The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

Papp-Wallace, Krisztina M.

doi:10.1080/14656566.2019.1660772

Cited by 100 publications

(96 citation statements)

References 132 publications

(149 reference statements)

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“…The potency of QPX7728 was expressed as PVmax, minimal potentiating concentration of the BLI to reduce antibiotic MIC to the level seen in the parent strain that lacks KPC (corresponding to complete inhibition of KPC). 1 All strains produce KPC-2 encoded in recombinant plasmid pUCP24-KPC-2 2 oprD mutant PAM4756 (oprD::fs_aa126) was selected from PAM4135 on 128 µg/ml of biapenem (4XMIC) 3 Meropenem/QPX7728 checkerboard plates contained PMBN at a fixed concentration of 2.5 µg/ml and 5 µg/ml Cefepime and meropenem MIC in the presence of BLIs at PVmax are marked with green color. 1 All strains produce KPC-2 encoded in recombinant plasmid pUCP24-KPC-2.…”

Section: Discussionmentioning

confidence: 99%

“…2 Specific efflux pump overexpressed due to mutations in respective regulators are shown in brackets 3 Mutation in mexT also results in a partial downregulation of the carbapenem specific porin oprD 4 GM-MIC, a geometric mean of the antibiotic MIC values for the beta-lactamase-producing and the vector only strain (calculated as the square root of the product of the antibiotic MIC values for the beta-lactamase-producing and the vector only strain). 5 PV50, a concentration of a BLI to achieve 50% of antibiotic potentiation effect or a concentration of a BLI to reduce antibiotic MIC to or below the middle point of the MIC range between the MIC of the beta-lactamase producing strain and the MIC of the vector only strain.…”

Section: Tablesmentioning

confidence: 99%

“…QPX7728 differs from investigational beta-lactamase inhibitors in clinical development such as the avibactam analog durlobactam and the bicyclic boronate taniborbactam (3). Durlobactam spectrum includes OXA enzymes from Acinetobacter and its potency to inhibit these enzymes appears to be similar to that of QPX7728 (based on Kd values) but it does not inhibit Class B metallo beta-lactamases (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…PVmax, minimal potentiating concentration of the BLI to reduce meropenem MIC to the level seen in the parent strain that lacks KPC, which corresponds to complete inhibition of KPC 3. QPX, QPX7728 and VAB, vaborbactam at 4 µg/ml4 Duplication of two amino acids, Gly134 and Asp135, located within the L3 internal loop and associated with the reduced susceptibility to carbapenems due to constriction of the channel ompK35_fs and ompK36_fs, truncated porins due to the frame-shift mutation; ramR*, truncated ramR due to the stop codon; FL, full length; NF, non-functional; BL, basal level; Up, overexpressed; down, downregulated.on September 8, 2020 by guest http://aac.asm.org/ Downloaded from…”

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confidence: 99%

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Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

Lomovskaya

Nelson

Rubio-Aparicio

et al. 2020

Antimicrob Agents Chemother

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QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impacts of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3-producing isogenic strains of Klebsiella pneumoniae and Pseudomonas aeruginosa and OXA-23-producing strains of Acinetobacter baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multidrug resistance efflux pumps either in Enterobacteriaceae or in nonfermenters, such as P. aeruginosa or A. baumannii. Against P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane was permeabilized. The potency of QPX7728 against P. aeruginosa was not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8- to 16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed the KPC-mediated meropenem resistance in strains with porin mutations, consistent with the lesser effect of these mutations on the potency of QPX7728 compared to that of other agents. The ultrabroad-spectrum beta-lactamase inhibition profile, combined with enhancement of the activity of multiple beta-lactam antibiotics with various sensitivities to the intrinsic resistance mechanisms of efflux and permeability, indicates that QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

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Section: Discussionmentioning

confidence: 99%

Section: Tablesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

Lomovskaya

Nelson

Rubio-Aparicio

et al. 2020

Antimicrob Agents Chemother

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“…Three newer BLIs that are now in clinical use, avibactam (approved by the FDA in in combination with ceftazidime), vaborbactam (approved by the FDA in 2017 in combination with meropenem) and relebactam (approved by the FDA in 2019 in combination with imipenem), are all derived from non-beta-lactam scaffolds (Figure 1) (11). Avibactam and relebactam are diazabicyclooctane derivatives (DBOs) while vaborbactam is based on a cyclic boronic acid pharmacophore (12).…”

Section: Downloaded Frommentioning

confidence: 99%

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

Tsivkovski

Totrov

Lomovskaya

2020

Antimicrob Agents Chemother

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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 k2/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 Kis 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.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

Cited by 100 publications

References 132 publications

Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

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

Medicinal Chemistry of β‐Lactam Antibiotics

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