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Publication Abstract from PubMed

The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of beta-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-beta-lactamases (SBLs) and some clinically important metallo-beta-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 (sp(3)) 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 beta-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.

Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-beta-Lactamases.,Krajnc A, Brem J, Hinchliffe P, Calvopina K, Panduwawala TD, Lang PA, Kamps JJAG, Tyrrell JM, Widlake E, Saward BG, Walsh TR, Spencer J, Schofield CJ J Med Chem. 2019 Sep 26;62(18):8544-8556. doi: 10.1021/acs.jmedchem.9b00911. Epub, 2019 Sep 16. PMID:31454231^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.