Identifying weaknesses in the outer membrane protein assembly pathway to underpin the discovery of new antibiotic targets

Antibiotic resistance is a major issue for the health of the world, with gramnegative bacteria comprising 9 of the 12 bacteria that pose the greatest threat to human health as identified by the World-Health Organisation. The outer membrane (OM) of gram-negative bacteria is crowded with OM proteins (OMPs) that are vital for bacterial survival. New OMPs are made by the bacteria in the cytoplasm, and must then undertake a long journey to the OM. Complex protein machinery has evolved to enable this process, including chaperones in the periplasm (Skp and SurA), that escort OMPs to the OM, and BAM (beta-barrel assembly machinery), which inserts them into the OM. Perturbing this pathway leads to a loss of bacterial viability and is hence a new avenue for controlling gram-negative pathogens responsible for infections, including those that are multi-drug resistant.

This project will exploit state-of-the-art proteomics and structural mass spectrometry methods to elucidate the molecular basis by which the components of the OMP biogenesis pathway coordinate to fold OMPs, and reveal the molecular mechanism by which drug-like molecules target this process. This will aid in the design of much-needed new antibiotics against gram-negative bacteria that cause disease to humans, plants and animals.