Tackling antibiotic resistance by inducing transient and robust collateral sensitivity

In this work, the authors induce ciprofloxacin resistance in clinical isolates of Pseudomonas aeruginosa to investigate transient collateral sensitivity to tobramycin. Collateral sensitivity (CS) is an evolutionary trade-off traditionally linked to the mutational acquisition of antibiotic resistance (AR). However, AR can be temporally induced, and the possibility that this causes transient, non-inherited CS, has not been addressed. Mutational acquisition of ciprofloxacin resistance leads to robust CS to tobramycin in pre-existing antibiotic-resistant mutants of Pseudomonas aeruginosa. Further, the strength of this phenotype is higher when nfxB mutants, over-producing the efflux pump MexCD-OprJ, are selected. Here, we induce transient nfxB-mediated ciprofloxacin resistance by using the antiseptic dequalinium chloride. Notably, non-inherited induction of AR renders transient tobramycin CS in the analyzed antibiotic-resistant mutants and clinical isolates, including tobramycin-resistant isolates. Further, by combining tobramycin with dequalinium chloride we drive these strains to extinction. Our results support that transient CS could allow the design of new evolutionary strategies to tackle antibiotic-resistant infections, avoiding the acquisition of AR mutations on which inherited CS depends.

Automated summary

In this study, the authors induced ciprofloxacin resistance in clinical isolates of Pseudomonas aeruginosa and found transient collateral sensitivity to tobramycin. This non-inherited induction of antibiotic resistance allows for the eradication of antibiotic-resistant strains when combined with tobramycin. These results suggest that transient collateral sensitivity could be a new evolutionary strategy to combat antibiotic-resistant infections.