| 總結: | <p>β-Lactam containing compounds are the most important antibacterials. Following the discovery of the penicillins, successive generations of β-lactams (penicillins, cephalosporins, monobactams, carbapenems) have saved countless lives. Their use is threatened by growing resistance, of which the most important mechanism involves their hydrolysis by β-lactamases. There are two types of β-lactamases: the serine-β-lactamases (SBLs) and the metallo-β- lactamases (MBLs). Whereas SBL inhibitors are available, there are no clinically useful MBL inhibitors. This work covered the development of new types of MBL and SBL inhibitors.</p> <p>One aspect of this work involved the development of new types of MBL inhibitors, in part inspired by structural and high-throughput screening approaches. Extensive chemical synthesis and screening of heteroaryl-carboxylate compounds were performed. Some of these exhibited potent inhibition against a panel of clinically relevant MBLs, including VIM-2. Lactivicin is the only naturally occurring small molecule that acts similarly to β-lactams which does not contain a β-lactam ring. However, very little structural-activity relationship studies have been performed on lactivicin. In my work, the synthesis of a novel lactivicin analogue with a modified lactone ring was achieved.</p> <p>The Class D OXA SBLs are arguably the most worrying of all β-lactamases mediated resistance processes. Studies on OXA SBLs were performed with an array of inhibitors; the results inform on the mechanism of OXA inhibition, including the role of protein carbamylation in catalysis and inhibition.</p> <p>Overall, the results suggest new possibilities for β-lactamase inhibition and should contribute to the effort to combat β-lactamase mediated resistance.</p>
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