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

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.