Biosynthetic Gene Clusters and Natural Product Diversity

Natural products arise from specialised metabolic pathways encoded by contiguous sets of genes known as biosynthetic gene clusters (BGCs). These clusters direct the assembly of diverse secondary metabolites, including antibiotics, pigments and signalling molecules, which mediate ecological interactions and underpin numerous pharmaceutical and biotechnological applications. Advances in high-throughput sequencing, genome mining and synthetic biology have transformed our capacity to identify and characterise BGCs from both cultured microbes and complex environmental communities. Metagenome-assembled genomes (MAGs) now reveal a vast untapped reservoir of cryptic BGCs in underexplored phyla and habitats, while heterologous expression systems enable the functional validation of novel pathways. The resulting expansion of chemical diversity promises new drug leads, agrichemicals and industrial enzymes, highlighting the global significance of BGC research for human health, food security and environmental sustainability.

Research from Nature Portfolio

Recent studies employing genome-resolved metagenomics in a permanently anoxic marine basin have reconstructed hundreds of MAGs and uncovered over a thousand distinct BGCs. Variation in water redox conditions and microbial lifestyle (particle-associated versus free-living) correlates with shifts in both the composition and expression of secondary metabolite pathways, revealing overlooked producers such as Planctomycetota. A global survey integrating cultivated genomes, single-cell assemblies and thousands of draft MAGs from ocean samples has catalogued nearly 40 000 putative new BGCs, including those from a previously unsuspected lineage (‘Candidatus Eudoremicrobiaceae’). Characterisation of representative pathways yielded unusual peptide and polyketide structures, demonstrating the power of environmental sequencing to uncover novel enzymology and bioactive compounds. Foundational work in culture-independent discovery has also showcased platforms that capture environmental DNA and functionally express BGCs in heterologous hosts, leading to the identification of calcium-dependent antibiotics with potent activity against multidrug-resistant pathogens.

Biosynthetic Gene Clusters and Natural Product Diversity publication trend

The graph below shows the total number of articles in biosynthetic gene clusters and natural product diversity across all publications each year (not limited to Nature Index journals).

Technical terms

Biosynthetic Gene Cluster (BGC): A contiguous set of genes encoding enzymes, regulators and transporters for the biosynthesis of a specific secondary metabolite.

Secondary Metabolite: A low-molecular-weight compound not directly involved in primary growth or reproduction, often serving ecological or defensive roles.

Metagenome-Assembled Genome (MAG): A genome reconstructed from environmental sequencing data through assembly and binning, representing an uncultured organism.

Nonribosomal Peptide Synthetase (NRPS): A multi-modular enzyme complex that assembles peptide natural products without ribosomes, often yielding cyclic or modified structures.

Polyketide Synthase (PKS): A class of modular enzymes that build polyketide chains through sequential condensation of simple carboxylic acid units.

Metagenomics: The culture-independent study of genetic material recovered directly from environmental samples, enabling analysis of microbial diversity and function.

References

1. Diverse secondary metabolites are expressed in particle-associated and free-living microorganisms of the permanently anoxic Cariaco Basin. Nature Communications (2023).
2. Biosynthetic potential of the global ocean microbiome. Nature (2022).
3. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nature Microbiology (2018).
4. Metagenomics reveals the habitat specificity of biosynthetic potential of secondary metabolites in global food fermentations. Microbiome (2023).
5. Biogeographic patterns of biosynthetic potential and specialized metabolites in marine sediments. The ISME Journal: Multidisciplinary Journal of Microbial Ecology (2023).
6. Succession of microbial community composition and secondary metabolism during marine biofilm development. ISME Communications (2024).