungi activates a rare class of 2-alkenyl-tetrahydropyran. Journal of Natural Products 80:1167–1172.
https://doi.org/10.1021/acs.jnatprod.7b00144
Sharma A, Srivastava A, Shukla AK, Srivastava K, Srivastava AK, Saxena AK (2020) Entomopathogenic fungi: a potential source for biological control of insect pests. In: Solanki M, Kashyap P, Kumari B (eds) Phytobiomes: current insights and future vistas. Springer, Singapore, pp 225–250.
https://doi.org/10.1007/978-981-15-3151-4_9
Sharma S, Ciufo S, Starchenko E, Darji D, Chlumsky L, Karsch-Mizrachi I, Schoch CL (2018) The NCBI biocollections database. Database (Oxford) 2018:bay006.
https://doi.org/10.1093/database/bay006
Sheng Y, Wang J, Liu S, Jiang Y (2024) IMN4NPD: an integrated molecular networking workflow for natural product dereplication. Analytical Chemistry 96:2990–2997.
https://doi.org/10.1021/acs.analchem.3c04746
Siridechakorn I, Yue Z, Mittraphab Y, Lei X, Pudhom K (2017) Identification of spirobisnaphthalene derivatives with anti-tumor activities from the endophytic fungus Rhytidhysteron rufulum AS21B. Bioorganic & Medicinal Chemistry 25:2878–2882.
https://doi.org/10.1016/j.bmc.2017.02.054
Skellam E, Rajendran S, Li L (2024) Combinatorial biosynthesis for the engineering of novel fungal natural products. Communications Chemistry 7:89.
https://doi.org/10.1038/s42004-024-01172-9
Skinnider MA, Johnston CW, Gunabalasingam M, Merwin NJ, Kieliszek AM, MacLellan RJ, Li H, Ranieri MRM, Webster ALH, Cao MPT et al (2020) Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences. Nature Communications 11:6058.
https://doi.org/10.1038/s41467-020-19986-1
Souza CCd, Guimarães JM, Pereira SdS, et al (2021) The multifunctionality of expression systems in Bacillus subtilis: emerging devices for the production of recombinant proteins. Experimental Biology and Medicine 246:2443–2453.
https://doi.org/10.1177/15353702211030189
Steffan BN, Venkatesh N, Keller NP (2020) Let’s get physical: bacterial–fungal interactions and their consequences in agriculture and health. Journal of Fungi 6:243.
https://doi.org/10.3390/jof6040243
Swift CL, Louie KB, Bowen BP, Olson HM, Purvine SO, Salamov A, Mondo SJ, Solomon KV, Wright AT, Northen TR et al (2021) Anaerobic gut fungi are an untapped reservoir of natural products. Proceedings of the National Academy of Sciences 118:e2019855118.
https://doi.org/10.1073/pnas.2019855118
Tan JY, Wang S, Dick GJ, Young VB, Sherman DH, Burns MA, Lin XN (2020) Co-cultivation of microbial sub-communities in microfluidic droplets facilitates high-resolution genomic dissection of microbial ‘dark matter’. Integrative Biology 12:263–274.
https://doi.org/10.1093/intbio/zyaa021
Thissera B, Alhadrami H, Hassan M, Hassan HM, Behery FA, Bawazeer M, Yaseen M, Belbahri L, Rateb ME (2020) Induction of cryptic antifungal pulicatin derivatives from Pantoea agglomerans by microbial co-culture. Biomolecules 10:268.
https://doi.org/10.3390/biom10020268
van der Hooft JJJ, Wandy J, Barrett MP, Burgess KEV, Rogers S (2016) Topic modeling for untargeted substructure exploration in metabolomics. Proceedings of the National Academy of Sciences 113:13738–13743.
https://doi.org/10.1073/pnas.1608041113
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 Advances 4:18329–18335.
