Cyclobutanone Mimics of Intermediates in Metallo-β-Lactamase Catalysis.

ABSTRACT: The most important resistance mechanism to β-lactam antibiotics involves hydrolysis by two β-lactamase categories: the nucleophilic serine and the metallo-β-lactamases (SBLs and MBLs, respectively). Cyclobutanones are hydrolytically stable β-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 ¹⁹ F-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

SUBMITTER: Abboud MI 

PROVIDER: S-EPMC5947706 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature