Emerging trends in the discovery of natural product antibacterials

•Bioactivity-based discovery has yielded an array of new antibacterial compounds and targets.•Exploiting phenotypic determinants and intraspecies and interspecies interactions are potentially fruitful drug discovery strategies.•Efflux, quorum sensing, and host-based therapeutics are appealing discovery platforms.•Biosynthesis-guided discovery integrated with bioinformatics, chemical biology, and synthetic biology are areas of rapid innovation.

This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target bacterial pathogens that exhibit a variety of puzzling and evolutionarily complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antibacterial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting bacterial phenotypes. These efforts have identified a critical mass of natural product antibacterial lead compounds and discovery technologies with high probability of successful implementation against emerging bacterial pathogens.