One of the exciting movements in microbial sciences has been a refocusing and revitalization of efforts to mine the fungal secondary metabolome. The magnitude of biosynthetic gene clusters (BGCs) in a single filamentous fungal genome combined with the historic number of sequenced genomes suggests that the secondary metabolite wealth of filamentous fungi is largely untapped. Mining algorithms and scalable expression platforms have greatly expanded access to the chemical repertoire of fungal-derived secondary metabolites. In this Review, I discuss new insights into the transcriptional and epigenetic regulation of BGCs and the ecological roles of fungal secondary metabolites in warfare, defence and development. I also explore avenues for the identification of new fungal metabolites and the challenges in harvesting fungal-derived secondary metabolites.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nesbitt, B. F., O’Kelly, J., Sargeant, K. & Sheridan, A. Aspergillus flavus and turkey X disease: toxic metabolites of Aspergillus flavus. Nature 195, 1062–1063 (1962).
Quinn, R. Rethinking antibiotic research and development: World War II and the penicillin collaborative. Am. J. Public Health 103, 426–434 (2013).
Krause, D. J. et al. Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts. Proc. Natl Acad. Sci. USA 115, 11030–11035 (2018). This study characterizes the pulcherrimin cluster in K. lactis , a yeast that belongs to a taxon not associated with secondary metabolism.
Trail, F. et al. Physical and transcriptional map of an aflatoxin gene cluster in Aspergillus parasiticus and functional disruption of a gene involved early in the aflatoxin pathway. Appl. Environ. Microbiol. 61, 2665–2673 (1995).
Lind, A. L., Lim, F. Y., Soukup, A. A., Keller, N. P. & Rokas, A. An LaeA- and BrlA-dependent cellular network governs tissue-specific secondary metabolism in the human pathogen Aspergillus fumigatus. mSphere 3, e00050–18 (2018).
Lysøe, E., Seong, K.-Y. & Kistler, H. C. The transcriptome of Fusarium graminearum during the infection of wheat. Mol. Plant Microbe Interact. 24, 995–1000 (2011).
Spraker, J. E. et al. Conserved responses in a war of small molecules between fungi and a bacterium. mBio 9, e00820–18 (2018). The paper reports the conserved induction of an antibacterial secondary metabolite cluster across disparate fungal genera in response to a lipopeptide that is secreted by the invading bacterium.
Pelaez, F. in Handbook of Industrial Mycology (ed. Zhiqiang, A.) (Marcel Dekker, New York, NY, 2005).
Schueffler, A. & Anke, T. Fungal natural products in research and development. Nat. Prod. Rep. 31, 1425–1448 (2014).
Kück, U., Bloemendal, S. & Teichert, I. Putting fungi to work: harvesting a cornucopia of drugs, toxins, and antibiotics. PLOS Pathog. 10, e1003950 (2014).
Caldwell, G. A., Naider, F. & Becker, J. M. Fungal lipopeptide mating pheromones: a model system for the study of protein prenylation. Microbiol. Rev. 59, 406–422 (1995).
Clevenger, K. D. et al. A scalable platform to identify fungal secondary metabolites and their gene clusters. Nat. Chem. Biol. 13, 895–901 (2017). This paper presents a method to capture the entire secondary metabolome of a single species using FAC-MS technology.
Yun, C.-S., Motoyama, T. & Osada, H. Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme. Nat. Commun. 6, 8758 (2015).
Hur, G. H., Vickery, C. R. & Burkart, M. D. Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology. Nat. Prod. Rep. 29, 1074 (2012).
Schmidt-Dannert, C. Biosynthesis of terpenoid natural products in fungi. Adv. Biochem. Eng. Biotechnol. 148, 19–61 (2014).
Li, X.-W., Ear, A. & Nay, B. Hirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds. Nat. Prod. Rep. 30, 765 (2013).
Chiang, Y.-M., Oakley, B. R., Keller, N. P. & Wang, C. C. C. Unraveling polyketide synthesis in members of the genus Aspergillus. Appl. Microbiol. Biotechnol. 86, 1719–1736 (2010).
Umemura, M. et al. Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus. Fungal Genet. Biol. 68, 23–30 (2014). This study identifies the first BGC that produces a ribosomally encoded cyclic peptide.
