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

Journal article

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.

Authors: Krajnc, A; Brem, J; Hinchliffe, P; Calvopiña, K; Panduwawala, TD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 62
• Issue: 18
• Pages: 8544-8556
• Publication date: 2019-08-27
• Acceptance date: 2019-08-27
• DOI: 10.1021/acs.jmedchem.9b00911
• EISSN: 1520-4804
• ISSN: 0022-2623
• Pmid: 31454231
• Language: English
• Keywords: FFR