Bacterial RNA polymerase: a promising target for the discovery of new antimicrobial agents

Prokaryotic DNA-dependent RNA polymerase (RNAP) is a multi-subunit enzyme responsible for transcription in bacteria. It is an important target for antibacterial chemotherapy because it is essential for bacterial growth and survival, and possesses features that distinguish it from mammalian counterparts. The rifamycins are currently the only class of RNAP inhibitors that have been approved for clinical use, and consequently bacterial RNAP remains relatively underexploited as an antibacterial drug target. However, improved understanding of the molecular basis of rifamycin action, revealed by X-ray crystallographic studies, has resulted in the development of new rifamycins, such as the benzoxazinorifamycins, with improved properties. Structural studies on other RNAP inhibitors have also been described, and a number of older inhibitors now await detailed investigation to provide molecular explanations for their modes of action. New approaches have also resulted in the discovery of inhibitors of RNAP assembly. This review discusses various RNAP inhibitors in the context of their modes of action and potential development for therapeutic application. Opportunities for the discovery of new inhibitors are also discussed.