https://doi.org/10.1039/C4RA00274A
Vieira R, de Sousa KA, Castro-Gamboa I (2024) LUMIOS–label using machine in organic samples–a software for dereplication, molecular docking, and combined machine and deep learning. Expert Systems with Applications 248:123447.
https://doi.org/10.1016/j.eswa.2024.123447
Viggiano A (2020) Exploring the metabolic potential of Penicillium rubens. PhD thesis, University of Groningen.
https://doi.org/10.33612/diss.126598491
Vinogradov AA, Zhang Y, Hamada K, Chang JS, Okada C, Nishimura H, Terasaka N, Goto Y, Ogata K, Sengoku T et al (2022) De novo discovery of thiopeptide pseudo-natural products acting as potent and selective TNIK kinase inhibitors. Journal of the American Chemical Society 144:20332–20341.
https://doi.org/10.1021/jacs.2c07937
Waddington CH (2012) The epigenotype. International Journal of Epidemiology 41:10–13.
https://doi.org/10.1093/ije/dyr184
Wakefield J, Hassan HM, Jaspars M, Ebel R, Rateb ME (2017) Dual induction of new microbial secondary metabolites by fungal–bacterial co-cultivation. Frontiers in Microbiology 8:1284.
https://doi.org/10.3389/fmicb.2017.01284
Walsh CT, Tang Y (2017) Natural product biosynthesis: chemical logic and enzymatic machinery. Royal Society of Chemistry, Cambridge.
Wang C, Timári I, Zhang B, Li DW, Leggett A, Amer AO, Bruschweiler-Li L, Kopec RE, Brüschweiler R (2020a) COLMAR lipids web server and ultrahigh-resolution methods for two-dimensional nuclear magnetic resonance- and mass spectrometry-based lipidomics. Journal of Proteome Research 19:1674–1683.
https://doi.org/10.1021/acs.jproteome.9b00845
Wang G, Kell DB, Borodina I (2021) Harnessing the yeast Saccharomyces cerevisiae for the production of fungal secondary metabolites. Essays in Biochemistry 65:277–291.
https://doi.org/10.1042/EBC20200137
Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, Nguyen DD, Watrous J, Kapono CA, Luzzatto-Knaan T et al (2016) Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nature Biotechnology 34:828–837.
https://doi.org/10.1038/nbt.3597
Wang R, Zhao S, Wang Z, Koffas MA (2020b) Recent advances in modular co-culture engineering for synthesis of natural products. Current Opinion in Biotechnology 62:65–71.
https://doi.org/10.1016/j.copbio.2019.09.004
Wang X, Sena Filho 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. Journal of Natural Products 73:942–948.
https://doi.org/10.1021/np100142h
Wang Y, Mao XM (2025) Mining silent biosynthetic gene clusters for natural products in filamentous fungi. Chemistry & Biodiversity 22:e202402715.
https://doi.org/10.1002/cbdv.202402715
Watrous J, Roach P, Alexandrov T, Heath BS, Yang JY, Kersten RD, van der Voort M, Pogliano K, Gross H, Raaijmakers JM et al (2012) Mass spectral molecular networking of living microbial colonies. Proceedings of the National Academy of Sciences 109:E1743–E1752.
https://doi.org/10.1073/pnas.1203689109
Webster NS (2014) Cooperation, communication, and co-evolution: grand challenges in microbial symbiosis research. Frontiers in Microbiology 5:82293.
https://doi.org/10.3389/fmicb.2014.00164
Wei Q, Bai J, Yan D, Bao X, Li W, Liu B, Zhang D, Qi X, Yu D, Hu Y (2021) Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products. Acta Pharmaceutica Sinica B 11:572–587.
https://doi.org/10.1016/j.apsb.2020.07.020
Wu G, Zhou H, Zhang P, Wang X, Li W, Zhang W, Liu X, Liu HW, Keller NP, An Z et al (2016) Polyketide production of pestaloficiols and macrodiolide ficiolides revealed by manipulations of epigenetic regulators in an endophytic fungus. Organic Letters 18:1832–1835.
