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

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.