Dataset Information

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

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 target residence time ranging from minutes to several hours: 5 to 20 min for OXA carbapenemases from A. baumannii, ?50 min for OXA-48, and 2 to 3 h for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at a 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on-fast-off kinetics, with Ki s of 7.5?±?2.1?nM, 32?±?14?nM, and 240?±?30?nM for VIM-1, NDM-1, and IMP-1, respectively. QPX7728's ultrabroad spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

SUBMITTER: Tsivkovski R

PROVIDER: S-EPMC7269513 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Tsivkovski Ruslan R Totrov Maxim M Lomovskaya Olga O

Antimicrobial agents and chemotherapy 20200521 6

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 [IC<sub>50</sub>] range, 1 to 3 nM) and carbapenemases such as KPC (IC<sub>50</sub>, 2.9 ± 0.4 nM) as well as class ...[more]

PMID: 32152086

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Project description:QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of meropenem against CRE, with the meropenem MIC90 decreasing from >64 μg/ml to 0.5 μg/ml for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of meropenem against CRE with multiple resistance mechanisms; the reduction in the meropenem MIC90 with QPX7728 (8 μg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, meropenem with QPX7728 was the most potent beta-lactam-BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of meropenem with QPX7728 at 8 μg/ml or lower. The combination of QPX7728 with meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.

Dataset Information

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

Publications

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

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