In vitro and in vivo activities of novel 6-methylidene penems as β-lactamase inhibitors

William Weiss, Peter J. Petersen, Timothy M. Murphy, Lu Anna Tardio, Youjun Yang, Patricia A. Bradford, Aranapakam M. Venkatesan, Takao Abe, Takeshi Isoda, Ado Mihira, Hideki Ushirogochi, Tsuyoshi Takasake, Steve Projan, John O'Connell, Tarek S. Mansour

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Abstract

Novel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as β-lactamase inhibitors. The concentrations of these molecules that resulted in 50% inhibition of enzyme activity were 0.4 to 3.1 nM for the TEM-1 enzyme, 7.8 to 72 nM for Imi-1, 1.5 to 4.8 nM for AmpC, and 14 to 260 nM for a CcrA metalloenzyme. All the inhibitors were more stable than imipenem against hydrolysis by hog and human dehydropeptidases. Piperacillin was combined with a constant 4-μg/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2- to 32-fold for extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae strains. The MICs for piperacillin-resistant (MIC of piperacillin, >64 μg/ml) strains of Enterobacter spp., Citrobacter spp., and Serratia spp. were reduced to the level of susceptibility (MIC of piperacillin, ≤16 μg/ml) when the drug was combined with 4, 2, or 1 μg of these penem inhibitors/ml. Protection against acute lethal bacterial infections with class A and C β-lactamase- and ESBL-producing organisms in mice was also demonstrated with piperacillin plus inhibitor. Median effective doses were reduced by approximately two- to eightfold compared to those of piperacillin alone when the drug was combined with the various inhibitors at a 4:1 ratio. Pharmacokinetic analysis after intravenous administration of the various inhibitors showed mean residence times of 0.1 to 0.5 h, clearance rates of 15 to 81 ml/min/kg, and volumes of distribution between 0.4 and 2.5 liters/kg. The novel methylidene penem molecules inhibit both class A and class C enzymes and warrant further investigation for potential as therapeutic agents when used in combination with a β-lactam antibiotic.

Original languageEnglish
Pages (from-to)4589-4596
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume48
Issue number12
DOIs
StatePublished - 1 Dec 2004

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Piperacillin
meropenem
Enzymes
Citrobacter
Serratia
Lactams
Enterobacter
Imipenem
Klebsiella pneumoniae
In Vitro Techniques
Bacterial Infections
Pharmaceutical Preparations
Intravenous Administration
Hydrolysis
Pharmacokinetics
Escherichia coli
Anti-Bacterial Agents

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Weiss, W., Petersen, P. J., Murphy, T. M., Tardio, L. A., Yang, Y., Bradford, P. A., ... Mansour, T. S. (2004). In vitro and in vivo activities of novel 6-methylidene penems as β-lactamase inhibitors. Antimicrobial agents and chemotherapy, 48(12), 4589-4596. https://doi.org/10.1128/AAC.48.12.4589-4596.2004
Weiss, William ; Petersen, Peter J. ; Murphy, Timothy M. ; Tardio, Lu Anna ; Yang, Youjun ; Bradford, Patricia A. ; Venkatesan, Aranapakam M. ; Abe, Takao ; Isoda, Takeshi ; Mihira, Ado ; Ushirogochi, Hideki ; Takasake, Tsuyoshi ; Projan, Steve ; O'Connell, John ; Mansour, Tarek S. / In vitro and in vivo activities of novel 6-methylidene penems as β-lactamase inhibitors. In: Antimicrobial agents and chemotherapy. 2004 ; Vol. 48, No. 12. pp. 4589-4596.
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Weiss, W, Petersen, PJ, Murphy, TM, Tardio, LA, Yang, Y, Bradford, PA, Venkatesan, AM, Abe, T, Isoda, T, Mihira, A, Ushirogochi, H, Takasake, T, Projan, S, O'Connell, J & Mansour, TS 2004, 'In vitro and in vivo activities of novel 6-methylidene penems as β-lactamase inhibitors', Antimicrobial agents and chemotherapy, vol. 48, no. 12, pp. 4589-4596. https://doi.org/10.1128/AAC.48.12.4589-4596.2004

In vitro and in vivo activities of novel 6-methylidene penems as β-lactamase inhibitors. / Weiss, William; Petersen, Peter J.; Murphy, Timothy M.; Tardio, Lu Anna; Yang, Youjun; Bradford, Patricia A.; Venkatesan, Aranapakam M.; Abe, Takao; Isoda, Takeshi; Mihira, Ado; Ushirogochi, Hideki; Takasake, Tsuyoshi; Projan, Steve; O'Connell, John; Mansour, Tarek S.

In: Antimicrobial agents and chemotherapy, Vol. 48, No. 12, 01.12.2004, p. 4589-4596.

Research output: Contribution to journalArticle

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AU - Murphy, Timothy M.

AU - Tardio, Lu Anna

AU - Yang, Youjun

AU - Bradford, Patricia A.

AU - Venkatesan, Aranapakam M.

AU - Abe, Takao

AU - Isoda, Takeshi

AU - Mihira, Ado

AU - Ushirogochi, Hideki

AU - Takasake, Tsuyoshi

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