title: Bactericidal activities of BMS-284756, a novel Des-F(6)-quinolone, against Staphylococcus aureus strains with topoisomerase mutations.
abstract: The antistaphylococcal activities of BMS-284756 (T-3811ME), levofloxacin, moxifloxacin, and ciprofloxacin were compared against wild-type and grlA and grlA/gyrA mutant strains of Staphylococcus aureus. BMS-284756 was the most active quinolone tested, with MICs and minimal bactericidal concentrations against S. aureus wild-type strain MT5, grlA mutant MT5224c4, and grlA/gyrA mutant EN8 of 0.03 and 0.06, 0.125 and 0.125, and 4 and 4 microg/ml, respectively. In the time-kill studies, BMS-284756 and levofloxacin exhibited rapid killing against all strains. Ciprofloxacin, however, was not bactericidal for the double mutant, EN8. BMS-284756 and levofloxacin were bactericidal (3 log(10) decrease in CFU/ml) against the MT5 and MT5224c4 strains at two and four times the MIC within 2 to 4 h. Against EN8, BMS-284756 was bactericidal within 4 h at two and four times the MIC, and levofloxacin achieved similar results within 4 to 6 h. Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy. The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy. The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day. BMS-284756 was more potent than levofloxacin and equipotent with moxifloxacin against ISP794 both in vitro and in vivo, while BMS-284756 was more potent than levofloxacin and moxifloxacin against 2C6(1)-1.
authors.affiliation: BMSPRI, Infectious Diseases, Department of Microbilogy, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA. lawrencl@bms.com
authors.forename: Laura E
authors.initials: LE
authors.lastname: Lawrence
authors.forename: MaryBeth
authors.initials: M
authors.lastname: Frosco
authors.forename: Brenda
authors.initials: B
authors.lastname: Ryan
authors.forename: Susan
authors.initials: S
authors.lastname: Chaniewski
authors.forename: Hyekyung
authors.initials: H
authors.lastname: Yang
authors.forename: David C
authors.initials: DC
authors.lastname: Hooper
authors.forename: John F
authors.initials: JF
authors.lastname: Barrett
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001372:Aza Compounds; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D024841:Fluoroquinolones; D007211:Indoles; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D015242:Ofloxacin / Q000494:pharmacology; D011804:Quinolines; D015363:Quinolones; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D007211:Indoles; D011804:Quinolines; D015363:Quinolones; D064704:Levofloxacin; D015242:Ofloxacin; D004264:DNA Topoisomerases, Type I; D000077266:Moxifloxacin; C419689:garenoxacin