Using Fragment-Based Approaches to Discover New Antibiotics.

Fragment-based lead discovery has emerged over the past two decades as a successful approach to generate novel lead candidates in drug discovery programs. The two main advantages over conventional high-throughput screening (HTS) are more efficient sampling of chemical space and tighter control over the physicochemical properties of the lead candidates. Antibiotics are a class of drugs with particularly strict property requirements for efficacy and safety. The development of novel antibiotics has slowed down so much that resistance has now evolved against every available antibiotic drug. Here we give an overview of fragment-based approaches in screening and lead discovery projects for new antibiotics. We discuss several successful hit-to-lead development examples. Finally, we highlight the current challenges and opportunities for fragment-based lead discovery toward new antibiotics.