title: Dual-targeting properties of the 3-aminopyrrolidyl quinolones, DC-159a and sitafloxacin, against DNA gyrase and topoisomerase IV: contribution to reducing in vitro emergence of quinolone-resistant Streptococcus pneumoniae.
abstract: OBJECTIVE
  DC-159a (a novel quinolone) and sitafloxacin (DU-6859a) are structurally related quinolones, bearing a 3-aminopyrrolidyl substitution. We investigated the relationship between the target preferences of these 3-aminopyrrolidyl quinolones, in vitro potencies and emergence of quinolone-resistant mutants in Streptococcus pneumoniae, compared with other quinolones.
  
  
  METHODS
  MICs, resistance frequencies and mutant prevention concentrations (MPCs) were determined using quinolone-susceptible strains and first-step parC mutant strains of S. pneumoniae. Target preferences were tested by the following two methods: antibacterial activities against gyrA or parC mutants and in vitro enzyme assays for the determination of 50% inhibition (IC(50)) values.
  
  
  RESULTS
  DC-159a and sitafloxacin exhibited potent antibacterial activities, low frequencies of mutant selection, low MPCs and narrow mutant selection windows against both quinolone-susceptible strains and first-step parC mutants of S. pneumoniae, compared with gatifloxacin, moxifloxacin and other quinolones tested. DC-159a and sitafloxacin showed relatively low MIC ratios against single gyrA or parC mutants relative to the wild-type strain and low IC(50) ratios against DNA gyrase and topoisomerase IV.
  
  
  CONCLUSIONS
  DC-159a and sitafloxacin demonstrated a more balanced dual-targeting activity than gatifloxacin, moxifloxacin and other quinolones tested. In addition, DC-159a and sitafloxacin have a lower propensity for selecting first- and second-step resistant mutants.
authors.affiliation: Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. okumura.ryo.x7@daiichisankyo.co.jp
authors.forename: Ryo
authors.initials: R
authors.lastname: Okumura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirata
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Onodera
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Otani
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors
chemical_list: C530475:7-(7-amino-7-methyl-5-azaspiro(2.4)heptan-5-yl)-6-fluoro-1-(2-fluoro-1-cyclopropyl)-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; D000631:Aminopyridines; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C076246:sitafloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase