Abstract

Antimicrobial resistance (AMR) is a critical threat to global health and the economy. A promising strategy to address this challenge is the exploration of synergistic combinations of natural antimicrobials, which can broaden antibiotic spectra, enhance efficacy, and reduce the likelihood of resistance development. Such combinations often arise in bacteria through complex metabolic pathways encoded by biosynthetic superclusters (BSs)—genomic arrangements in which multiple biosynthetic gene clusters (BGCs) co-localize within the same genomic region, promoting co-regulation and co-production of specialized metabolites with complementary activities. This review provides an overview of current knowledge on biosynthetic gene superclusters in bacteria, focusing on their genomic architectures, regulatory connectivity, and the synergistic interaction profiles of the encoded metabolites as shaped by evolutionary pressures. Finally, we highlight how integrative genome–metabolome mining can be applied to discover, validate, and reprogram supercluster genes, positioning them as promising, naturally evolved platforms for the rational design of modular antimicrobial combinations to help combat AMR.