Resistance of pathogenic organisms toward beta-lactam antibiotics is a major international health problem. In most cases the reason for the resistance is the presence of beta-lactamases, produced by the infectious agent, which destroy the antibiotic properties of the beta-lactam. This research is directed toward an understanding of the mechanisms of catalysis and inhibition of beta-lactamases, with a long-term view of mechanism-based drug design. There are four components to the proposal: (1) investigations of the catalytic mechanism, including site-specific mutagenesis to confirm the identity of a postulated active-site residue, and isolation and characterization of intermediates trapped at low temperatures, (2) investigations of the mechanisms of reversible and irreversible inhibition, including those of suicide substrates, in particular structural characterization of the inactive forms of the enzyme, (3) comparison of reversible inhibition of Beta-lactamase with Beta-lactam antibiotic inhibition of cell-wall carboxypeptidase, to determine whether an analogous mechanism is operating, and (4) the design of active-site directed modifying reagents.
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