Hypermutation Is a Key Factor in Development of Multiple-Antimicrobial Resistance inPseudomonas aeruginosaStrains Causing Chronic Lung Infections

Abstract

Pseudomonas aeruginosa is the most relevant pathogen producing chronic lung infections in patients with chronic underlying diseases such as cystic fibrosis (CF), bronchiectasis, and chronic obstructive pulmonary disease (COPD). Hypermutable (or mutator) P. aeruginosa strains, characterized by increased (up to 1,000-fold) spontaneous mutation rates due to alterations of the DNA mismatch repair (MMR) system have been found at high frequencies in the lungs of CF patients, but their role in other chronic processes is still unknown. Sixty-two P. aeruginosa isolates from 30 patients with underlying non-CF chronic respiratory diseases (22 with bronchiectasis and 8 with COPD) and documented chronic infection were studied. Antibiotic susceptibility profiles and mutation frequencies were determined, and complementation assays using the cloned wild-type mutS gene and molecular epidemiology studies (pulsed-field electrophoresis, [PFGE]) were performed with these strains. Thirty-three (53%) of the isolates were hypermutable, and 17 (57%) of the 30 patients were colonized by hypermutable strains. Strains from 11 of the 17 patients were found to be defective in the MMR mutS gene by complementation assays. Interpatient transmission of strains was ruled out by PFGE. Multipleantimicrobial resistance was documented in 42% of the hypermutable strains in contrast to 0% resistance in the nonhypermutable strains (P < 0.0001). Hypermutable P. aeruginosa strains are extremely prevalent in chronic infections in contrast to what has been described in acute processes, suggesting a role of hypermutation in bacterial adaptation for long-term persistence. Furthermore, hypermutation is found to be a key factor for the development of multiple-antimicrobial resistance, and therefore these findings are expected to have important consequences for the treatment of chronic infections.

Environmental Stress and Antibiotic Resistance in Food-Related Pathogens

“…(ii) A second change might be hypermutability: growth conditions affect bacterial mutation rate, generating heterogeneous populations with increased spontaneous mutation rates (hypermutable strains) and thus clones which may survive the stressful environmental conditions (25). Such hypermutable pseudomonad strains have been reported forming colonies within the zone of inhibition surrounding antibiotic discs (24). (iii) A third change might be adaptive or directed mutations.…”

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

“…It is well recognized that Pa in CF patients is acquired largely from the immediate environment, rather than patient-to-patient transmission (Oliver & Mena, 2010, Macia et al, 2005, Pirnay et al, 2009. Longitudinal bacterial culture following patient disease progression suggests that a gradual decrease in bacterial diversity is associated with an increase in patient age and advanced pulmonary disease (Cox et al, 2010).…”

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

“…First, in the CF lung, these mucoid strains are frequently hypermutators [8]. Hypermutators are strains with mutations in genes, such as mutS, which are responsible for DNA repair.…”