Pettit, R. K. Small-molecule elicitation of microbial secondary metabolites. Microb. Biotechnol. 4, 471–478 (2011).
Lim, F. Y. et al. Fungal isocyanide synthases and xanthocillin biosynthesis in Aspergillus fumigatus. mBio 9, e00785–18 (2018). This study identifies novel BGCs that contain isocyanide synthases.
Yu, J. et al. Clustered pathway genes in aflatoxin biosynthesis. Appl. Environ. Microbiol. 70, 1253–1262 (2004).
Amaike, S., Affeldt, K. J. & Keller, N. P. in The Mycota: Agricultural Applications 2nd edn Vol. 11 (ed. Kempken, F.) 59–74 (Springer, Berlin, 2013).
Neubauer, L., Dopstadt, J., Humpf, H.-U. & Tudzynski, P. Identification and characterization of the ergochrome gene cluster in the plant pathogenic fungus Claviceps purpurea. Fungal Biol. Biotechnol. 3, 2 (2016).
Lebar, M. D. et al. Identification and functional analysis of the aspergillic acid gene cluster in Aspergillus flavus. Fungal Genet. Biol. 116, 14–23 (2018).
Keller, N. P. Translating biosynthetic gene clusters into fungal armor and weaponry. Nat. Chem. Biol. 11, 671–677 (2015).
Wiemann, P. et al. Prototype of an intertwined secondary-metabolite supercluster. Proc. Natl Acad. Sci. USA 110, 17065–17070 (2013). This report describes a supercluster in which the genes encoding the secondary metabolites fumagillin and pseurotin are intertwined.
Andersen, M. R. et al. Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc. Natl Acad. Sci. USA 110, E99–E107 (2013). This study identifies non-contiguous members within a BGC through expression data.
Ohsato, S. et al. Transgenic rice plants expressing trichothecene 3-O-acetyltransferase show resistance to the Fusarium phytotoxin deoxynivalenol. Plant Cell Rep. 26, 531–538 (2007).
Bradshaw, R. E. et al. Fragmentation of an aflatoxin-like gene cluster in a forest pathogen. New Phytol. 198, 525–535 (2013). This study reports the fragmentation of a gene cluster dedicated to the production of a secondary metabolite.
Lim, F. Y. & Keller, N. P. Spatial and temporal control of fungal natural product synthesis. Nat. Prod. Rep. 31, 1277–1286 (2014).
Kalinina, S. A., Jagels, A., Cramer, B., Geisen, R. & Humpf, H.-U. Influence of environmental factors on the production of penitrems A–F by Penicillium crustosum. Toxins 9, 210 (2017).
Hewage, R. T., Aree, T., Mahidol, C., Ruchirawat, S. & Kittakoop, P. One strain-many compounds (OSMAC) method for production of polyketides, azaphilones, and an isochromanone using the endophytic fungus Dothideomycete sp. Phytochemistry 108, 87–94 (2014).
Joffe, A. Z. & Lisker, N. Effects of light, temperature, and pH value on aflatoxin production in vitro. Appl. Microbiol. 18, 517–518 (1969).
Lind, A. L., Smith, T. D., Saterlee, T., Calvo, A. M. & Rokas, A. Regulation of secondary metabolism by the Velvet complex is temperature-responsive in Aspergillus. G3 6, 4023–4033 (2016).
Hagiwara, D. et al. Temperature during conidiation affects stress tolerance, pigmentation, and trypacidin accumulation in the conidia of the airborne pathogen Aspergillus fumigatus. PLOS ONE 12, e0177050 (2017).
Berthier, E. et al. Low-volume toolbox for the discovery of immunosuppressive fungal secondary metabolites. PLOS Pathog. 9, e1003289 (2013).
Nazari, L., Manstretta, V. & Rossi, V. A non-linear model for temperature-dependent sporulation and T-2 and HT-2 production of Fusarium langsethiae and Fusarium sporotrichioides. Fungal Biol. 120, 562–571 (2016).
Bazafkan, H. et al. SUB1 has photoreceptor dependent and independent functions in sexual development and secondary metabolism in Trichoderma reesei. Mol. Microbiol. 106, 742–759 (2017).
