Abstract
Long-term infection of the airways of cystic fibrosis patients with Pseudomonas aeruginosa is often accompanied by a reduction in bacterial growth rate. This reduction has been hypothesised to increase within-patient fitness and overall persistence of the pathogen. Here, we apply adaptive laboratory evolution to revert the slow growth phenotype of P. aeruginosa clinical strains back to a high growth rate. We identify several evolutionary trajectories and mechanisms leading to fast growth caused by transcriptional and mutational changes, which depend on the stage of adaptation of the strain. Return to high growth rate increases antibiotic susceptibility, which is only partially dependent on reversion of mutations or changes in the transcriptional profile of genes known to be linked to antibiotic resistance. We propose that similar mechanisms and evolutionary trajectories, in reverse direction, may be involved in pathogen adaptation and the establishment of chronic infections in the antibiotic-treated airways of cystic fibrosis patients.
Highlights
Long-term infection of the airways of cystic fibrosis patients with Pseudomonas aeruginosa is often accompanied by a reduction in bacterial growth rate
We selected hypermutator strains for their enhanced evolvability and because they represent a major fraction of the P. aeruginosa isolates from cystic fibrosis patients (CF) patients[21,22]
Pseudomonas aeruginosa is a common cause of nosocomial infections, and as such it has become a health threat, enhanced by our inability to efficiently treat chronic infections such as those affecting patients suffering from CF44
Summary
Long-term infection of the airways of cystic fibrosis patients with Pseudomonas aeruginosa is often accompanied by a reduction in bacterial growth rate This reduction has been hypothesised to increase within-patient fitness and overall persistence of the pathogen. The majority of adapted clinical isolates show a slow growth phenotype which is often associated with increased biofilm production and antibiotics resistance, opening the question of the role of reduced growth rate in chronic infections[8]. While slow growth has been described for bacterial pathogens to reduce antibiotic sensitivity and increase bacterial persistence[10,11,12,13], it is mostly unknown if in P. aeruginosa it is selected for in vivo as a CF specific trait, or if it is a mere consequence of other adaptive mutations with high fitness cost such as mucoidy, antibiotic resistance and biofilm production. Hypermutator subclones can represent up to 60% of P. aeruginosa population in CF airways and 30–50% of the infected CF patients have hypermutator isolates, indicating a critical role of hypermutation during within-host adaptation[22,23,24,25,26,27,28]
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