title: In vitro and in vivo activities of novel 6-methylidene penems as beta-lactamase inhibitors.
abstract: Novel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as beta-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-microg/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2- to 32-fold for extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae strains. The MICs for piperacillin-resistant (MIC of piperacillin, >64 microg/ml) strains of Enterobacter spp., Citrobacter spp., and Serratia spp. were reduced to the level of susceptibility (MIC of piperacillin, < or =16 microg/ml) when the drug was combined with 4, 2, or 1 microg of these penem inhibitors/ml. Protection against acute lethal bacterial infections with class A and C beta-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 beta-lactam antibiotic.
authors.affiliation: Infectious Disease and Oncology, Wyeth Research, Pearl River, New York 10965, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Petersen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Murphy
authors.forename: Luanna
authors.initials: L
authors.lastname: Tardio
authors.forename: Youjun
authors.initials: Y
authors.lastname: Yang
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Bradford
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Takao
authors.initials: T
authors.lastname: Abe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Isoda
authors.forename: Ado
authors.initials: A
authors.lastname: Mihira
authors.forename: Hideki
authors.initials: H
authors.lastname: Ushirogochi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takasake
authors.forename: Steve
authors.initials: S
authors.lastname: Projan
authors.forename: John
authors.initials: J
authors.lastname: O'Connell
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000627:therapeutic use; D010878:Piperacillin / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases; D010878:Piperacillin