Characterization of Metallo-B-Lactamases

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EXCEED THE SPACE PROVIDED. Bacterial resistance to antibiotics is one of the most important problems in biomedicine today. The most commonly prescribed antibiotics are beta-lactam containing compounds, such as the penicillins and cephalosporins, due to their effectiveness, production costs, and relative low side effects. Most often, bacteria become resistant to these antibiotics by producing beta-lactamases, which hydrolyze and inactivate the antibiotics. One particularly troubling group of beta-lactamases contains 1-2 Zn(ll) ions and are called metallo-beta-lactamases (MbL's). MbL's are currently produced by at least 25 different bacterial strains, and these enzymes hydrolyze all known beta-lactam containing antibiotics, including the compounds that inhibit the serine active site beta-lactamases. Biochemical and structural studies have demonstrated that there are three distinct classes of MbL's, and these differences suggest that an inhibitor against one MbL may not inhibit another MbL. The strategy described in this proposal involves characterization of a MbL from each of the distinct classes of enzymes, identifying common structural and mechanistic aspects of the enzymes, and designing inhibitors based on those common features. The MbL's from Stenotrophomonas maltophilia, Bacteroides fragilis, and Aeromonas sobria will be characterized using kinetic, spectroscopic, and biochemical studies. The specific aims of this proposed research are (1) to probe substrate binding, (2) to probe the reaction mechanism, and (3) to continue efforts to prepare inhibitors of these enzymes. The results from these studies will allow for a more complete understanding of the structure and mechanism of these clinically-important enzymes specifically that can be used to design or redesign inhibitors. Relevance: Bacterial resistance to antibiotics is rapidly-emerging medical problem in which bacterial infections that were recently treatable are no longer susceptible to antibiotics. Results from these proposed studies should allow for the preparation of new drugs, when given in combination with currently available antibiotics will be effective in treating antibiotic-resistant bacterial infections. PERFORMANCE SITE ========================================Section End===========================================