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Microbial secondary metabolites: advancements to accelerate discovery towards application

Nature Reviews Microbiology (2025)Cite this article

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Abstract

Microbial secondary metabolites not only have key roles in microbial processes and relationships but are also valued in various sectors of today’s economy, especially in human health and agriculture. The advent of genome sequencing has revealed a previously untapped reservoir of biosynthetic capacity for secondary metabolites indicating that there are new biochemistries, roles and applications of these molecules to be discovered. New predictive tools for biosynthetic gene clusters (BGCs) and their associated pathways have provided insights into this new diversity. Advanced molecular and synthetic biology tools and workflows including cell-based and cell-free expression facilitate the study of previously uncharacterized BGCs, accelerating the discovery of new metabolites and broadening our understanding of biosynthetic enzymology and the regulation of BGCs. These are complemented by new developments in metabolite detection and identification technologies, all of which are important for unlocking new chemistries that are encoded by BGCs. This renaissance of secondary metabolite research and development is catalysing toolbox development to power the bioeconomy.

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Fig. 1: Overview of microbial secondary metabolites, biosynthetic gene clusters and their biosynthesis.
Fig. 2: Example workflow for microbial secondary metabolite discovery.
Fig. 3: Standard and evolutionary genome-mining tools that are currently available for predicting different cluster types.
Fig. 4: Pipelines for extracting BGCs from the environment.
Fig. 5: High-throughput approaches for activating BGCs in native producers.
Fig. 6: Comparison of current cell-based and proposed cell-free workflows for testing and optimizing heterologous BGC expression.

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Acknowledgements

The work conducted by the U.S. Department of Energy Joint Genome Institute (https://ror.org/04xm1d337), a DOE Office of Science User Facility, is supported by the Office of Science of the U.S. Department of Energy operated under Contract No. DE-AC02-05CH11231.

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  1. US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Jaime Lorenzo N. Dinglasan, Hiroshi Otani, Drew T. Doering, Daniel Udwary & Nigel J. Mouncey

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J.L.N.D. wrote the initial draft and made most of the revisions. The remaining authors contributed equally to all other aspects of the article.

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Dinglasan, J.L.N., Otani, H., Doering, D.T. et al. Microbial secondary metabolites: advancements to accelerate discovery towards application. Nat Rev Microbiol (2025). https://doi.org/10.1038/s41579-024-01141-y

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