https://doi.org/10.1021/acs.orglett.6b00562
Wu JS, Yao GS, Shi XH, Rehman SU, Xu Y, Fu XM, Zhang XL, Liu Y, Wang CY (2020) Epigenetic agents trigger the production of bioactive nucleoside derivatives and bisabolane sesquiterpenes from the marine-derived fungus Aspergillus versicolor. Frontiers in Microbiology 11:513465.
https://doi.org/10.3389/fmicb.2020.00085
Wu Z, Wang Y, Ye W (2022) Advances in research on novel strategies and approaches for the efficient discovery of bioactive natural molecules. Progress in Pharmaceutical Sciences 46:163–172.
Xiao N, Suzuki K, Nishimiya Y, Kondo H, Miura A, Tsuda S, Hoshino T (2010) Comparison of functional properties of two fungal antifreeze proteins from Antarctomyces psychrotrophicus and Typhula ishikariensis. FEBS Journal 277:394–403.
https://doi.org/10.1111/j.1742-4658.2009.07490.x
Xie CL, Liu Q, He ZH, Gai YB, Zou ZB, Shao ZZ, Liu GM, Chen HF, Yang XW (2021) Discovery of andrastones from the deep-sea-derived Penicillium allii-sativi MCCC 3A00580 by OSMAC strategy. Bioorganic Chemistry 108:104671.
https://doi.org/10.1016/j.bioorg.2021.104671
Xie CL, Xia JM, Lin T, Lin YJ, Lin YK, Xia ML, Chen HF, Luo ZH, Shao ZZ, Yang XW (2019) Andrastone A from the deep-sea-derived fungus Penicillium allii-sativi acts as an inducer of caspase- and RXRα-dependent apoptosis. Frontiers in Chemistry 7:692.
https://doi.org/10.3389/fchem.2019.00692
Xie F, Li HT, Wang M, Chen JY, Duan HJ, Xia DD, Xie TP, Gao YH, Zhou H, Ding ZT (2022) Phialocetones A–J, C12 lactones from the rhizospheric soil-derived fungus Phialocephala sp. YUD18001 associated with Gastrodia elata. Phytochemistry 202:113359.
https://doi.org/10.1016/j.phytochem.2022.113359
Xie F, Sun Y, Zi ZF, Wang WJ, Wan DY, Zhou H, Ding ZT (2023) Discovery of pyranonaphthoquinones and an eighteen-membered ring macrolide from the rhizospheric soil-derived fungus Phialocephala sp. YUD18001 by OSMAC strategy. Fitoterapia 171:105690.
https://doi.org/10.1016/j.fitote.2023.105690
Xu N, Wei L, Liu J (2019) Recent advances in the applications of promoter engineering for the optimization of metabolite biosynthesis. World Journal of Microbiology and Biotechnology 35:1–10.
https://doi.org/10.1007/s11274-019-2606-0
Xu XR, Sun YH, Zhang AX, Li S, Zhang S, Chen S, Lou C, Cai L, Chen Y, Luo C et al (2024) Quantitative characterization of gene regulatory circuits associated with fungal secondary metabolism to discover novel natural products. Advanced Science 11:2407195.
https://doi.org/10.1002/advs.202407195
Xue M, Hou X, Fu J, Zhang J, Wang J, Zhao Z, Xu D, Lai D, Zhou L (2023) Recent advances in search of bioactive secondary metabolites from fungi triggered by chemical epigenetic modifiers. Journal of Fungi 9:172.
https://doi.org/10.3390/jof9020172
Yadav A, Mohite S (2020) Production of statins by fungal fermentation. International Journal of Scientific Research in Chemistry 5:59–64.
