Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms12406
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Funding
- Medical Research Council (MRC)/Canadian Grant [G1100135]
- MRC [MR/L007665/1, MC-PC-14103, MR/N002679/1]
- CONACyT, Mexico
- Biotechnology and Biological Sciences Research Council [1360493] Funding Source: researchfish
- Cancer Research UK [16466] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039202/1] Funding Source: researchfish
- Medical Research Council [MR/L007665/1, MR/N002679/1, G1100135] Funding Source: researchfish
- EPSRC [EP/K039202/1] Funding Source: UKRI
- MRC [G1100135, MR/N002679/1, MR/L007665/1] Funding Source: UKRI
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beta-Lactamases enable resistance to almost all beta-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-beta-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent beta-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-beta-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.
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