Bayram, O. et al. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320, 1504–1506 (2008). This paper describes the identification of a conserved transcriptional complex that coordinates global regulation of secondary metabolism.
Pruss, S. et al. Role of the Alternaria alternata blue-light receptor LreA (white-collar 1) in spore formation and secondary metabolism. Appl. Environ. Microbiol. 80, 2582–2591 (2014).
Monroy, A. A., Stappler, E., Schuster, A., Sulyok, M. & Schmoll, M. A. CRE1-regulated cluster is responsible for light dependent production of dihydrotrichotetronin in Trichoderma reesei. PLOS ONE 12, e0182530 (2017).
Purschwitz, J. et al. Functional and physical interaction of blue- and red-light sensors in Aspergillus nidulans. Curr. Biol. 18, 255–259 (2008).
Calvo, A. M. & Cary, J. W. Association of fungal secondary metabolism and sclerotial biology. Front. Microbiol. 6, 62 (2015).
Kenne, G. et al. Activation of aflatoxin biosynthesis alleviates total ROS in Aspergillus parasiticus. Toxins 10, 57 (2018).
Montibus, M., Pinson-Gadais, L., Richard-Forget, F., Barreau, C. & Ponts, N. Coupling of transcriptional response to oxidative stress and secondary metabolism regulation in filamentous fungi. Crit. Rev. Microbiol. 41, 295–308 (2015).
Fountain, J. C. et al. Oxidative stress and carbon metabolism influence Aspergillus flavus transcriptome composition and secondary metabolite production. Sci. Rep. 6, 38747 (2016).
Macheleidt, J. et al. Regulation and role of fungal secondary metabolites. Annu. Rev. Genet. 50, 371–392 (2016).
Fernandes, M., Keller, N. P. & Adams, T. H. Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol. Microbiol. 28, 1355–1365 (1998).
Brown, D. W. et al. Identification of a 12-gene fusaric acid biosynthetic gene cluster in Fusarium species through comparative and functional genomics. Mol. Plant Microbe Interact. 28, 319–332 (2015).
Yin, W.-B. et al. A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus. Aspergillus fumigatus. J. Am. Chem. Soc. 135, 2064–2067 (2013).
Wiemann, P. et al. Perturbations in small molecule synthesis uncovers an iron-responsive secondary metabolite network in Aspergillus fumigatus. Front. Microbiol. 5, 530 (2014).
Bergmann, S. et al. Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl. Environ. Microbiol. 76, 8143–8149 (2010).
Bok, J. W. & Keller, N. P. in The My cota: Biochemistry and Molecular Biology 3rd edn Vol. 3 (ed. Hoffmeister, D.) 21–29 (Springer International, Switzerland, 2016).
Chettri, P. & Bradshaw, R. E. LaeA negatively regulates dothistromin production in the pine needle pathogen Dothistroma septosporum. Fungal Genet. Biol. 97, 24–32 (2016).
Oakley, C. E. et al. Discovery of McrA, a master regulator of Aspergillus secondary metabolism. Mol. Microbiol. 103, 347–365 (2017).
Lim, F. Y., Ames, B., Walsh, C. T. & Keller, N. P. Co-ordination between BrlA regulation and secretion of the oxidoreductase FmqD directs selective accumulation of fumiquinazoline C to conidial tissues in Aspergillus fumigatus. Cell. Microbiol. 16, 1267–1283 (2014).
Mulinti, P. et al. Accumulation of ergot alkaloids during conidiophore development in Aspergillus fumigatus. Curr. Microbiol. 68, 1–5 (2014).
Cichewicz, R. H. Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat. Prod. Rep. 27, 11–22 (2010).
Roze, L. V., Arthur, A. E., Hong, S.-Y., Chanda, A. & Linz, J. E. The initiation and pattern of spread of histone H4 acetylation parallel the order of transcriptional activation of genes in the aflatoxin cluster. Mol. Microbiol. 66, 713–726 (2007).
Shwab, E. K. et al. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 6, 1656–1664 (2007).
Gacek, A. & Strauss, J. The chromatin code of fungal secondary metabolite gene clusters. Appl. Microbiol. Biotechnol. 95, 1389–1404 (2012).