https://doi.org/10.26438/ijsrch/v5i6.5964
Yamazaki H, Takahashi O, Murakami K, Namikoshi M (2015) Induced production of a new unprecedented epitrithiodiketopiperazine, chlorotrithiobrevamide, by a culture of the marine-derived Trichoderma cf. brevicompactum with dimethyl sulfoxide. Tetrahedron Letters 56:6262–6265.
https://doi.org/10.1016/j.tetlet.2015.09.113
Yang JY, Sanchez LM, Rath CM, Liu X, Boudreau PD, Bruns N, Glukhov E, Wodtke A, de Felicio R, Fenner A et al (2013) Molecular networking as a dereplication strategy. Journal of Natural Products 76:1686–1699.
https://doi.org/10.1021/np400413s
Yang W, Chen T, Chen Y, Tan Q, Ou Y, Li G, Wang B, Hu D, Yao H, She Z (2022) Antiplasmodial asperterpenoids from two Aspergillus oryzae transformants with heterologous expression of sesterterpene genes. Journal of Organic Chemistry 87:16807–16819.
https://doi.org/10.1021/acs.joc.2c02501
Yang W, Chen T, Tan Q, Zang Z, Chen Y, Ou Y, Li G, Hu D, Wang B, Yao H et al (2023) Plasmodium-resistant indole diterpenoid biosynthesis gene cluster derived from Aspergillus oryzae was activated by exogenous P450 gene AstB. Journal of Natural Products 86:1392–1401.
https://doi.org/10.1021/acs.jnatprod.2c01172
Yang X, Feng P, Yin Y, Bushley K, Spatafora JW, Wang C (2018) Cyclosporine biosynthesis in Tolypocladium inflatum benefits fungal adaptation to the environment. mBio 9:e01028–18.
https://doi.org/10.1128/mbio.01211-18
Ye Y, Zhang Y (2023) New interdisciplinary strategies for the research on natural products. Progress in Pharmaceutical Sciences 47:241–243
Yin T, Yu Y, Liu Q, Zhu G, Bai L, Zhang W, Jiang Z (2023) 13C-NMR-based MixONat strategy coupled with 2D NMR for rapid dereplication and identification of new secondary metabolites from Aloe vera. Journal of Food Composition and Analysis 115:104975.
https://doi.org/10.1016/j.jfca.2022.104975
Yu H, Zheng Y, Du Y, et al (2021) Microbial promoter engineering strategies in synthetic biology. Synth Biol J 2:598
Yu Z, Gao J, Igbalajobi O, Skoneczny M, Sieńko M, Maciejewska AM, Brzywczy J, Fischer R (2021) The sulfur metabolism regulator MetR is a global regulator controlling phytochrome-dependent light responses in Aspergillus nidulans. Science Bulletin 66:592–602.
https://doi.org/10.1016/j.scib.2020.11.001
Yuan B, Zhou Z, Jiang B, Kamal GM, Zhang X, Li C, Zhou X, Liu M (2021) NMR for mixture analysis: concentration-ordered spectroscopy. Analytical Chemistry 93:9697–9703.
https://doi.org/10.1021/acs.analchem.1c00831
Yuan MX, Qiu Y, Ran YQ, Feng GK, Deng R, Zhu XF, Lan WJ, Li HJ (2019) Exploration of indole alkaloids from marine fungus Pseudallescheria boydii F44-1 using an amino acid-directed strategy. Marine Drugs 17:77.
https://doi.org/10.3390/md17020077
Zani CL, Carroll AR (2017) Database for rapid dereplication of known natural products using data from MS and fast NMR experiments. Journal of Natural Products 80:1758–1766.
https://doi.org/10.1021/acs.jnatprod.6b01093
Zhang C, Idelbayev Y, Roberts N, Tao Y, Nannapaneni Y, Duggan BM, Min J, Lin EC, Gerwick EC, Cottrell GW et al (2017) Small molecule accurate recognition technology (SMART) to enhance natural products research. Scientific Reports 7:14243.
