Mechanism of quinolone mutagenicity in bacteria.
Gyrase inhibitors of the quinolone type are genotoxic in bacteria. A functioning excision-repair system is needed to show the mutagenic activity in the Ames tester strains. The antibiotics do not interact with DNA directly but induce the gyrase enzyme to cleave the DNA with protein covalently bound at the site-specific double-strand scission. A prominent site of action is shown to be located at a distance of about 80 bp from the hisG428 sequence at which mutations are scored in the responsive strain TA102. Since the interaction of quinolones with the mammalian counterparts of gyrase, topoisomerase II, is lower by orders of magnitude, it is argued that the bacterial screening tests are of little relevance for predicting effects in mammalian cells.
Gocke
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Department of Toxicology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
D000890:Anti-Infective Agents / Q000494:pharmacology; D015139:Blotting, Southern; D002939:Ciprofloxacin / Q000031:analogs & derivatives / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D000077422:Enrofloxacin; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D016576:Fleroxacin; D024841:Fluoroquinolones; D005798:Genes, Bacterial / Q000187:drug effects*; D009154:Mutation / Q000187:drug effects*; D009675:Novobiocin / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D010093:Oxolinic Acid / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D012475:Salmonella / Q000187:drug effects / Q000235:genetics*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; D009675:Novobiocin; D000077422:Enrofloxacin; D002939:Ciprofloxacin; D015242:Ofloxacin; D004250:DNA Topoisomerases, Type II; D010093:Oxolinic Acid; D016576:Fleroxacin