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.
The β-lactams remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by β-lactamases. Although β-lactam and non-β-lactam inhibitors forming stable acyl–enzyme complexes with nucleophilic serine β-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-β-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its β-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme–inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to ‘morph’ between sp
2
and sp
3
hybridisation states may help enable potent inhibition. There is limited structure–activity relationship information on the (bi)cyclic boronate inhibitors compared to β-lactams, hence scope for creativity towards new boron-based β-lactamase inhibitors/antibacterials.
he increase in antibiotic resistance raises concerns that, at least in some regions, we are returning to a pre-antibiotic era, in particular for Gram-negative infections. The increased prevalence of extended-spectrum serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs) means β-lactams are increasingly ineffective in treating Gram-negative infections 1,2 . The advent of mobilized colistin resistance-1 in 2015 3 and transferable tigecycline resistance genes (tetX3-tetX5) in 2019 4 , which mediate resistance to colistin and tigecycline, respectively, means all clinically vital antibiotics for serious Gram-negative infections are compromised.
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