2. Academic Validation
  3. Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

  • J Med Chem. 2019 Sep 26;62(18):8544-8556. doi: 10.1021/acs.jmedchem.9b00911.
Alen Krajnc 1,  Jürgen Brem 1,  Philip Hinchliffe 2,  Karina Calvopiña 1,  Tharindi D Panduwawala 1,  Pauline A Lang 1,  Jos J A G Kamps 1,  Jonathan M Tyrrell 3,  Emma Widlake 3,  Benjamin G Saward 1,  Timothy R Walsh 3,  James Spencer 2,  Christopher J Schofield 1
Affiliations

Affiliations

  • 1 Chemistry Research Laboratory, Department of Chemistry , University of Oxford , 12 Mansfield Road , Oxford OX1 3TA , United Kingdom.
  • 2 School of Cellular and Molecular Medicine, Biomedical Sciences Building, University Walk , University of Bristol , Bristol BS8 1TD , United Kingdom.
  • 3 Department of Medical Microbiology & Infectious Disease , Institute of Infection & Immunity , UHW Main Building, Heath Park , Cardiff CF14 4XN , United Kingdom.
PMID: 31454231 DOI: 10.1021/acs.jmedchem.9b00911
Abstract

The bicyclic boronate VNRX-5133 (taniborbactam) 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 MBL 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 binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. 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.

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