Fan, A. et al. Deletion of a histone acetyltransferase leads to the pleiotropic activation of natural products in Metarhizium robertsii. Org. Lett. 19, 1686–1689 (2017).
Gacek-Matthews, A. et al. KdmB, a Jumonji histone H3 demethylase, regulates genome-wide H3K4 trimethylation and is required for normal induction of secondary metabolism in Aspergillus nidulans. PLOS Genet. 12, e1006222 (2016). Using genome-wide chromatin immunoprecipitation coupled with RNA-seq and liquid chromatography with tandem mass spectrometry (LC-MS/MS), this study presents unprecedented insight into the global epigenetic regulation of cryptic BGCs in one species.
Williams, R. B., Henrikson, J. C., Hoover, A. R., Lee, A. E. & Cichewicz, R. H. Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem. 6, 1895 (2008).
Albright, J. C. et al. Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. ACS Chem. Biol. 10, 1535–1541 (2015).
Reyes-Dominguez, Y. et al. Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol. Microbiol. 76, 1376–1386 (2010).
Karimi-Aghcheh, R. et al. Functional analyses of Trichoderma reesei LAE1 reveal conserved and contrasting roles of this regulator. G 3 3, 369–378 (2013).
Niehaus, E.-M. et al. Analysis of the global regulator Lae1 uncovers a connection between Lae1 and the histone acetyltransferase HAT1 in Fusarium fujikuroi. Appl. Microbiol. Biotechnol. 102, 279–295 (2018).
Nützmann, H.-W. et al. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc. Natl Acad. Sci. USA 108, 14282–14287 (2011). This paper reports the bacterial induction of a cryptic BGC via a chromatin remodelling enzyme complex.
Netzker, T. et al. Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Front. Microbiol. 6, 299 (2015).
Bok, J. W. et al. VeA and MvlA repression of the cryptic orsellinic acid gene cluster in Aspergillus nidulans involves histone 3 acetylation. Mol. Microbiol. 89, 963–974 (2013).
Tsai, H. F., Wheeler, M. H., Chang, Y. C. & Kwon-Chung, K. J. A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J. Bacteriol. 181, 6469–6477 (1999). This article presents the first identification of a BGC required for fungal development.
Zhang, P. et al. A cryptic pigment biosynthetic pathway uncovered by heterologous expression is essential for conidial development in Pestalotiopsis fici. Mol. Microbiol. 105, 469–483 (2017).
Leonard, K. J. Virulence, temperature optima, and competitive abilities of isolines of races T and 0 of Bipolaris maydis. Phytopathology 67, 1273–1279 (1977).
Shukla, S. et al. Total phenolic content, antioxidant, tyrosinase and α-glucosidase inhibitory activities of water soluble extracts of noble starter culture Doenjang, a Korean fermented soybean sauce variety. Food Control 59, 854–861 (2016).
Eisenman, H. C. & Casadevall, A. Synthesis and assembly of fungal melanin. Appl. Microbiol. Biotechnol. 93, 931–940 (2012).
Jacobson, E. S. Pathogenic roles for fungal melanins. Clin. Microbiol. Rev. 13, 708–717 (2000).
Zhao, L., Kim, J.-C., Paik, M.-J., Lee, W. & Hur, J.-S. A. Multifunctional and possible skin UV protectant, (3R)-5-hydroxymellein, produced by an endolichenic fungus isolated from Parmotrema austrosinense. Molecules 22, 26 (2016).
Zheng, H. et al. Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus. Curr. Biol. 25, 29–37 (2015).
Scherlach, K. & Hertweck, C. Mediators of mutualistic microbe-microbe interactions. Nat. Prod. Rep. 35, 303–308 (2018).
Zeilinger, S. et al. Friends or foes? Emerging insights from fungal interactions with plants. FEMS Microbiol. Rev. 40, 182–207 (2016).
Rohlfs, M. Fungal secondary metabolite dynamics in fungus-grazer interactions: novel insights and unanswered questions. Front. Microbiol. 5, 788 (2014).
Partida-Martinez, L. P. & Hertweck, C. Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature 437, 884–888 (2005).
Scherlach, K., Busch, B., Lackner, G., Paszkowski, U. & Hertweck, C. Symbiotic cooperation in the biosynthesis of a phytotoxin. Angew. Chem. Int. Ed. 51, 9615–9618 (2012).
