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

DOI: 10.1038/nchem.2110
PMID: 25411887

Authors: Jurgen Brem (University of Oxford) , Sander S. Van Berkel (University of Oxford) , Wei Shen Aik (University of Oxford) , Anna M. Rydzik (University of Oxford) , Matthew B. Avison (University of Bristol) , Ilaria Pettinati (University of Oxford) , Klaus-Daniel Umland (University of Oxford) , Akane Kawamura (University of Oxford) , Jim Spencer (University of Bristol) , Timothy D. W. Claridge (University of Oxford) , Michael Mcdonough (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemistry , VOL 6 (12) , PAGES 1084 - 1090

State: Published (Approved)
Published: November 2014
Diamond Proposal Number(s): 8922

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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 01/04/2015 09:25

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)