title: In vitro and in vivo activities of Syn2190, a novel beta-lactamase inhibitor.
abstract: Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.
authors.affiliation: Antimicrobial Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishida
authors.forename: C
authors.initials: C
authors.lastname: Kunugita
authors.forename: T
authors.initials: T
authors.lastname: Uji
authors.forename: F
authors.initials: F
authors.lastname: Higashitani
authors.forename: A
authors.initials: A
authors.lastname: Hyodo
authors.forename: N
authors.initials: N
authors.lastname: Unemi
authors.forename: S N
authors.initials: SN
authors.lastname: Maiti
authors.forename: O A
authors.initials: OA
authors.lastname: Phillips
authors.forename: P
authors.initials: P
authors.lastname: Spevak
authors.forename: K P
authors.initials: KP
authors.lastname: Atchison
authors.forename: S M
authors.initials: SM
authors.lastname: Salama
authors.forename: H
authors.initials: H
authors.lastname: Atwal
authors.forename: R G
authors.initials: RG
authors.lastname: Micetich
mesh_terms: D000818:Animals; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D016971:Citrobacter freundii / Q000187:drug effects / Q000201:enzymology; D004357:Drug Synergism; D016972:Enterobacter cloacae / Q000187:drug effects / Q000201:enzymology; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology*; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000096:biosynthesis; D000097572:Cefpirome
chemical_list: D002442:Ceftazidime; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D008997:Monobactams; D010397:Penicillanic Acid; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000097572:Cefpirome; C120996:Syn 2190