Biosynthetic crosstalk in bacteria: routes to chimeric natural products.

Abstract

Covering: up to the end of April 2026Chimeric natural products are formed when biosynthetic inputs from distinct pathways, gene clusters, or metabolic branches are integrated into a single scaffold. In bacteria, such crosstalk-driven assembly can generate structurally diverse metabolites with distinct biological activities. However, these metabolites remain underexplored because most discovery pipelines are optimized to connect one metabolite family to one co-localized biosynthetic gene cluster (BGC). As a result, metabolites produced through inter-pathway collaboration, recruitment of primary-metabolic intermediates, or non-enzymatic coupling of products from separate pathways are often deprioritized as genome-metabolome mismatches. Here, we describe chimeric natural products as an important yet overlooked class of bacterial metabolites and present a discovery framework that prioritizes candidate hybrid scaffolds from LC-MS-based metabolomics. We suggest that public-repository spectral searching, multi-class MS/MS annotation, retrospective genome-to-metabolite linkage, and isotope-guided validation can improve discovery of these overlooked scaffolds. Prioritizing such metabolites can expand natural product discovery beyond canonical frameworks, uncover new biosynthetic design principles, and inform future efforts to engineer hybrid molecules.