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Patricia D. Williams - One of the best experts on this subject based on the ideXlab platform.
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correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics biapenem imipenem cilastatin and meropenem
Toxicology Letters, 1995Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. WilliamsAbstract:The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the Carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the Carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.
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Correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics, biapenem, imipenem/cilastatin and meropenem.
Toxicology letters, 1995Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. WilliamsAbstract:The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the Carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the Carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.
Gregory Bokinsky - One of the best experts on this subject based on the ideXlab platform.
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Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli
Nature Chemical Biology, 2018Co-Authors: Helena Shomar, Sophie Gontier, Héctor Tejeda Mora, Marek J. Noga, Peter-leon Hagedoorn, Niels J F Van Den Broek, Gregory BokinskyAbstract:Efficient production of a simple carbapenem antibiotic in Escherichia coli is achieved by a combination of feedback-resistant enzymes for increased precursor biosynthesis and inhibition of fatty acid synthesis for tolerance toward the toxic product. Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural Carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli . By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring Carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.
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Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli
Nature Chemical Biology, 2018Co-Authors: Helena Shomar, Sophie Gontier, Marek J. Noga, Peter-leon Hagedoorn, Niels J. F. Van Den Broek, Héctor Tejeda Mora, Gregory BokinskyAbstract:Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural Carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring Carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.
Ivana P. Day - One of the best experts on this subject based on the ideXlab platform.
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correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics biapenem imipenem cilastatin and meropenem
Toxicology Letters, 1995Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. WilliamsAbstract:The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the Carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the Carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.
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Correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics, biapenem, imipenem/cilastatin and meropenem.
Toxicology letters, 1995Co-Authors: Ivana P. Day, Joy Goudie, Katsutuki Nishiki, Patricia D. WilliamsAbstract:The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the Carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the Carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.
Mitchell J Schwaber - One of the best experts on this subject based on the ideXlab platform.
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the effects of group 1 versus group 2 Carbapenems on imipenem resistant pseudomonas aeruginosa an ecological study
Diagnostic Microbiology and Infectious Disease, 2011Co-Authors: Yehuda Carmeli, Shiri Klarfeld Lidji, Esther Shabtai, Shiri Navonvenezia, Mitchell J SchwaberAbstract:Use of the group 2 Carbapenems, imipenem and meropenem, may lead to emergence of Pseudomonas aeruginosa resistance. The group 1 carbapenem ertapenem has limited activity against P. aeruginosa and is not associated with imipenem-resistant P. aeruginosa (IMP-R PA) in vitro. This retrospective, group-level, longitudinal study collected patient, antibiotic use, and resistance data from 2001 to 2005 using a hospital database containing information on 9 medical wards. A longitudinal data time series analysis was done to evaluate the association between carbapenem use (defined daily doses, or DDDs) and IMP-R PA. A total of 139 185 patient admissions were included, with 541 150 antibiotics DDDs prescribed: 4637 DDDs of group 2 Carbapenems and 2130 DDDs of ertapenem. A total of 779 IMP-R PA were isolated (5.6 cases/1000 admissions). Univariate analysis found a higher incidence of IMP-R PA with group 2 Carbapenems (P < 0.001), aminoglycosides (P = 0.034), and penicillins (P = 0.05), but not with ertapenem. Multivariate analysis showed a yearly increase in incidence of IMP-R-PA (3.8%, P < 0.001). Group 2 carbapenem use was highly associated with IMP-R PA, with a 20% increase in incidence (P = 0.0014) for each 100 DDDs. Group 2 carbapenem use tended to be associated with an increased proportion of IMP-R PA (P = 0.0625) in multivariate analysis. Ertapenem was not associated with IMP-R PA. These data would support preferentially prescribing ertapenem rather than group 2 Carbapenems where clinically appropriate.
Helena Shomar - One of the best experts on this subject based on the ideXlab platform.
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Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli
Nature Chemical Biology, 2018Co-Authors: Helena Shomar, Sophie Gontier, Héctor Tejeda Mora, Marek J. Noga, Peter-leon Hagedoorn, Niels J F Van Den Broek, Gregory BokinskyAbstract:Efficient production of a simple carbapenem antibiotic in Escherichia coli is achieved by a combination of feedback-resistant enzymes for increased precursor biosynthesis and inhibition of fatty acid synthesis for tolerance toward the toxic product. Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural Carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli . By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring Carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.
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Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli
Nature Chemical Biology, 2018Co-Authors: Helena Shomar, Sophie Gontier, Marek J. Noga, Peter-leon Hagedoorn, Niels J. F. Van Den Broek, Héctor Tejeda Mora, Gregory BokinskyAbstract:Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural Carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring Carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.