期刊
CURRENT OPINION IN CHEMICAL BIOLOGY
卷 50, 期 -, 页码 101-110出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.cbpa.2019.03.001
关键词
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资金
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Biotechnology and Biological Research Council [BB/S50676X/1]
- National PhD Training Programme in Antimicrobial Resistance Research by the Medical Research Foundation [MRF-145-0004-TPG-AVISO]
- Innovative Medicines Initiative (European Lead factory)
- Innovative Medicines Initiative (ENABLE components)
The beta-lecterns remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by beta-lactamases. Although beta-lactam and non-p-lactam inhibitors forming stable acyl-enzyme complexes with nucleophilic serine beta-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-beta-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its beta-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to 'morph' between sp(2) and sp(3) hybridisation states may help enable potent inhibition. There is limited structure-activity relationship information on the (bi)cyclic boronate inhibitors compared to beta-lecterns, hence scope for creativity towards new boron-based beta-lactamase inhibitors/antibacterials.
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