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Cyclobutanone Mimics of Intermediates in Metallo‐β‐Lactamase Catalysis
Author(s) -
Abboud Martine I.,
Kosmopoulou Magda,
Krismanich Anthony P.,
Johnson Jarrod W.,
Hinchliffe Philip,
Brem Jürgen,
Claridge Timothy D. W.,
Spencer James,
Schofield Christopher J.,
Dmitrienko Gary I.
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201705886
Subject(s) - chemistry , cyclobutanone , hydrolase , stereochemistry , hydrogen bond , hydrate , nucleophile , crystal structure , hydrolysis , combinatorial chemistry , catalysis , molecule , crystallography , enzyme , organic chemistry , ring (chemistry)
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 contacts with aromatic residues. NMR analyses using a 13 C‐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.