Spraker, J. E., Sanchez, L. M., Lowe, T. M., Dorrestein, P. C. & Keller, N. P. Ralstonia solanacearum lipopeptide induces chlamydospore development in fungi and facilitates bacterial entry into fungal tissues. ISME J. 10, 2317–2330 (2016).
Khalid, S. et al. NRPS-derived isoquinolines and lipopetides mediate antagonism between plant pathogenic fungi and bacteria. ACS Chem. Biol. 13, 171–179 (2018).
Schumacher, J. et al. A functional bikaverin biosynthesis gene cluster in rare strains of Botrytis cinerea is positively controlled by VELVET. PLOS ONE 8, e53729 (2013).
Campbell, M. A., Rokas, A. & Slot, J. C. Horizontal transfer and death of a fungal secondary metabolic gene cluster. Genome Biol. Evol. 4, 289–293 (2012).
Oh, D.-C., Poulsen, M., Currie, C. R. & Clardy, J. Dentigerumycin: a bacterial mediator of an ant-fungus symbiosis. Nat. Chem. Biol. 5, 391–393 (2009).
Dhodary, B., Schilg, M., Wirth, R. & Spiteller, D. Secondary metabolites from Escovopsis weberi and their role in attacking the garden fungus of leaf-cutting ants. Chemistry 24, 4445–4452 (2018).
Tauber, J. P., Gallegos-Monterrosa, R., Kovács, Á. T., Shelest, E. & Hoffmeister, D. Dissimilar pigment regulation in Serpula lacrymans and Paxillus involutus during inter-kingdom interactions. Microbiology 164, 65–77 (2018).
Tauber, J. P., Schroeckh, V., Shelest, E., Brakhage, A. A. & Hoffmeister, D. Bacteria induce pigment formation in the basidiomycete Serpula lacrymans. Environ. Microbiol. 18, 5218–5227 (2016).
Fan, Y. et al. Regulatory cascade and biological activity of Beauveria bassiana oosporein that limits bacterial growth after host death. Proc. Natl Acad. Sci. USA 114, E1578–E1586 (2017). This paper reports the finding that a fungus-derived antibacterial compound poisons the food supply to limit microbial competition.
Drott, M. T., Lazzaro, B. P., Brown, D. L., Carbone, I. & Milgroom, M. G. Balancing selection for aflatoxin in Aspergillus flavus is maintained through interference competition with, and fungivory by insects. Proc. Biol. Sci. 284, 20172408 (2017). This article provides evidence that a toxic secondary metabolite provides a fitness advantage to the fungus during confrontations with insects.
Dolan, S. K., O’Keeffe, G., Jones, G. W. & Doyle, S. Resistance is not futile: gliotoxin biosynthesis, functionality and utility. Trends Microbiol. 23, 419–428 (2015).
Teijeira, F. et al. The transporter CefM involved in translocation of biosynthetic intermediates is essential for cephalosporin production. Biochem. J. 418, 113–124 (2009).
Scharf, D. H. et al. Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. J. Am. Chem. Soc. 132, 10136–10141 (2010).
Abe, Y. et al. Effect of increased dosage of the ML-236B (compactin) biosynthetic gene cluster on ML-236B production in Penicillium citrinum. Mol. Genet. Genomics 268, 130–137 (2002).
Yeh, H.-H. et al. 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, 2275–2284 (2016). This paper provides the first evidence that duplicated, resistant target genes within a BGC provide self-protection.
Yue, Q. et al. Genomics-driven discovery of a novel self-resistance mechanism in the echinocandin-producing fungus Pezicula radicicola. Environ. Microbiol. 20, 3154–3167 (2018).
Yan, Y. et al. Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action. Nature 559, 415–418 (2018). This study describes a genomics approach to identify duplicated resistance genes and the discovery of a bioactive natural-product herbicide.
Hansen, B. G. et al. A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi. BMC Microbiol. 11, 202 (2011). This study reports on the initial demonstration that a duplicated target gene within a BGC can provide resistance to the BGC product using a heterologous host.
Larkin, E. L., Dharmaiah, S. & Ghannoum, M. A. Biofilms and beyond: expanding echinocandin utility. J. Antimicrob. Chemother. 73, i73–i81 (2018).
