Abstract
Natural products have served as a fruitful starting point for antibiotic drug development. Evolution has served both as a catalyst to optimize their structures and also as a hinderance to render them ineffective through a variety of resistance mechanisms. To combat this, there has been a significant effort to discover new antibiotics with non-conventional mechanisms of action. Toward this end, researchers have continued to leverage natural products as a key source of novel scaffolds in an effort to discover new biological targets. In this review, we provide an overview of the conventional mechanisms of action and new advances in antibiotic natural product discovery. We detail recent successes of diverted total synthesis strategies in a two-pronged approach: (1) developing potent antibiotics that overcome bacterial resistance and (2) discovering new chemical probes for biological investigation. We close by discussing affinity-based protein profiling, a chemical proteomics method that can be used in concert with resistance selection approaches to overcome some inherent limitations.