Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases.

Antimicrobial Agents and Chemotherapy
Ruslan TsivkovskiOlga Lomovskaya

Abstract

QPX7728 is a new ultrabroad-spectrum inhibitor of serine and metallo-beta-lactamases (MBLs) from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A extended-spectrum beta-lactamases (ESBLs) (50% inhibitory concentration [IC50] range, 1 to 3 nM) and carbapenemases such as KPC (IC50, 2.9 ± 0.4 nM) as well as class C P99 (IC50 of 22 ± 8 nM) with a potency that is comparable to or higher than recently FDA-approved beta-lactamase inhibitors (BLIs) avibactam, relebactam, and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/58, IC50 range, 1 to 2 nM) as well as MBLs such as NDM-1 (IC50, 55 ± 25 nM), VIM-1 (IC50, 14 ± 4 nM), and IMP-1 (IC50, 610 ± 70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high-efficiency k 2/K ranging from 6.3 × 104 (for P99) to 9.9 × 105 M-1 s-1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with t...Continue Reading

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Citations

Jun 7, 2020·Biomolecules·Antonella R PalaciosAlejandro J Vila
Jul 22, 2020·Antimicrobial Agents and Chemotherapy·Sara E BoydWilliam W Hope
Mar 28, 2020·International Journal of Environmental Research and Public Health·Yanling WangJianfeng Wang
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Jun 20, 2020·Expert Opinion on Pharmacotherapy·Martina SpazianteMario Venditti
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Dec 10, 2020·International Journal of Molecular Sciences·Juan C Vázquez-UchaAlejandro Beceiro
Mar 24, 2021·Antimicrobial Agents and Chemotherapy·Viivi H A HirvonenMarc W van der Kamp
May 26, 2021·Expert Review of Anti-infective Therapy·Ilias KaraiskosHelen Giamarellou
Jul 12, 2021·The Lancet Infectious Diseases·Maria F MojicaRobert A Bonomo
Aug 15, 2021·European Journal of Medicinal Chemistry·Kalyan C Nagulapalli VenkataSiddharth K Tripathi
Mar 10, 2020·Journal of Medicinal Chemistry·Scott J HeckerMichael N Dudley

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Methods Mentioned

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GraphPad
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