Mettalloenzyme Structure/Function

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The long-term goal of this research is to understand, at the molecular level, the catalytic mechanism and inhibition of beta-lactamases and through this understanding facilitate the development of small-molecule therapeutics. Bacterial resistance to beta-lactam antibiotics has emerged over the past decade as a major health concern. Beta-lactam antibiotics kill bacteria by preventing the complete synthesis of the bacterial cell wall leading to a defective cell wall, which ruptures under the high internal pressure of the cell. Bacteria have developed antibiotic- resistance strategies in three major ways: production of hydrolytic enzymes known as beta-lactamases, changes in the permeability of the cell membrane, and alterations of the target enzymes. Among these mechanisms, beta-lactamase production, relentlessly fueled by natural selection, is generally considered as the primary route of resistance to beta-lactam antibiotics. Significantly, these enzymes can be chromosome or plasmid encoded and are secreted into the periplasmic space of Gram- negative bacteria or into the outer medium by Gram-positive bacteria, which facilitates the spread of beta-lactam resistance. The emerg3ence of anti-beta-lactam activity also has a tremendous social and financial impact because of the continuous need to discover novel antibiotics. The tools that will be used to reach the long-term goal are those of theoretical chemistry, medicinal chemistry and biochemistry. The primary enzymes that will be studied are the beta-lactamases from B. cereus and B. Fragilis. With the aid of these tools the nature and energetics of beta-lactamase-substrate interactions, beta-lactamase- inhibitor interactions and reactions catalyzed by these beta-lactamases will be examined. The insights obtained into these processes will have a major impact on human health by facilitating the design of new drugs that will eliminate at least one bacterial mechanism for anti-beta-lactam activity, which will in turn increase the lifetime of existing antibiotics.