Trade-offs of antibiotic resistance evolution, such as fitness cost and collateral sensitivity, could be exploited to drive evolution towards antibiotic susceptibility. Decline of resistance may occur when resistance to other drug leads to collateral sensitivity to the first one and when compensatory mutations, or genetic reversion of the original ones, reduce fitness cost. Here we describe the impact of antibiotic-free and sub-lethal environments on declining ceftazidime resistance in different Pseudomonas aeruginosa resistant mutants. We determined that decline of ceftazidime resistance occurs within 450 generations, which is caused by newly acquired mutations and not by reversion of the original ones, and that the original collateral sensitivity of these mutants is preserved. In addition, we observed that the frequency and degree of this decline is contingent on genetic background. Our results are relevant to implement evolution-based therapeutic approaches, as well as to redefine global policies of antibiotic use, such as drug cycling.

DOI: http://doi.org/10.1093/molbev/msac049