Bacterial hypermutation in cystic fibrosis, not only for antibiotic resistance

Hypermutable or mutator microorganisms are those that have an increased spontaneous mutation rate as a result of defects in DNA repair or error avoidance systems. Over the last two decades, several studies have provided strong evidence for a relevant role of mutators in the evolution of natural bacterial populations, particularly in the field of infectious diseases. Among them, chronic respiratory infection with Pseudomonas aeruginosa in cystic fibrosis (CF) patients was the first natural environment to reveal the high prevalence and important role of mutators. A remarkable positive selection of mutators during the course of the chronic infection has been reported, mainly as a result of the emergence of DNA mismatch repair system (mutS, mutL or mutU)-deficient mutants, although strains defective in the GO system (mutM, mutY and mutT) have also been observed. High frequencies of mutators have also been noted among other pathogens in the CF setting, particularly Staphylococcus aureus and Haemophilus influenzae. Enhanced antimicrobial resistance development is the most thoroughly studied consequence of mutators in CF and other chronic infections, although recent studies show that mutators may additionally have important effects on the evolution of virulence, genetic adaptation to the airways of CF patients, persistence of colonization, transmissibility, and perhaps lung function decline. Further prospective clinical studies are nevertheless still needed for an in-depth evaluation of the impact of mutators on disease progression and outcome.