Collateral Sensitivity to Fosfomycin of Tobramycin-Resistant Mutants of Pseudomonas aeruginosa Is Contingent on Bacterial Genomic Background

Abstract

Understanding the consequences in bacterial physiology of the acquisition of drug resistance is needed to identify and exploit the weaknesses derived from it. One of them is collateral sensitivity, a potentially exploitable phenotype that, unfortunately, is not always conserved among different isolates. The identification of robust, conserved collateral sensitivity patterns is then relevant for the translation of this knowledge into clinical practice. We have previously identified a robust fosfomycin collateral sensitivity pattern of Pseudomonas aeruginosa that emerged in different tobramycin-resistant clones. To go one step further, here, we studied if the acquisition of resistance to tobramycin is associated with robust collateral sensitivity to fosfomycin among P. aeruginosa isolates. To that aim, we analyzed, using adaptive laboratory evolution approaches, 23 different clinical isolates of P. aeruginosa presenting diverse mutational resistomes. Nine of them showed collateral sensitivity to fosfomycin, indicating that this phenotype is contingent on the genetic background. Interestingly, collateral sensitivity to fosfomycin was linked to a larger increase in tobramycin minimal inhibitory concentration. Further, we unveiled that fosA low expression, rendering a higher intracellular accumulation of fosfomycin, and a reduction in the expression of the P. aeruginosa alternative peptidoglycan-recycling pathway enzymes, might be on the basis of the collateral sensitivity phenotype.

The role of hypermutation and collateral sensitivity in antimicrobial resistance diversity of Pseudomonas aeruginosa populations in cystic fibrosis lung infection

“…We next wanted to ascertain if there was any evidence of evolutionary trade-offs involving AMR in these populations. Collateral sensitivity is sensitive to genetic background ( 17 , 19 , 59 , 60 ) and must be proven robust across a wide range of genetic backgrounds in order to be broadly applicable as a therapeutic strategy ( 61 ). Therefore, we searched for evidence of collateral sensitivity within our populations and additionally for evidence of trade-offs between AMR and fitness (i.e., growth rate) in a CF sputum-like medium, SCFM ( 42 ).…”

The Role of Hypermutation and Collateral Sensitivity in Antimicrobial Resistance Diversity ofPseudomonas aeruginosaPopulations in Cystic Fibrosis Lung Infection

“…We next wanted to ascertain if there was any evidence of evolutionary tradeoffs involving AMR in these populations. Collateral sensitivity is sensitive to genetic background [17,19,59,60] and must be proven robust across a wide range of genetic backgrounds in order to be broadly applicable as a therapeutic strategy [61]. Therefore, we searched for evidence of collateral sensitivity within our populations, and additionally for evidence of trade-offs between AMR and fitness (i.e., growth rate) in a CF sputum-like medium, SCFM [42].…”