Increased fluoroquinolone resistance co-selected with improved bacterial fitness

Abstract number: O344

Hughes D., Marcusson L.

Objectives: We asked how fluoroquinolone-resistant clinical isolates of E. coli maintain fitness despite accumulating several mutations affecting DNA gyrase, topoisomerase IV and drug efflux. We investigated the possibility that different resistance-associated mutations might mutually compensate fitness costs. We also asked whether bacterial fitness itself might be a selected parameter driving the evolution of fluoroquinolone resistance.

Methods: To test this experimentally we constructed a set of 29 isogenic strains carrying combinations of up to 5 resistance mutations found commonly in clinical isolates, and measured their associated levels of resistance and fitness. Fitness was measured in pairwise growth competition in vitro.

Results: The mean MIC for ciprofloxacin increased as a simple function of the number of resistance mutations in the isogenic strains. As expected, mean relative fitness decreased as a function of addition of the first three resistance mutations (1; 0.95; 0.89; 0.8). However, the downward trend was reversed by the addition of 4th and 5th mutations (0.8; 0.87; 0.9). We identified 6 strains in which an additional resistance mutation increased both resistance and fitness. These strains were deconstructed and reconstructed to confirm the relationship between the resistance mutations present and the resulting fitness/resistance phenotype. We also evolved strains for increased fitness in the absence of drug and observed the selection of variants with decreased susceptibility to fluoroquinolones.

Conclusions: Bacteria can use different strategies to minimize the fitness costs of the genetic alterations selected for drug resistance. Two of these are well documented: the selection of low-cost mutations, and the selection of additional fitness compensating mutations. Here we identify a third strategy that reduces the fitness costs of resistance to fluoroquinolones: particular resistance mutations, when in combination, increase both resistance level and bacterial fitness. This relationship between drug-resistance mutations and improved bacterial fitness could be one force driving the evolution of fluoroquinolone resistance. An important implication is that strains carrying low level resistance mutations could evolve by Darwinian selection to higher levels of resistance, in the absence of direct selection by the drug.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Location: Barcelona, Spain
Presentation type:
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