The Challenging Life of Mutators: How Pseudomonas aeruginosa Survives between Persistence and Evolution in Cystic Fibrosis Lung

Cystic fibrosis (CF) is a life-threatening genetic disease characterised by chronic lung infections sustained by opportunistic pathogens such as <i>Pseudomonas aeruginosa.</i> During the chronic long-lasting lung infections, <i>P. aeruginosa</i> adapts to the host environment. Hypermutability, mainly due to defects in the DNA repair system, resulting in an increased spontaneous mutation rate, represents a way to boost the rapid adaptation frequently encountered in CF <i>P. aeruginosa</i> isolates. We selected 609 isolates from 51 patients with CF chronically colonised by <i>P. aeruginosa</i> to study, by full-length genome sequencing, the longitudinal evolution of the bacterium. We recovered at least one hypermutable (mutator) isolate in 57% of patients. By combining genomic information and phenotypic analyses, we followed the evolutionary pathways of the <i>P. aeruginosa</i> mutator strains, identifying their contribution to multi-drug resistance and the emergence of new sub-lineages. By implementing patient clinical data, we observed that mutators preferentially follow a specific evolutionary trajectory in patients with a negative clinical outcome and that maintenance antibiotic polytherapy, based on alternating molecules, apparently reduces the occurrence of hypermutability. Finally, we draw attention to the possibility that modulator-induced changes in the pulmonary environment may be associated with the onset of hypermutability.