title: Contribution of the 8-methoxy group to the activity of gatifloxacin against type II topoisomerases of Streptococcus pneumoniae.
abstract: The inhibitory activities (50% inhibitory concentrations [IC(50)s]) of gatifloxacin and other quinolones against both DNA gyrase and topoisomerase IV of the wild-type Streptococcus pneumoniae IID553 were determined. The IC(50)s of 10 compounds ranged from 4.28 to 582 microg/ml against DNA gyrase and from 1.90 to 35.2 microg/ml against topoisomerase IV. The inhibitory activity against DNA gyrase was more varied than that against topoisomerase IV among fluoroquinolones. The IC(50)s for DNA gyrase of the 8-methoxy quinolones gatifloxacin and AM-1147 were approximately seven times lower than those of their 8-H counterparts AM-1121 and ciprofloxacin, whereas the IC(50)s for topoisomerase IV were 1.5 times lower. Moreover, the IC(50) ratios (IC(50) for DNA gyrase/IC(50) for topoisomerase IV) of gatifloxacin, AM-1147, and moxifloxacin, which possess 8-methoxy groups, were almost the same. The 8-methoxy quinolones showed higher antibacterial activity and less mutant selectivity against IID553 than their 8-H counterparts. These results suggest that the 8-methoxy group enhances both target inhibition, especially for DNA gyrase, leading to potent antipneumococcal activity and dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga, Tochigi 329-0114, Japan. ryuuta.kishii@mb2.kyorin-pharm.co.jp
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Fukuda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Hosaka
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001483:Base Sequence; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D013296:Streptococcus pneumoniae / Q000201:enzymology* / Q000235:genetics; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D000077734:Gatifloxacin