期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 24, 期 22, 页码 5734-5737出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201705886
关键词
antimicrobial resistance; beta-lactam analogues; beta-lactamases; cyclobutanones; transition state analogues
资金
- Diamond Light Source
- MRC [G1100135]
- SWON alliance
- Wellcome Trust
- Canadian Institute of Health Research [FRN114046, FRN106532]
- Sir Hans Krebs Memorial Award
- National Institute of Allergy and Infectious Diseases (NIH) [R01AI100560]
- Medical Research Council [MR/L007665/1, G1100135, MC_PC_14103] Funding Source: researchfish
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI100560] Funding Source: NIH RePORTER
- MRC [MR/L007665/1, MC_PC_14103] Funding Source: UKRI
The most important resistance mechanism to beta-lactam antibiotics involves hydrolysis by two beta-lactamase categories: the nucleophilic serine and the metallo-beta-lactamases (SBLs and MBLs, respectively). Cyclobutanones are hydrolytically stable beta-lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM-1. NMR experiments using F-19-labeled SPM-1 imply the cyclobutanone binds to SPM-1 with micromolar affinity. A crystal structure of the SPM-1:cyclobutanone complex reveals binding of the hydrated cyclobutanone through interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc-bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a C-13-labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition-state and/or intermediate analogues as inhibitors of all beta-lactamase classes.
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