In vitro development of resistance to a novel fluoroquinolone, DW286, in methicillin-resistant Staphylococcus aureus clinical isolates.
In vitro development of resistance to a novel fluoroquinolone, DW286, as well as to ciprofloxacin, gemifloxacin, sparfloxacin and trovafloxacin, was investigated in eight methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates. The strains were subcultured in subinhibitory concentrations of each agent during a 50 day period. Subculturing in most agents led to the selection of 37 mutants with increased MICs. The DW286 MICs were increased from 0.004-0.031 to 0.125-0.5 mg/L in five strains after 13-47 passages, and were not increased in three strains. The ciprofloxacin, gemifloxacin, sparfloxacin and trovafloxacin-selected mutants showed relatively weak cross-resistance to DW286. DNA sequencing analyses of all of the selected mutants revealed a few point mutations responsible for the high level of resistance, but actually these variations did not confer high resistance to fluoroquinolones. In the presence of reserpine, an inhibitor of the Gram-positive efflux pump, of 36 mutants 22 had two- to 16-fold lower ciprofloxacin MICs, and 20 had two- to 16-fold lower gemifloxacin MICs. However, sparfloxacin, trovafloxacin and DW286 were not good substrates for efflux pumps.
Kim
Mi-Jeong
MJ
College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Yun
Hee-Jeong
HJ
Kang
Jin-Wook
JW
Kim
Sunghoon
S
Kwak
Jin-Hwan
JH
Choi
Eung-Chil
EC
D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D016521:Electrophoresis, Gel, Pulsed-Field; D005838:Genotype; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D009287:Naphthyridines / Q000378:metabolism / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism
C471029:7-(3-(aminomethyl)-4-(methoxyimino)-3-methyltetrahydro-1H-1-pyrrolyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro(1,8)naphthyridine-3-carboxylic acid; D000890:Anti-Infective Agents; D004269:DNA, Bacterial; D009287:Naphthyridines; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II