title: Antagonism of wild-type and resistant Escherichia coli and its DNA gyrase by the tricyclic 4-quinolone analogs ofloxacin and S-25930 stereoisomers.
abstract: The mechanism of action of the quinolone analogs ofloxacin and S-25930, which are unusual because of the presence of a third ring with an asymmetric carbon, was studied. Drug-resistant strains of Escherichia coli were selected by serial passage in the presence of ofloxacin, and a mutation was mapped near the gyrA gene of DNA gyrase. DNA gyrase containing the A subunit purified from this strain as compared with the isogenic wild-type strain exhibited increased resistance to ofloxacin, proving that the mutation was located in the gyrA gene. For S-25930, the S stereoisomer was more potent than the R isomer in inhibiting wild-type E. coli and DNA gyrase containing an A subunit isolated from this strain. Both isomers had decreased potency against the isogenic ofloxacin-resistant (gyrA) strain and its purified enzyme, but the S isomer remained more potent than the R isomer. These studies, using a combined genetic and biochemical approach, demonstrate (i) that DNA gyrase is a target of the tricyclics ofloxacin and S-25930, (ii) that serial exposure to ofloxacin can select resistance to tricyclic quinolone agents by mutation in the gyrA gene, and (iii) that the more potent antibacterial activity of S relative to R S-25930 correlates with increased activity against DNA gyrase for both wild-type and ofloxacin-resistant (gyrA) isogenic strains.
authors.affiliation: Medical Services, Massachusetts General Hospital, Boston 02114.
authors.forename: J S
authors.initials: JS
authors.lastname: Wolfson
authors.forename: D C
authors.initials: DC
authors.lastname: Hooper
authors.forename: E Y
authors.initials: EY
authors.lastname: Ng
authors.forename: K S
authors.initials: KS
authors.lastname: Souza
authors.forename: G L
authors.initials: GL
authors.lastname: McHugh
authors.forename: M N
authors.initials: MN
authors.lastname: Swartz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D015242:Ofloxacin; D010078:Oxazines / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D010078:Oxazines; D011807:Quinolizines; D059005:Topoisomerase II Inhibitors; C049886:ibafloxacin; D015242:Ofloxacin