Structure-guided discovery of novel antibiotics inhibiting bacterial cell wall formation

The emergence of drug-resistant Gram-negative bacteria causes a significant global health problem, because the available antibiotics are limited and the discovery of new compounds cannot keep pace with the emergence of drug-resistant strains. The difficulty to combat these pathogens is largely due to their unique dual-membrane cell wall which efficiently blocks the entry of antibiotics. Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria plays key roles in cell wall formation and antibiotic resistance. Thus, LPS biosynthesis is a particularly attractive target for developing new classes of antibiotics. LPS is synthesized in the inner membrane and subsequently transported to the outer membrane, a process critically dependent on two ATP-binding cassette transporters (MsbA and LptB₂FGC). My laboratory has made important contributions in characterizing the structure and function of these LPS transporters. Here we propose to leverage our experience and mechanistic insights of MsbA to develop novel antibiotics. This will be achieved by establishing a targeted screening pipeline that comprises chemical screen, cryo-electron microscopy (cryo-EM), computational docking, and activity assays. Once established, this pipeline can be applied to target many other bacterial membrane transporters.