What is it about?
The most important resistance mechanism to β-lactam antibiotics involves hydrolysis by two β-lactamase categories: the nucleophilic serine (SBL) and the metallo- (MBL) β-lactamases. 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 19F-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 via 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 13C-labeled cyclobutanone support assignment of the bound species as the hydrated ketone.
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Why is it important?
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 β-lactamase classes.
Perspectives
Writing this article was a great pleasure as it has co-authors with whom I have absolutely enjoyed collaborating. This article also leads to better understanding antimicrobial resistance mechanisms and thus designing new inhibitors/antibiotics.
Martine I Abboud
University of Oxford
Read the Original
This page is a summary of: Cyclobutanone Mimics of Intermediates in Metallo-β-Lactamase Catalysis, Chemistry - A European Journal, December 2017, Wiley,
DOI: 10.1002/chem.201705886.
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