Studies of novel antibacterial agents and antibiotic resistance breakers towards combating multidrug resistant bacteria

Thesis

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.

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.

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.

Overall, the results suggest new possibilities for β-lactamase inhibition and should contribute to the effort to combat β-lactamase mediated resistance.

Authors: Wang, Y

• DOI: 10.5287/ora-qmgdewnjo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford