Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-β-lactamase inhibition

Guo-Bo Li; Jürgen Brem; Robert Lesniak; Martine I. Abboud; Christopher T. Lohans; Ian J. Clifton; Sheng-Yong Yang; Juan-Carlos Jiménez-Castellanos; Matthew B. Avison; James Spencer; Michael A. McDonough; Christopher J. Schofield

doi:10.1039/C7CC02394D

Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-β-lactamase inhibition†

Guo-Bo Li,^ab Jürgen Brem,*^a Robert Lesniak,^a Martine I. Abboud,

^a Christopher T. Lohans,^a Ian J. Clifton,

^a Sheng-Yong Yang,^b Juan-Carlos Jiménez-Castellanos,^c Matthew B. Avison,^c James Spencer,^c Michael A. McDonough

^a and Christopher J. Schofield

*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, UK
E-mail: christopher.schofield@chem.ox.ac.uk, jurgen.brem@chem.ox.ac.uk

^b Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China

^c School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, UK

Abstract

Crystallographic analyses of the VIM-5 metallo-β-lactamase (MBL) with isoquinoline inhibitors reveal non zinc ion binding modes. Comparison with other MBL–inhibitor structures directed addition of a zinc-binding thiol enabling identification of potent B1 MBL inhibitors. The inhibitors potentiate meropenem activity against clinical isolates harboring MBLs.

Chemical Communications

Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-β-lactamase inhibition†

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Crystallographic analyses of isoquinoline complexes reveal a new mode of metallo-β-lactamase inhibition

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