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I04-Macromolecular Crystallography	Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition Jurgen Brem , Sander S. Van Berkel , Wei Shen Aik , Anna M. Rydzik , Matthew B. Avison , Ilaria Pettinati , Klaus-Daniel Umland , Akane Kawamura , Jim Spencer , Timothy D. W. Claridge , Michael Mcdonough , Christopher J. Schofield Nature Chemistry 6 (12), 1084 - 1090 DOI: 10.1038/nchem.2110 PMID: 25411887 Diamond Proposal Number(s): [8922] Show Abstract ▼ Abstract: The use of beta-lactam antibiotics is compromised by resistance, which is provided by beta-lactamases belonging to both metallo (MBL)- and serine (SBL)-beta-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 beta-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 19F 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.	Nov 2014

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I04-Macromolecular Crystallography

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