Protein Antibiotics: Discovery, mode of action and development (360G-Wellcome-201505_Z_16_Z)

The rise of antibiotic resistant bacteria poses a catastrophic threat to humanity. Despite the pressing need, few new antibiotics have entered the clinic in the last 30 years. The situation is particularly urgent for multidrug resistant Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae. We will address this problem through the use of bacteriocins, which are species-specific protein antibiotics made by Gram-negative bacteria during environmental stress. We recently discovered that pyocins, deployed by P. aeruginosa to kill neighbouring Pseudomonad spp, are more effective at protecting mice infected with an acute P. aeruginosa lung infection than tobramycin, the leading antibiotic used clinically for the treatment of pulmonary infections. Through this multidisciplinary, multicentre collaborative award, which brings together experts in bacteriocin structure and function (Kleanthous, Walker), pathogen genetics and genomics (Maiden, Parkhill) and animal models of bacterial disease (Evans, Taylor), we will (i) uncover the mechanism(s) by which pyocins translocate across the P. aeruginosa cell envelope, capitalizing on exciting new structural and microscopy data, (ii) investigate the efficacy of pyocins as antibiotics in animal models of disease, and (iii) initiate the first such studies on klebicins, bacteriocins that target Klebsiella pneumoniae.