Studt, L., Wiemann, P., Kleigrewe, K., Humpf, H.-U. & Tudzynski, B. Biosynthesis of fusarubins accounts for pigmentation of Fusarium fujikuroi perithecia. Appl. Environ. Microbiol. 78, 4468–4480 (2012).
Zhao, Y. et al. Production of a fungal furocoumarin by a polyketide synthase gene cluster confers the chemo-resistance of Neurospora crassa to the predation by fungivorous arthropods. Environ. Microbiol. 19, 3920–3929 (2017).
Schindler, D. & Nowrousian, M. The polyketide synthase gene pks4 is essential for sexual development and regulates fruiting body morphology in Sordaria macrospora. Fungal Genet. Biol. 68, 48–59 (2014).
Becker, J., Liermann, J. C., Opatz, T., Anke, H. & Thines, E. GKK1032A2, a secondary metabolite from Penicillium sp. IBWF-029-96, inhibits conidial germination in the rice blast fungus Magnaporthe oryzae. J. Antibiot. 65, 99–102 (2012).
Nielsen, J. C. et al. Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species. Nat. Microbiol. 2, 17044 (2017).
Medema, M. H. et al. Minimum information about a biosynthetic gene cluster. Nat. Chem. Biol. 11, 625–631 (2015). This article presents a community effort to standardize annotations and metadata on BGCs and their products.
Alberti, F., Foster, G. D. & Bailey, A. M. Natural products from filamentous fungi and production by heterologous expression. Appl. Microbiol. Biotechnol. 101, 493–500 (2017).
Chavali, A. K. & Rhee, S. Y. Bioinformatics tools for the identification of gene clusters that biosynthesize specialized metabolites. Brief. Bioinform. 19, 1022–1034 (2017).
Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).
Medema, M. H. et al. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 39, W339–W346 (2011).
Galagan, J. E. et al. Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438, 1105–1115 (2005).
Machida, M. et al. Genome sequencing and analysis of Aspergillus oryzae. Nature 438, 1157–1161 (2005).
Nierman, W. C. et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438, 1151–1156 (2005).
Mohimani, H. et al. Dereplication of microbial metabolites through database search of mass spectra. Nat. Commun. 9, 4035 (2018).
Janevska, S. et al. Establishment of the inducible Tet-On system for the activation of the silent trichosetin gene cluster in Fusarium fujikuroi. Toxins 9, 126 (2017).
Jiang, T. et al. Overexpression of the global regulator LaeA in Chaetomium globosum leads to the biosynthesis of chaetoglobosin Z. J. Nat. Prod. 79, 2487–2494 (2016).
Palonen, E. K. et al. Transcriptomic complexity of Aspergillus terreus Velvet gene family under the influence of butyrolactone I. Microorganisms 5, 12 (2017).
Adnani, N., Rajski, S. R. & Bugni, T. S. Symbiosis-inspired approaches to antibiotic discovery. Nat. Prod. Rep. 34, 784–814 (2017).
Billingsley, J. M., DeNicola, A. B. & Tang, Y. Technology development for natural product biosynthesis in Saccharomyces cerevisiae. Curr. Opin. Biotechnol. 42, 74–83 (2016).
He, Y. et al. Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp. Biotechnol. Adv. 36, 739–783 (2018).
Yin, W.-B. et al. Discovery of cryptic polyketide metabolites from dermatophytes using heterologous expression in Aspergillus nidulans. ACS Synth. Biol. 2, 629–634 (2013).
Harvey, C. J. B. et al. HEx: a heterologous expression platform for the discovery of fungal natural products. Sci. Adv. 4, eaar5459 (2018). This paper describes the tool and protocol development that led to the expression of 41 BGCs and 22 compounds in a yeast heterologous expression system.
Stepien, Ł. The use of Fusarium secondary metabolite biosynthetic genes in chemotypic and phylogenetic studies. Crit. Rev. Microbiol. 40, 176–185 (2014).
Khaldi, N., Collemare, J., Lebrun, M.-H. & Wolfe, K. H. Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol. 9, R18 (2008). This early phylogenetic study provides evidence for horizontal transfer of natural-product BGCs in fungi.
