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Antimicrobial Agents and Chemotherapy, December 2004, p. 4589-4596, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4589-4596.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of Novel 6-Methylidene Penems as ß-Lactamase Inhibitors

William J. Weiss,1,{dagger} Peter J. Petersen,1* Timothy M. Murphy,1 LuAnna Tardio,1 Youjun Yang,1 Patricia A. Bradford,1 Aranapakam M. Venkatesan,2 Takao Abe,3 Takeshi Isoda,3 Ado Mihira,3 Hideki Ushirogochi,3 Tsuyoshi Takasake,3 Steve Projan,4 John O'Connell,1 and Tarek S. Mansour2

Infectious Disease and Oncology,1 Chemical and Screening Sciences, Wyeth Research, Pearl River, New York,2 Wyeth-Lederle Japan, Saitama, Japan,3 Protein Technologies, Wyeth Research, Cambridge, Massachusetts4

Received 10 March 2004/ Returned for modification 31 May 2004/ Accepted 29 August 2004

Novel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as ß-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 ß-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 ß-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 ß-lactam antibiotic.

* Corresponding author. Mailing address: 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-3070. Fax: (845) 602-5671. E-mail: petersp{at}wyeth.com.

{dagger} Present address: Cumbre Inc., Dallas, TX 75235.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4589-4596, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4589-4596.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Petersen, P. J., Jones, C. H., Venkatesan, A. M., Bradford, P. A. (2009). Efficacy of Piperacillin Combined with the Penem {beta}-Lactamase Inhibitor BLI-489 in Murine Models of Systemic Infection. Antimicrob. Agents Chemother. 53: 1698-1700 [Abstract] [Full Text]  
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