Evolution and inhibition of beta-lactamase activity in antibiotic resistance

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DESCRIPTION (provided by applicant): The production of serine ¿-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens against ¿-lactam antibiotics, which include the widely used penicillins and cephalosporins, as well as last resort antibiotics such as the carbapenems. The development of novel ¿-lactamase inhibitors is a pressing need underscored by the continuing mutation of ¿-lactamases. We propose the development of high affinity non-covalent ¿-lactamase inhibitors by targeting conserved structural motifs, particularly those essential for extended spectrum ¿-lactamase activity. Prototypes of these inhibitors have already been identified. Specifically, using the CTX-M Class A ¿-lactamases as a model system, we aim to: 1) apply a fragment-based and structure-guided approach to develop novel ¿-lactamase inhibitor chemotypes; 2) study resistance and ligand binding by ultrahigh-resolution and room-temperature X-ray crystallography; and 3) investigate the evolution of resistance mutations against non-covalent inhibitors. These experiments will lead to new ¿- lactamase inhibitors with clinical potential, while providing a deeper understanding of ¿-lactamase mutations relevant to resistance evolution.