High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA.
The mechanism of high-level fluoroquinolone resistance was studied in strains of Streptococcus pneumoniae, either selected in vitro or isolated from clinical samples. By using DNA from these high-level-resistant strains, low-level-resistant transformants (MIC of pefloxacin, > or = 32 micrograms/ml; MIC of ciprofloxacin, 4 micrograms/ml; MIC of sparfloxacin, 0.50 micrograms/ml) were obtained at high frequencies (ca.10(-2)), while high-level-resistant transformants (MIC of pefloxacin, > or = 64 micrograms/ml; MIC of ciprofloxacin, 16 to 64 micrograms/ml; MIC of sparfloxacin, > or = 8 micrograms/ml) were obtained only at low frequencies (ca.10(-4)). This suggested that mutations in at least two unlinked genes were necessary to obtain high-level resistance. Low-level resistance was associated with ParC mutations (change from Ser to Tyr at position 79 [Ser79Tyr], Ser79Phe, or Asp83Gly). ParC mutations were associated, in high-level-resistant strains and transformants, with alterations in the quinolone resistance-determining region of GyrA (Ser84Tyr, Ser84Phe, and/or Glu88Lys). Low-level resistance was shown to be necessary for expression of the gyrA mutations. No mutation in the region corresponding to the quinolone resistance-determining region of GyrB and no alteration of drug accumulation were found.
Janoir
C
C
L.R.M.A., Université Paris VI, France.
Zeller
V
V
Kitzis
M D
MD
Moreau
N J
NJ
Gutmann
L
L
D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D027081:DNA Gyrase; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics*; D024841:Fluoroquinolones; D005798:Genes, Bacterial / Q000187:drug effects / Q000235:genetics*; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics*; D014170:Transformation, Genetic; D015366:Pefloxacin
D042462:4-Quinolones; D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D027081:DNA Gyrase; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II; D024841:Fluoroquinolones; D015363:Quinolones; D015366:Pefloxacin; C061363:sparfloxacin