Research

Overall theme

Antibiotic resistance has become a major clinical problem worldwide. Our lab is interested in the structure-based

design of inhibitors that target antibiotic resistance mechanisms or novel targets essential to bacterial pathogenesis.

 

Beta-lactam resistance The key determinant of broad-spectrum beta-lactam resistance is methicillin-resistant superbug strains is the membrane-spanning penicillin-binding protein 2a (PBP2a), a transpeptidase that is required to produce peptide cross-links that give the bacterial cell wall its necessary strength and rigidity. Due to its low affinity for beta-lactams, PBP2a provides cross-linking transpeptidase activity at beta-lactam concentrations that inhibit other cell wall transpeptidases normally produced by Staphylococcus aureus and other pathogenic Gram positive bacteria. We have determined the crystal structures of native PBP2a from methicillin-resistant S. aureus (MRSA) as well as acyl-enzymes complexes with various beta-lactam antibiotic substrates. An analysis of the PBP2a active site reveals the structural basis of its broad-spectrum resistance to approximately 50 clinically utilized beta-lactam antibiotics and identifies features important for high-affinity binding. This information is currently used in structure-based inhibitor design aiming to combat MRSA resistance.

Novel antibiotic targets Our laboratory has made significant progress on the understanding the structure a function of the type III secretion system (TTSS) which is common to many Gram negative bacterial pathogens. The TTSS allows for the specific injection of bacterial proteins into human host cells, where they mediate their pathogenic effects. We have recently determined the high-resolution crystal structures of a number of proteins consituting the TTSS, including EspA, the translocation tube which bridges the gap between bacterial membranes and the host cellular membrane, the outer membrane (OM) secretin pilot protein MxiM, and the inner membrane polymeric ring protein EscJ that is thought to act as the initial "platform" upon which other TTSS structural components assemble. These structures provide the necessary foundation for understanding the molecular details of this pathogenic process as well as for the design of novel antimicrobials.

                                                 We gratefully acknowledge the following agencies for funding our research work