Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump.
Fluoroquinolone-resistant mutants, selected from a wild-type Escherichia coli K-12 strain and its Mar mutant by exposure to increasing levels of ofloxacin on solid medium, were analyzed by Northern (RNA) blot analysis, sequencing, and radiolabelled ciprofloxacin accumulation studies. Mutations in the target gene gyrA (DNA gyrase), the regulatory gene marR, and additional, as yet unidentified genes (genes that probably affect efflux mediated by the multidrug efflux pump AcrAB) all contributed to fluoroquinolone resistance. Inactivation of the acrAB locus made all strains, including those with target gene mutations, hypersusceptible to fluoroquinolones and certain other unrelated drugs. These studies indicate that, in the absence of the AcrAB pump, gyrase mutations fail to produce clinically relevant levels of fluoroquinolone resistance.
Oethinger
M
M
Center for Adaptation Genetics and Drug Resistance, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Kern
W V
WV
Jellen-Ritter
A S
AS
McMurry
L M
LM
Levy
S B
SB
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000502:physiology*; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000502:physiology*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D029968:Escherichia coli Proteins; D017353:Gene Deletion; D005798:Genes, Bacterial; D005809:Genes, Regulator; D006801:Humans; D008074:Lipoproteins / Q000502:physiology*; D026901:Membrane Transport Proteins; D009154:Mutation
C083497:AcrA protein, E coli; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D002939:Ciprofloxacin; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II