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Michael N Dudley - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of the ultra broad spectrum Beta Lactamase Inhibitor qpx7728 in combination with meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Ruslan Tsivkovski, Michael N Dudley, Dongxu Sun, Maxim Totrov, Olga Lomovskaya
    Abstract:

    QPX7728 is a recently discovered ultra-broad-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 Beta-Lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/Inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

  • in vitro activity of the ultrabroad spectrum Beta Lactamase Inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N Dudley, Dongxu Sun, Olga Lomovskaya
    Abstract:

    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.

  • Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics against Isogenic Strains Expressing Single Be
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Kirk Nelson, Ruslan Tsivkovski, Debora Rubio-aparicio, Dongxu Sun, Maxim Totrov, Michael N Dudley
    Abstract:

    QPX7728 is an ultrabroad-spectrum boronic acid Beta-Lactamase Inhibitor, with potent inhibition of key serine and metallo-Beta-Lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of Beta-Lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-Beta-Lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum Beta-Lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the Beta-Lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C Beta-Lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent Inhibitor of many class B metallo-Beta-Lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete Beta-Lactamase inhibition. The ultrabroad-spectrum Beta-Lactamase inhibition profile makes QPX7728 a viable candidate for further development.

  • 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
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Michael N Dudley
    Abstract:

    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.

  • pharmacokinetics pharmacodynamics of vaborbactam a novel Beta Lactamase Inhibitor in combination with meropenem
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: David C Griffith, Olga Lomovskaya, Mojgan Sabet, Ziad Tarazi, Michael N Dudley
    Abstract:

    Vaborbactam is a novel Beta-Lactamase Inhibitor with activity against important Beta-Lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae . The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae . For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 – 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model.

Olga Lomovskaya - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of the ultra broad spectrum Beta Lactamase Inhibitor qpx7728 in combination with meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Ruslan Tsivkovski, Michael N Dudley, Dongxu Sun, Maxim Totrov, Olga Lomovskaya
    Abstract:

    QPX7728 is a recently discovered ultra-broad-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 Beta-Lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/Inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

  • in vitro activity of the ultrabroad spectrum Beta Lactamase Inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N Dudley, Dongxu Sun, Olga Lomovskaya
    Abstract:

    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.

  • Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics against Isogenic Strains Expressing Single Be
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Kirk Nelson, Ruslan Tsivkovski, Debora Rubio-aparicio, Dongxu Sun, Maxim Totrov, Michael N Dudley
    Abstract:

    QPX7728 is an ultrabroad-spectrum boronic acid Beta-Lactamase Inhibitor, with potent inhibition of key serine and metallo-Beta-Lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of Beta-Lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-Beta-Lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum Beta-Lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the Beta-Lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C Beta-Lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent Inhibitor of many class B metallo-Beta-Lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete Beta-Lactamase inhibition. The ultrabroad-spectrum Beta-Lactamase inhibition profile makes QPX7728 a viable candidate for further development.

  • 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
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Michael N Dudley
    Abstract:

    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.

  • pharmacokinetics pharmacodynamics of vaborbactam a novel Beta Lactamase Inhibitor in combination with meropenem
    Antimicrobial Agents and Chemotherapy, 2018
    Co-Authors: David C Griffith, Olga Lomovskaya, Mojgan Sabet, Ziad Tarazi, Michael N Dudley
    Abstract:

    Vaborbactam is a novel Beta-Lactamase Inhibitor with activity against important Beta-Lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae . The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae . For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 – 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model.

Kirk Nelson - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of the ultra broad spectrum Beta Lactamase Inhibitor qpx7728 in combination with meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Ruslan Tsivkovski, Michael N Dudley, Dongxu Sun, Maxim Totrov, Olga Lomovskaya
    Abstract:

    QPX7728 is a recently discovered ultra-broad-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 Beta-Lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/Inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

  • in vitro activity of the ultrabroad spectrum Beta Lactamase Inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N Dudley, Dongxu Sun, Olga Lomovskaya
    Abstract:

    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.

  • Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics against Isogenic Strains Expressing Single Be
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Kirk Nelson, Ruslan Tsivkovski, Debora Rubio-aparicio, Dongxu Sun, Maxim Totrov, Michael N Dudley
    Abstract:

    QPX7728 is an ultrabroad-spectrum boronic acid Beta-Lactamase Inhibitor, with potent inhibition of key serine and metallo-Beta-Lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of Beta-Lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-Beta-Lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum Beta-Lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the Beta-Lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C Beta-Lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent Inhibitor of many class B metallo-Beta-Lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete Beta-Lactamase inhibition. The ultrabroad-spectrum Beta-Lactamase inhibition profile makes QPX7728 a viable candidate for further development.

  • 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
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Michael N Dudley
    Abstract:

    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.

  • vaborbactam spectrum of Beta Lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, David C Griffith, Michael N Dudley
    Abstract:

    ABSTRACT Vaborbactam (formerly RPX7009) is a new Beta-Lactamase Inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of Beta-Lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with Beta-Lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent Inhibitor of class A carbapenemases, such as KPC, as well as an Inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) Beta-Lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC Beta-Lactamase. Consistent with broad-spectrum Beta-Lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum Beta-Lactamase production, class C Beta-Lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 μg/ml results in meropenem MICs of ≤2 μg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active Beta-Lactamase Inhibitor that restores the activity of meropenem and other Beta-lactam antibiotics in Beta-Lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae.

Debora Rubioaparicio - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of the ultra broad spectrum Beta Lactamase Inhibitor qpx7728 in combination with meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Ruslan Tsivkovski, Michael N Dudley, Dongxu Sun, Maxim Totrov, Olga Lomovskaya
    Abstract:

    QPX7728 is a recently discovered ultra-broad-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 Beta-Lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/Inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

  • in vitro activity of the ultrabroad spectrum Beta Lactamase Inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N Dudley, Dongxu Sun, Olga Lomovskaya
    Abstract:

    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.

  • 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
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Michael N Dudley
    Abstract:

    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.

  • vaborbactam spectrum of Beta Lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, David C Griffith, Michael N Dudley
    Abstract:

    ABSTRACT Vaborbactam (formerly RPX7009) is a new Beta-Lactamase Inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of Beta-Lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with Beta-Lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent Inhibitor of class A carbapenemases, such as KPC, as well as an Inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) Beta-Lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC Beta-Lactamase. Consistent with broad-spectrum Beta-Lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum Beta-Lactamase production, class C Beta-Lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 μg/ml results in meropenem MICs of ≤2 μg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active Beta-Lactamase Inhibitor that restores the activity of meropenem and other Beta-lactam antibiotics in Beta-Lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae.

Ruslan Tsivkovski - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of the ultra broad spectrum Beta Lactamase Inhibitor qpx7728 in combination with meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Kirk Nelson, Debora Rubioaparicio, Ruslan Tsivkovski, Michael N Dudley, Dongxu Sun, Maxim Totrov, Olga Lomovskaya
    Abstract:

    QPX7728 is a recently discovered ultra-broad-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 Beta-Lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/Inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

  • Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics against Isogenic Strains Expressing Single Be
    Antimicrobial agents and chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Kirk Nelson, Ruslan Tsivkovski, Debora Rubio-aparicio, Dongxu Sun, Maxim Totrov, Michael N Dudley
    Abstract:

    QPX7728 is an ultrabroad-spectrum boronic acid Beta-Lactamase Inhibitor, with potent inhibition of key serine and metallo-Beta-Lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of Beta-Lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-Beta-Lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum Beta-Lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the Beta-Lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C Beta-Lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent Inhibitor of many class B metallo-Beta-Lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete Beta-Lactamase inhibition. The ultrabroad-spectrum Beta-Lactamase inhibition profile makes QPX7728 a viable candidate for further development.

  • 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
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Michael N Dudley
    Abstract:

    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.

  • vaborbactam spectrum of Beta Lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Olga Lomovskaya, Debora Rubioaparicio, Kirk Nelson, Ruslan Tsivkovski, David C Griffith, Michael N Dudley
    Abstract:

    ABSTRACT Vaborbactam (formerly RPX7009) is a new Beta-Lactamase Inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of Beta-Lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with Beta-Lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent Inhibitor of class A carbapenemases, such as KPC, as well as an Inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) Beta-Lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC Beta-Lactamase. Consistent with broad-spectrum Beta-Lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum Beta-Lactamase production, class C Beta-Lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 μg/ml results in meropenem MICs of ≤2 μg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active Beta-Lactamase Inhibitor that restores the activity of meropenem and other Beta-lactam antibiotics in Beta-Lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae.