Abstract
In 474 genome sequenced Pseudomonas aeruginosa isolates from 34 cystic fibrosis (CF) patients, 40% of these harbor mutations in the mexZ gene encoding a negative regulator of the MexXY-OprM efflux pump associated with aminoglycoside and fluoroquinolone resistance. Surprisingly, resistance to aminoglycosides and fluoroquinolones of mexZ mutants was far below the breakpoint of clinical resistance. However, the fitness increase of the mutant bacteria in presence of the relevant antibiotics, as demonstrated in competition experiments between mutant and ancestor bacteria, showed that 1) very small phenotypic changes cause significant fitness increase with severe adaptive consequences, and 2) standardized phenotypic tests fail to detect such low-level variations. The frequent appearance of P. aeruginosa mexZ mutants in CF patients is directly connected to the intense use of the target antibiotics, and low-level antibiotic resistance, if left unnoticed, can result in accumulation of additional genetic changes leading to high-level resistance.
Highlights
Pseudomonas aeruginosa is a frequent colonizer of the airways of cystic fibrosis (CF) patients, where it adapts and readily establishes chronic infections[1,2]
We identified 110 insertion or deletions (INDELs) and 83 single-nucleotide non-synonymous mutations (SNPs) constituting 40 unique sequence variants that were scattered throughout the gene coding sequence with no apparent mutational hot-spots (Supplementary Fig. S1 and Table S1)
The striking finding of this study is that very small increases in antibiotic resistance associated with mexZ mutations, which normally are undetected or neglected in the clinical microbiological laboratory using current standardized diagnostic methods, seem to be drivers of selection of mexZ mutants in CF patients
Summary
Pseudomonas aeruginosa is a frequent colonizer of the airways of cystic fibrosis (CF) patients, where it adapts and readily establishes chronic infections[1,2]. A large number of P. aeruginosa isolates (n = 474) obtained from 34 young CF patients were genotyped by whole genome sequencing, and it was found that a small number of genes (n = 52) were targeted by patho-adaptive mutations, suggested to increase P. aeruginosa fitness during adaptation in the CF lungs[5]. Among these mutations, it was found that mutations in the mexZ gene were more frequent than any other patho-adaptive mutation in agreement with findings from other studies[6,7,8,9,10,11]. It was considered important to determine the phenotype of mexZ mutant strains in order to identify the selection pressure in CF airways, which could enrich for the occurrence and maintenance of mexZ bacterial cell lines
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