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Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition
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Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition
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Journal Article
Rhodanine hydrolysis leads to potent thioenolate mediated metallo-beta-lactamase inhibition
2014
Overview
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 (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.
Publisher
Nature Publishing Group
Subject
