title: Mode of action of the dual-action cephalosporin Ro 23-9424.
abstract: Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at less than or equal to 2 micrograms/ml to the essential penicillin-binding proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decomposition product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addition of Ro 23-9424, decreased after addition of cefotaxime, and stopped immediately after addition of fleroxacin. The results, together with the chemical stability of Ro 23-9424 (half-life, approximately 3 h at pH 7.4 and 37 degrees C), suggest that in E. coli the compound acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decomposition of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.
authors.affiliation: Roche Research Center, Nutley, New Jersey 07110.
authors.forename: N H
authors.initials: NH
authors.lastname: Georgopapadakou
authors.forename: A
authors.initials: A
authors.lastname: Bertasso
authors.forename: K K
authors.initials: KK
authors.lastname: Chan
authors.forename: J S
authors.initials: JS
authors.lastname: Chapman
authors.forename: R
authors.initials: R
authors.lastname: Cleeland
authors.forename: L M
authors.initials: LM
authors.lastname: Cummings
authors.forename: B A
authors.initials: BA
authors.lastname: Dix
authors.forename: D D
authors.initials: DD
authors.lastname: Keith
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004269:DNA, Bacterial / Q000096:biosynthesis; D004754:Enterobacter / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D016576:Fleroxacin / Q000031:analogs & derivatives*; D024841:Fluoroquinolones; D006602:Hexosyltransferases; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D046915:Penicillin-Binding Proteins; C060441:Ro-23-9424; D002939:Ciprofloxacin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D002439:Cefotaxime; D016576:Fleroxacin