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Fluoroquinolone (FQ) resistance is highly prevalent among clinical strains of  Pseudomonas aeruginosa , limiting treatment options. We have reported previously that highly virulent strains containing the  exoU  gene of the type III secretion system are more likely to be FQ-resistant than strains containing the  exoS  gene, as well as more likely to acquire resistance-conferring mutations in  gyrA/B  and  parC/E . We hypothesize that FQ-resistance imposes a lower fitness cost on  exoU  compared to  exoS  strains, thus allowing for better adaptation to the FQ-rich clinical environment. We created isogenic mutants containing a common FQ-resistance conferring point mutation in  parC  from three  exoU  to three  exoS  clinical isolates and tested fitness  in vitro  using head-to-head competition assays. The mutation differentially affected fitness in the  exoU  and  exoS  strains tested. While the addition of the  parC  mutation dramatically increased fitness in one of the  exoU  strains leaving the other two unaffected, all three  exoS  strains displayed a general decrease in fitness. In addition, we found that  exoU  strains may be able to compensate for the fitness costs associated with the mutation through better regulation of supercoiling compared to the  exoS  strains. These results may provide a biological explanation for the observed predominance of the virulent  exoU  genotype in FQ-resistant clinical subpopulations and represent the first investigation into potential differences in fitness costs of FQ-resistance that are linked to the virulence genotype of  P. aeruginosa . Understanding the fitness costs of antibiotic resistance and possibilities of compensation for these costs is essential for the rational development of strategies to combat the problem of antibiotic resistance.

Fitness Cost of Fluoroquinolone Resistance in Clinical Isolates of Pseudomonas aeruginosa Differs by Type III Secretion Genotype