Linking genomes to metabolites in antimicrobial discovery: integrative metagenomic and metabolomic approaches to combat antimicrobial resistance

Abstract

Antimicrobial resistance (AMR) continues to compromise the clinical utility of existing antibiotics, underscoring the urgent need for alternative discovery strategies that can access novel chemical space. Traditional culture-dependent approaches have reached a plateau, shifting attention toward omics based methods that enable systematic exploration of biologically and chemically diverse natural systems. Extreme ecological niches and medicinal plant-associated environments represent underexplored reservoirs of secondary metabolites shaped by unique selective pressures and chemical interactions, offering promising opportunities for antimicrobial discovery. Metagenomics provides direct access to the biosynthetic potential of uncultured microorganisms, allowing the identification of cryptic biosynthetic gene clusters and previously inaccessible antimicrobial pathways from extreme environments. In parallel, metabolomics facilitates comprehensive profiling, annotation, and functional evaluation of bioactive metabolites derived from medicinal plants and their associated microbiomes. When applied independently, these approaches have expanded the repertoire of antimicrobial candidates; however, their true potential emerges through integrative strategies that connect genomic information with metabolite production and biological activity. This review focuses on recent advances in metagenomics and metabolomics-driven antimicrobial discovery, with particular emphasis on integrative, resistance-aware approaches that bridge genomes, metabolites, and antimicrobial phenotypes. We highlight representative case studies, methodological innovations, and chemical biology perspectives that contribute to the identification of novel antimicrobial agents, targets, and mechanisms of action. Finally, we discuss key analytical challenges and emerging developments, including multi-omics integration, computational tools, and data-driven frameworks, that are shaping future pipelines for antimicrobial discovery. Together, these insights underscore the value of integrated omics approaches in addressing the escalating challenge of antimicrobial resistance.