DsbA inhibitors as potential antimicrobials (2007-2009)

Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor involved in the generation of bacterial virulence. This protein is found in most bacteria and contributes to pathogenicity by promoting the formation of toxins and virulence factors. We will design specific inhibitors of DsbA by using a structure-based approach, implementing the leading edge technologies of fragment-based lead discovery by crystallography and NMR. We will then optimise the fragments to develop lead compounds and evaluate their suitability as DsbA inhibitors by in vitro and in vivo assays.