The human oral microbiome is a densely populated and chemically dynamic ecosystem where interspecies competition and cooperation shape community structure and influence host health. Metagenomic analyses reveal the immense biosynthetic potential of oral microbes to encode biosynthetic gene clusters (BGCs) and produce natural products. These metabolites are increasingly recognized as key mediators of microbial interactions, with many oral BGCs linked to health and disease. This review focuses on natural products in the oral microbiome derived from nonribosomal peptide synthetases and polyketide synthases, which are notable for their large size, modular machinery, and ecological relevance. We review the biosynthetic origins and bioactivities of these specialized metabolites in oral bacteria and discuss their biosynthetic regulation within the broader microbial community. Continued investment in whole-genome sequencing, integrative omics, and natural product discovery pipelines is essential for elucidating the microbial biochemical drivers of disease and advancing strategies to promote oral health.
Yao et al. (2026) studied this question.