Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 3, Pages 1255-1260Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01728
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Funding
- Medical Research Council (MRC)/Canadian Grant [G1100135]
- Wellcome Trust
- Biotechnology and Biological Research Council (BBSRC)
- Cancer Research UK (CR-UK) through Cancer Research UK Oxford Centre [C5255/A18085]
- EPSRC [EP/K039202/1] Funding Source: UKRI
- MRC [MR/P007503/1, G1100135, MR/N002679/1, MC_PC_16092, MR/L007665/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1360493, 1231970] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039202/1] Funding Source: researchfish
- Medical Research Council [MC_PC_16092, G1100135, MR/P007503/1, MR/N002679/1, MR/L007665/1] Funding Source: researchfish
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Zinc ion-dependent beta-lactamases (MBLs) catalyze the hydrolysis of almost all beta-lactam antibiotics and resist the action of clinically available beta-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-beta-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.
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