https://doi.org/10.1038/s41598-017-13923-x
Zhang C, Idelbayev Y, Roberts N, Tao Y, Nannapaneni Y, Duggan BM, Min J, Lin EC, Gerwick EC, Cottrell GW et al (2020) Author correction: small molecule accurate recognition technology (SMART) to enhance natural products research. Scientific Reports 10:4724.
https://doi.org/10.1038/s41598-020-60108-0
Zhang H, Wang X (2016) Modular co-culture engineering, a new approach for metabolic engineering. Metabolic Engineering 37:114–121.
https://doi.org/10.1016/j.ymben.2016.05.007
Zhang JJ, Tang X, Moore BS (2019) Genetic platforms for heterologous expression of microbial natural products. Natural Product Reports 36:1313–1332.
https://doi.org/10.1039/C9NP00025A
Zhang M, Otsuki K, Li W (2023) Molecular networking as a natural products discovery strategy. Acta Materia Medica 2:126–141.
https://doi.org/10.15212/AMM-2023-0007
Zhang MW, Chen MR, Liu SW, et al (2020) The roles of LaeA in secondary metabolism, growth and development and other important biological processes of filamentous fungi: a review. Mycosystema 39:548–555.
https://doi.org/10.13346/j.mycosystema.190284
Zhang T, Pang X, Zhao J, Guo Z, He W, Cai G, Su J, Cen S, Yu L (2022) Discovery and activation of the cryptic cluster from Aspergillus sp. CPCC 400735 for asperphenalenone biosynthesis. ACS Chemical Biology 17:1524–1533.
https://doi.org/10.1021/acschembio.2c00204
Zhang T, Wan J, Zhan Z, Bai J, Liu B, Hu Y (2018) Activation of an unconventional meroterpenoid gene cluster in Neosartorya glabra leads to the production of new berkeleyacetals. Acta Pharmaceutica Sinica B 8:478–487.
https://doi.org/10.1016/j.apsb.2017.12.005
Zhang WY, Zhong Y, Yu Y, Shi DF, Huang HY, Tang XL, Wang YH, Chen GD, Zhang HP, Liu CL et al (2020) 4-Hydroxy pyridones from heterologous expression and cultivation of the native host. Journal of Natural Products 83:3338–3346.
https://doi.org/10.1021/acs.jnatprod.0c00675
Zhang Y, Gallant É, Park JD, Seyedsayamdost MR (2022) The small-molecule language of dynamic microbial interactions. Annual Review of Microbiology 76:641–660.
https://doi.org/10.1146/annurev-micro-042722-091052
Zhao L, Li L, Xu Y, Hu M, Fang Y, Dong N (2024) Heterologous expression and activity of α-helical antimicrobial peptide SW in Bacillus subtilis. Biochemical Engineering Journal 203:109224.
https://doi.org/10.1016/j.bej.2024.109224
Zhen X, Gong T, Wen YH, Yan DJ, Chen JJ, Zhu P (2018) Chrysoxanthones A–C, three new xanthone–chromanone heterodimers from sponge-associated Penicillium chrysogenum HLS111 treated with histone deacetylase inhibitor. Marine Drugs 16:357.
https://doi.org/10.3390/md16100357
Zhou K, Qiao K, Edgar S, Stephanopoulos G (2015) Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nature Biotechnology 33:377–383.
https://doi.org/10.1038/nbt.3095
Zhu W, Zhang H (2024) Enhancing chemical diversity of fungal secondary metabolites by OSMAC strategy. In: Deshmukh SK, Takahashi JA, Saxena S (eds) Fungi bioactive metabolites. Springer, Singapore, pp 567–604.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles in this journal are copyrighted by the x may be read and used for academic purposes, such as teaching, research, or citation, with proper credit given to the author and the journal.use or modification of the articles is prohibited without permission.
statements expressed in the articles are solely the opinions of the authors.
authors are fully responsible for the content and accuracy of their articles.
other reuse or republication requires permission from the journal."
