The analysis of trade-offs, as collateral sensitivity, associated with the acquisition
of antibiotic resistance, is mainly based on the use of model strains. However, the
possibility of exploiting these trade-offs for fighting already resistant isolates
has not been addressed in depth, despite the fact that bacterial pathogens are frequently
antibiotic-resistant, forming either homogeneous or heterogeneous populations. Using
a set of Pseudomonas aeruginosa-resistant mutants, we found that ceftazidime selects
pyomelanogenic tobramycin-hypersusceptible mutants presenting chromosomal deletions
in the analyzed genetic backgrounds. Since pyomelanogenic resistant mutants frequently
coexist with other morphotypes in patients with cystic fibrosis, we analyzed the exploitation
of this trade-off to drive extinction of heterogeneous resistant populations by using
tobramycin/ceftazidime alternation. Our work shows that this approach is feasible
because phenotypic trade-offs associated with the use of ceftazidime are robust.The
identification of conserved collateral sensitivity networks may guide the rational
design of evolution-based antibiotic therapies in P. aeruginosa infections.
