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Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases

DOI: 10.1021/acs.jmedchem.9b00911 DOI Help

Authors: Alen Krajnc (University of Oxford) , Jurgen Brem (University of Oxford) , Philip Hinchliffe (University of Bristol) , Karina Calvopina (University of Bristol) , Tharindi Panduwawala (University of Oxford) , Pauline A. Lang (University of Oxford) , Jos J. A. G. Kamps (University of Oxford) , Jonathan M. Tyrell (Cardiff University) , Emma Widlake (Cardiff University) , Benjamin G. Saward (University of Oxford) , Timothy R. Walsh (Cardiff University) , James Spencer (University of Bristol) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 17212 , 18069

Abstract: The bicyclic boronate VNRX-5133 is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain-dependent binding modes for bicyclic boronates imply scope for optimisation. The results further support the ‘high energy intermediate’ analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron-inhibitors to interchange between different hybridization states / binding modes.

Journal Keywords: Boron; boronic acid; boronate drugs; VNRX-5133; Vaborbactam; β-lactam antibiotics; antibacterials; serine- and metallo-β-lactamase inhibitors; antibiotic resistance; carbapenems; cephalosporins

Subject Areas: Chemistry


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography