Fungal secondary metabolism: regulation, function and drug discovery


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.

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Fig. 1: The typical building blocks of secondary metabolites and a schematic overview of a biosynthetic gene cluster.
Fig. 2: Regulation of the sterigmatocystin biosynthetic gene cluster.
Fig. 3: The ecological roles of secondary metabolites.
Fig. 4: Integration of genome mining with fungal biology yields valuable secondary metabolites.
Fig. 5: Chromosomal position of Aspergillus fumigatus biosynthetic gene clusters and their known or predicted products.


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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.

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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.

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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.

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Keller, N.P. Fungal secondary metabolism: regulation, function and drug discovery. Nat Rev Microbiol 17, 167–180 (2019).

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