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Fluoroquinolones are antibacterial drugs that inhibit DNA Gyrase and Topoisomerase IV. These essential enzymes facilitate chromosome replication and RNA transcription by regulating chromosome supercoiling. High-level resistance to fluoroquinolones in  E. coli  requires the accumulation of multiple mutations, including those that alter target genes and genes regulating drug efflux. Previous studies have shown some drug-resistance mutations reduce bacterial fitness, leading to the selection of fitness-compensatory mutations. The impact of fluoroquinolone-resistance on bacterial fitness was analyzed in constructed isogenic strains carrying up to 5 resistance mutations. Some mutations significantly decreased bacterial fitness both  in vitro  and  in vivo . We identified low-fitness triple-mutants where the acquisition of a fourth resistance mutation significantly increased fitness  in vitro  and  in vivo  while at the same time dramatically decreasing drug susceptibility. The largest effect occurred with the addition of a  parC  mutation (Topoisomerase IV) to a low-fitness strain carrying resistance mutations in  gyrA  (DNA Gyrase) and  marR  (drug efflux regulation). Increased fitness was accompanied by a significant change in the level of  gyrA  promoter activity as measured in an assay of DNA supercoiling. In selection and competition experiments made in the absence of drug,  parC  mutants that improved fitness and reduced susceptibility were selected. These data suggest that natural selection for improved growth in bacteria with low-level resistance to fluoroquinolones could in some cases select for further reductions in drug susceptibility. Thus, increased resistance to fluoroquinolones could be selected even in the absence of further exposure to the drug.

Interplay in the Selection of Fluoroquinolone Resistance and Bacterial Fitness