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Biochemical Activity of Vaborbactam

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...

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Autores principales: Tsivkovski, Ruslan, Lomovskaya, Olga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985712/
https://www.ncbi.nlm.nih.gov/pubmed/31712199
http://dx.doi.org/10.1128/AAC.01935-19
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author Tsivkovski, Ruslan
Lomovskaya, Olga
author_facet Tsivkovski, Ruslan
Lomovskaya, Olga
author_sort Tsivkovski, Ruslan
collection PubMed
description 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.
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spelling pubmed-69857122020-02-11 Biochemical Activity of Vaborbactam Tsivkovski, Ruslan Lomovskaya, Olga Antimicrob Agents Chemother Mechanisms of Action: Physiological Effects 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. American Society for Microbiology 2020-01-27 /pmc/articles/PMC6985712/ /pubmed/31712199 http://dx.doi.org/10.1128/AAC.01935-19 Text en Copyright © 2020 Tsivkovski and Lomovskaya. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Mechanisms of Action: Physiological Effects
Tsivkovski, Ruslan
Lomovskaya, Olga
Biochemical Activity of Vaborbactam
title Biochemical Activity of Vaborbactam
title_full Biochemical Activity of Vaborbactam
title_fullStr Biochemical Activity of Vaborbactam
title_full_unstemmed Biochemical Activity of Vaborbactam
title_short Biochemical Activity of Vaborbactam
title_sort biochemical activity of vaborbactam
topic Mechanisms of Action: Physiological Effects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985712/
https://www.ncbi.nlm.nih.gov/pubmed/31712199
http://dx.doi.org/10.1128/AAC.01935-19
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