Mutators in cystic fibrosis chronic lung infection: Prevalence, mechanisms, and consequences for antimicrobial therapy

Abstract

Hypermutable (or mutator) microorganisms are those that have an increased spontaneous mutation rate due to defects in DNA repair or error avoidance systems. Over last decade, several studies have provided strong evidence of a relevant role of mutators in the evolution of natural bacterial populations, with a special emphasis in the field of infectious diseases. Among them, chronic respiratory infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients was the first natural environment revealing a high prevalence and important role of mutators. High frequencies of mutators have also been noted for other pathogens in the CF setting, particularly Staphylococcus aureus and Haemophilus influenzae. In addition to a strong statistical link between hypermutation and antibiotic resistance (i.e., mutators are more frequently resistant against antibiotics) obtained from the analysis of collections of clinical isolates from CF patients, several in vitro and in vivo experiments have further highlighted the dramatic consequences of hypermutation, especially when acting on microorganisms that are genetically equipped to acquire efficient resistance to most antibiotics by mutations in chromosomal genes such as P. aeruginosa. Recent studies additionally showed that mutators accelerate genetic adaptation of P. aeruginosa to the airways of CF patients and that patients infected by mutator strains have a poorer lung function. Further prospective clinical studies are nevertheless needed for a deep evaluation of the impact of mutators in disease progression and outcome. Future research should particularly focus on the investigation of the optimal therapeutical strategies to prevent the emergence of mutator strains in the lungs of CF patients and to avoid multiple-antimicrobial resistance development if they have already been selected.