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Cyclobutanone Mimics of Intermediates in Metallo-β-Lactamase Catalysis

DOI: 10.1002/chem.201705886 DOI Help

Authors: Martine I. Abboud (University of Oxford) , Magda Kosmopoulou (University of Bristol) , Anthony Krismanich (University of Waterloo) , Jarrod W. Johnson (University of Waterloo) , Philip Hinchliffe (University of Bristol) , Jurgen Brem (University of Oxford) , Timothy D. W. Claridge (University of Oxford) , James Spencer (University of Bristol) , Christopher J. Schofield (University of Oxford) , Gary I. Dmitrienko (University of Waterloo)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry - A European Journal

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 313

Abstract: 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. 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.

Journal Keywords: β-lactamases; antimicrobial resistance; Transition State Analogues; cyclobutanones; β-lactam analogues

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 08/01/2018 15:38

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