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-lactam antibiotics with the active sites of two groups of bacterial enzymes, the Beta-lactamases on one hand, which catalyse the hydrolysis of the antibiotics, and the D-alanyl-D-alanine transpeptidase/carbgoxypeptidases on the other, which catalyze 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 reasons to believe that all of the Beta-lactam binding sites have much in common. An understanding of the structure and function of the sites and of the relationship between them is fundamental to future antibiotic design -- both Beta-lactam and otherwise. The object of the proposed research is to explore further the chemical functionality and conformational adaptability of a series of the active sites, using a number of modified substrates, novel inhibitors, and potential effectors. These studies should lead to a more useful picture of Beta-lactamase active sites, a better idea as to their relationship to D-alanyl-D-alanine transpeptidase sites, and thus to new directions of antibiotic development.
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