Exploiting current understanding of antibiotic action for discovery of new drugs

Abstract

The introduction of antibiotics for the chemotherapy of bacterial infections has been one of the most important medical achievements of the past 50 years. However, the emergence of bacterial resistance to antibiotics undermines the therapeutic utility of existing agents, creating a requirement for the discovery of new antibacterial drugs. Several drug discovery strategies have emerged, including incremental improvements to existing antibiotics by chemical manipulation and the search for novel drug targets based on genomic approaches. An alternative strategy seeks to exploit opportunities for drug discovery arising from an understanding of the mode of action of existing antibiotics. Thus biochemical pathways or processes inhibited by antibiotics already in clinical use may nevertheless contain key functions that represent unexploited targets for further drug discovery. A major benefit of employing pathways or processes that are already known to contain drug targets is that proof of principle for drug intervention is already established. This approach to drug discovery is illustrated by reviewing target sites for existing antibiotics and considering how this information might be applied for the discovery of new agents inhibiting peptidoglycan synthesis, tRNA synthesis, transcription and DNA replication.