Bacterial resistance to beta-lactam antibiotics continues to become more prevalent and more clinically important. It is likely, however, that a large part of the resistance can be understood and investigated experimentally in terms of the chemistry of the interactions of beta- lactamases on one hand, which catalyse the hydrolysis of the antibodies, and the D-alanyl-D-alanine transpeptidase/-carboxypeptidases on the other, which catalyse the synthesis and maintenance of the peptide cross-links of bacterial cell walls, and which are inhibited by beta-lactam antibiotics. There is now good reason to believe that all of these beta-lactam binding sites have much in common. An understanding of the structure and function of these sites and of the relationship between them is fundamental to future antibiotics design -- both beta-lactam and otherwise. The object of the proposed research is to explore further the chemical functionality and the substrate binding properties of a series of these active sites, using a number of modified substrates, novel inhibitors, and potential effectors. In particular, a novel series of acyclic substrates and derived inhibitors will be employed. A mechanistic study of these sites, designed to determine the role of the functional groups present and the relationship between the mechanism of action of these enzymes and that of other more closely studied enzymes, e.g. serine proteinases, will also be commenced. These studies should lead to a more useful picture of beta-lactamase active sites, to a better idea as to their relationship to D-alanyl-D-alanine transpeptidase sites, and thus to new directions or antibiotic development.
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