title: Escherichia coli resistant to cephalosporins and quinolones is still susceptible to the cephalosporin-quinolone ester Ro 23-9424.
abstract: Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Its activity against mutants of Escherichia coli TE18 resistant to both antibacterial components was examined. E. coli TE18 overproduces the AmpC beta-lactamase and is resistant to several cephalosporins, including desacetylcefotaxime (MIC, 50 micrograms/ml), although it is still susceptible to Ro 23-9424 (MIC, 0.2 microgram/ml). Thirty-five spontaneous, two-step mutants of E. coli TE18 which were resistant to fleroxacin (MIC, 50 micrograms/ml) were isolated. In the mutants, replicative DNA biosynthesis (permeabilized cells) was resistant to fleroxacin, and some mutants had porin abnormalities. However, all remained susceptible to Ro 23-9424 (MIC, 0.5 microgram/ml). Examination of beta-lactamase activity in the parent strain revealed that it hydrolyzes desacetylcefotaxime more rapidly than it does Ro 23-9424. Thus, Ro 23-9424 may be less susceptible to the gram-negative, chromosomal beta-lactamases that hydrolyze several broad-spectrum cephalosporins and may be effective in cases in which neither of its two components is active.
authors.affiliation: Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110-1199.
authors.forename: J
authors.initials: J
authors.lastname: Pace
authors.forename: A
authors.initials: A
authors.lastname: Bertasso
authors.forename: N H
authors.initials: NH
authors.lastname: Georgopapadakou
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000235:genetics; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000502:physiology; D002511:Cephalosporins / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003090:Coliphages; D004261:DNA Replication; D004269:DNA, Bacterial / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016576:Fleroxacin / Q000031:analogs & derivatives; D024841:Fluoroquinolones; D015964:Gene Expression Regulation, Bacterial; D006602:Hexosyltransferases; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000235:genetics; D009154:Mutation; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D018272:Porins; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D046915:Penicillin-Binding Proteins; D018272:Porins; C060441:Ro-23-9424; D002939:Ciprofloxacin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D002439:Cefotaxime; D016576:Fleroxacin