Reynolds, H. T. et al. Differential retention of gene functions in a secondary metabolite cluster. Mol. Biol. Evol. 34, 2002–2015 (2017).
Bignell, E., Cairns, T. C., Throckmorton, K., Nierman, W. C. & Keller, N. P. Secondary metabolite arsenal of an opportunistic pathogenic fungus. Phil. Trans. R. Soc. B 371, 20160023 (2016).
Perrin, R. M. et al. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLOS Pathog. 3, e50 (2007).
Lind, A. L. et al. Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species. PLOS Biol. 15, e2003583 (2017). This study compares DNA sequences of the BGCs of 66 A. fumigatus isolates and establishes 5 drivers of genetic diversity that explain BGC macroevolutionary patterns.
Droce, A. et al. Functional analysis of the fusarielin biosynthetic gene cluster. Molecules 21, 1710 (2016).
Campbell, M. A., Staats, M., van Kan, J. A. L., Rokas, A. & Slot, J. C. Repeated loss of an anciently horizontally transferred gene cluster in Botrytis. Mycologia 105, 1126–1134 (2013).
Nielsen, K. F. & Larsen, T. O. The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. Front. Microbiol. 6, 71 (2015).
Chiang, Y.-M. et al. Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew. Chem. Int. Ed. 55, 1662–1665 (2016).
Díez, B. et al. The cluster of penicillin biosynthetic genes: identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J. Biol. Chem. 265, 16358–16365 (1990).
Smith, D. J., Burnham, M. K., Edwards, J., Earl, A. J. & Turner, G. Cloning and heterologous expression of the penicillin biosynthetic gene cluster from Penicillum chrysogenum. Biotechnology 8, 39–41 (1990).
Keller, N. P. & Hohn, T. M. Metabolic pathway gene clusters in filamentous fungi. Fungal Genet. Biol. 21, 17–29 (1997).
Goffeau, A. et al. Life with 6000 genes. Science 274, 546–567 (1996).
Inglis, D. O. et al. Comprehensive annotation of secondary metabolite biosynthetic genes and gene clusters of Aspergillus nidulans, A. fumigatus, A. niger and A. oryzae. BMC Microbiol. 13, 91 (2013).
Samson, R. A. et al. Phylogeny, identification and nomenclature of the genus Aspergillus. Stud. Mycol. 78, 141–173 (2014).
Visagie, C. M. et al. Identification and nomenclature of the genus Penicillium. Stud. Mycol. 78, 343–371 (2014).
Kirk, P. M., Cannon, P. F., David, J. C. & Stalpers, J. A. (eds) Ainsworth & Bisby’s Dictionary of the Fungi 9th edn (CABI, 2001).
Schoch, C. L. et al. A class-wide phylogenetic assessment of Dothideomycetes. Stud. Mycol. 64, 1–15 (2009).
Jahn, L. et al. Linking secondary metabolites to biosynthesis genes in the fungal endophyte Cyanodermella asteris: the anti-cancer bisanthraquinone skyrin. J. Biotechnol. 257, 233–239 (2017).
Yin, W.-B. et al. An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR. Mol. Microbiol. 83, 1024–1034 (2012).
Soukup, A. A. et al. Overexpression of the Aspergillus nidulans histone 4 acetyltransferase EsaA increases activation of secondary metabolite production. Mol. Microbiol. 86, 314–330 (2012).
Itoh, E. et al. Sirtuin A regulates secondary metabolite production by Aspergillus nidulans. J. Gen. Appl. Microbiol. 63, 228–235 (2017).
Ahuja, M. et al. Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. J. Am. Chem. Soc. 134, 8212–8221 (2012).
Brakhage, A. A. Regulation of fungal secondary metabolism. Nat. Rev. Microbiol. 11, 21–32 (2013).
Pfannenstiel, B. T. et al. Revitalization of a forward genetic screen identifies three new regulators of fungal secondary metabolism in the genus Aspergillus. mBio 8, e01246–17 (2017).
Gacek-Matthews, A. et al. KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. Mol. Microbiol. 96, 839–860 (2015).
Strauss, J. & Reyes-Dominguez, Y. Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet. Biol. 48, 62–69 (2011).
