Table 1.
Genotypes, susceptibility, and fitness of isogenic strains.
Figure 1.
Resistance and fitness of constructed strains.
For the wild-type and each of the 28 constructed isogenic strains the MIC for ciprofloxacin (part A) and the relative fitness per generation in in vitro growth competition (part B) is shown as a function of the number of resistance mutations per strain. Each diamond symbol represents one strain. In some cases more than one symbol occupies the same space. Strain identification numbers are shown for four strains of particular interest (Table 2).
Table 2.
Single mutations decrease drug susceptibility and increase fitness.
Figure 2.
Fitness in vitro as a function of fitness in vivo in a mouse UTI model.
Samples from urine, kidney, and bladder are illustrated with black diamonds, triangles, and squares, respectively. The addition of one extra resistance mutation to either LM695, or LM882 created LM707, with increased fitness in vitro and in vivo and an increase in MIC for ciprofloxacin from 0.75 to 32 µg/ml.
Table 3.
Selection of LM695 to faster growth and increased MIC.
Figure 3.
A general model illustrating evolutionary paths for a lineage under antibiotic selection.
Mutual compensation, the acquisition of a mutation that simultaneously improves fitness and reduces susceptibility to the antibiotic, is the pathway presented in this manuscript.