Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases

DOI: 10.1016/j.bmc.2018.02.043

Authors: Dong Zhang (University of Oxford) , Marios S. Markoulides (University of Oxford) , Dmitrijs Stepanovs (University of Oxford) , Anna M. Rydzik (University of Oxford) , Ahmed El-Hussein (University of Oxford; The National Institute of Laser Enhanced Science, Cairo University) , Corentin A. M. Bon (University of Oxford) , Jos J. A. G. Kamps (University of Oxford) , Klaus-Daniel Umland (University of Oxford) , Patrick M. Collins (Diamond Light Source) , Samuel T. Cahill (University of Oxford) , David Y. Wang (University of Oxford) , Timothy D. W. Claridge (University of Oxford) , Jurgen Brem (University of Oxford) , Michael Mcdonough (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 9306 , 12346 , 16949

Abstract: Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging ‘hydrolytic’ water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

Journal Keywords: Metallo β-lactamase; Antibiotic resistance; Carbapenemase; Inhibitors; Structure activity relationships

Diamond Keywords: Bacteria

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


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 01/03/2018 15:50

Documents:
1-s2.0-S0968089618301858-main.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)