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

Jürgen Brem, Sander S van Berkel, WeiShen Aik, Anna M Rydzik, Matthew B Avison, Ilaria Pettinati, Klaus-Daniel Umland, Akane Kawamura, Jim Spencer, Timothy D W Claridge, Michael A McDonough, Christopher J Schofield

Research output: Contribution to journalArticle (Academic Journal)peer-review

83 Citations (Scopus)


The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-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-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.

Original languageEnglish
Pages (from-to)1084-90
Number of pages7
JournalNature Chemistry
Issue number12
Early online date17 Nov 2014
Publication statusPublished - Dec 2014


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