Wiemann, P. et al. CoIN: co-inducible nitrate expression system for secondary metabolites in Aspergillus nidulans. Fungal Biol. Biotechnol. 5, 6 (2018).
Blin, K. et al. antiSMASH 4.0 — improvements in chemistry prediction and gene cluster boundary identification. Nucleic Acids Res. 45, W36–W41 (2017).
Skinnider, M. A. et al. Genomes to natural products prediction informatics for secondary metabolomes (PRISM). Nucleic Acids Res. 43, 9645–9662 (2015).
Wolf, T., Shelest, V., Nath, N. & Shelest, E. CASSIS and SMIPS: promoter-based prediction of secondary metabolite gene clusters in eukaryotic genomes. Bioinformatics 32, 1138–1143 (2016).
Vesth, T. C., Brandl, J. & Andersen, M. R. FunGeneClusterS: predicting fungal gene clusters from genome and transcriptome data. Synth. Syst. Biotechnol. 1, 122–129 (2016).
Zierep, P. F. et al. SeMPI: a genome-based secondary metabolite prediction and identification web server. Nucleic Acids Res. 45, W64–W71 (2017).
Conway, K. R. & Boddy, C. N. ClusterMine360: a database of microbial PKS/NRPS biosynthesis. Nucleic Acids Res. 41, D402–D407 (2013).
Hadjithomas, M. et al. IMG-ABC: a knowledge base to fuel discovery of biosynthetic gene clusters and novel secondary metabolites. mBio 6, e00932 (2015).
Medema, M. H. et al. Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products. PLOS Comput. Biol. 10, e1003822 (2014).
Dejong, C. A. et al. Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching. Nat. Chem. Biol. 12, 1007–1014 (2016).
Röttig, M. et al. NRPSpredictor2 — a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res. 39, W362–W367 (2011).
The author thanks F. Y. Lim for generating the original figure 5 and J. Winans and C. D. Nwagwu for help with formatting the text. N.P.K. is funded by US National Institutes of Health (NIH) grants R01GM112739-01 and R01 AI065728-01.
Nature Reviews Microbiology thanks M. Andersen, J. Cary, D. Hoffmeister and the other anonymous reviewer(s) for their contribution to the peer review of this work.
There is no competing interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The total number of small molecules in a biological sample.
- Primary metabolites
Metabolites that are produced by many unrelated taxa and are required for normal growth, development and reproduction.
- Tailoring enzymes
Enzymes that modify non-ribosomal peptides, polyketide backbones and/or terpenoid backbones after chain elongation from respective synthetases, synthases or cyclases.
- Velvet complex
A conserved transcriptional complex in filamentous fungi that is critical for the regulation of fungal secondary metabolism and reproduction in response to light and other environmental signals.
A red-light photoreceptor found in fungi, bacteria and plants.
The asexual spore (called conidium) bearing structure that is produced by many filamentous fungi. Specific secondary metabolites are associated with asexual spore formation.
Highly condensed chromatin tightly wound around histones and less available to the transcriptional machinery. The heterochromatin state is dependent on specific post-translational histone modifications, such as deacetylation.
Lightly packed chromatin with looser arrangement around histones and accessible to the transcriptional machinery. The euchromatin state is dependent on specific post-translational histone modifications, such as acetylation and methylation.
Sexual fruiting bodies containing sexual spores of some Ascomycete fungi.
A screen in secondary metabolite analysis to eliminate already-known compounds from the discovery process.
About this article
Cite this article
Keller, N.P. Fungal secondary metabolism: regulation, function and drug discovery. Nat Rev Microbiol 17, 167–180 (2019). https://doi.org/10.1038/s41579-018-0121-1
Azaphilones biosynthesis complements the defence mechanism of Trichoderma guizhouense against oxidative stress
Environmental Microbiology (2020)
Transcriptomic and Exometabolomic Profiling Reveals Antagonistic and Defensive Modes of Clonostachys rosea Action Against Fusarium graminearum
Molecular Plant-Microbe Interactions® (2020)
Biological Reviews (2020)
The importance of researches on the fungal bioactive secondary metabolites in developing the comprehensive health industry
Chinese Journal of Natural Medicines (2020)
Journal of Chemical Information and Modeling (2020)