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Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Lookup NU author(s): Professor Akane Kawamura


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© 2014 Macmillan Publishers Limited. All rights reserved.The use of β 2-lactam antibiotics is compromised by resistance, which is provided by β 2-lactamases belonging to both metallo (MBL)- and serine (SBL)-β 2-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in β 2-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including 19 F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.

Publication metadata

Author(s): Brem J, Van Berkel SS, Aik W, Rydzik AM, Avison MB, Pettinati I, Umland K-D, Kawamura A, Spencer J, Claridge TDW, McDonough MA, Schofield CJ

Publication type: Article

Publication status: Published

Journal: Nature Chemistry

Year: 2014

Volume: 6

Issue: 12

Pages: 1084-1090

Online publication date: 17/11/2014

Acceptance date: 08/10/2014

ISSN (print): 1755-4330

ISSN (electronic): 1755-4349

Publisher: Nature Publishing Group


DOI: 10.1038/nchem.2110

PubMed id: 25411887


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