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.
Highlights
The minimal inhibitory concentration (MIC) values of cefepime/meropenem were significantly reduced in the presence of VNRX-5133 compared to those in its absence (MIC > 64 μg mL−1). Both cefepime/VNRX-5133 and meropenem/VNRX-5133 combinations were highly active against all six of the NDM-1producing clinical isolates tested, with MIC ranges of 16−0.25 and 1−0.125 μg mL−1, respectively. These results reveal the potential of VNRX-5133 to act against clinically relevant MBLs (i.e., NDM-1) in bacteria, consistent with the results from clinical trials with VNRX-5133.44,45
The coverage of clinically relevant MBLs by VNRX-5133, is imperfect, with significantly lower or no inhibition being observed for clinically relevant IMP-1, L1, or OXA-48 (Table 1)
It is possible that bicyclic boronates can bind to SBLs and MBLs in their sp[2] hybridization state, which mimics that of the βlactam.[23]
Summary
We synthesized VNRX-5133 and tested it for inhibition against a panel of SBLs and MBLs. The results support the potential of bicyclic boronates for broadspectrum β-lactamase inhibition. Variation in the pre-incubation times of VNRX-5133 with subclass B1 MBL NDM-1 did not result in different IC50 values (Supporting Information Table S2 and Figure S33), supporting the case for the reversible inhibition by VNRX-5133, as observed for related bicyclic boronate inhibitors.[29,40]
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