z-logo
open-access-imgOpen Access
Biochemical Activity of Vaborbactam
Author(s) -
Ruslan Tsivkovski,
Olga Lomovskaya
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01935-19
Subject(s) - antibiotics , lactam , bacteria , enzyme , microbiology and biotechnology , gram negative bacteria , chemistry , potency , biology , pharmacology , biochemistry , in vitro , escherichia coli , stereochemistry , genetics , gene
The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring. Inhibition of β-lactamase activity with small-molecule drugs is a proven strategy to restore the potency of many β-lactam antibiotics. Vaborbactam (formerly RPX7009) is a cyclic boronic acid β-lactamase inhibitor (BLI) with a broad spectrum of activity against various serine β-lactamases, including KPC carbapenemases. The combination of vaborbactam and meropenem is approved in the United States and Europe for the treatment of various nosocomial infections. We attempted to gain more insight into the mechanism of action of vaborbactam by conducting detailed kinetic characterization of its interaction with various recombinant His-tagged β-lactamases. Vaborbactam demonstrated potent inhibition of class A and class C enzymes with K i values ranging from 0.022 to 0.18 μM, while inhibition of class D enzymes was rather poor, and no activity against class B β-lactamases was detected. Importantly, vaborbactam inhibited KPC-2, KPC-3, BKC-1, and SME-2 carbapenemases at 1:1 stoichiometry, while these numbers were higher for other class A and C enzymes. Vaborbactam was also shown to be a potent progressive inactivator of several enzymes, including KPCs with inactivation constants k 2 / K in the range of 3.4 × 10 3 to 2.4 × 10 4 M -1 s -1 Finally, experiments on the recovery of enzyme activity demonstrated the high stability of the vaborbactam-KPC complex, with 0.000040 s -1 k off values and a corresponding residence time of 7 h, whereas the release of vaborbactam bound to other serine β-lactamases was substantially faster. The biochemical characteristics of vaborbactam described in this study may facilitate further chemical optimization efforts to develop boronic BLIs with improved affinity and broader spectrum of inhibition.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here