Antibiotic pressure compensates the biological cost associated with Pseudomonas aeruginosa hypermutable phenotypes in vitro and in a murine model of chronic airways infection

• Published in: Journal of antimicrobial chemotherapy Vol. 67; no. 4; pp. 962 - 969
• Main Authors: Alcalá-Franco, Beatriz, Montanari, Sara, Cigana, Cristina, Bertoni, Giovanni, Oliver, Antonio, Bragonzi, Alessandra
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2012; Oxford Publishing Limited (England)
• Subjects: Animal models; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Bacterial Load; Biological and medical sciences; Chronic Disease; Chronic infection; Colonization; Competition; Cystic fibrosis; Cystic Fibrosis - complications; Drug Resistance, Bacterial; Errors of metabolism; Genotype & phenotype; Genotypes; Humans; Lung; Lung - microbiology; Lung diseases; Male; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Miscellaneous hereditary metabolic disorders; Mutation; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - growth & development; Pseudomonas Infections - microbiology; Respiratory tract; Respiratory Tract Infections - microbiology; Survival Analysis; chronic airway infection; mouse model; hypermutators; cystic fibrosis; Pseudomonadales; Animal model; Costs; Respiratory tract; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Pancreatic disease; P. aeruginosa; Respiratory disease; Rodentia; Metabolic diseases; Cystic fibrosis; In vitro; Pressure; Genetic disease; Infection; Vertebrata; Antibiotic; Chronic; Phenotype; Mammalia; Mouse; Health economy; Digestive diseases; Economic aspect; Antibacterial agent
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkr587

Objectives Hypermutable strains of Pseudomonas aeruginosa frequently emerge during chronic airways infection in cystic fibrosis (CF) patients. While the increased accumulation of mutations by hypermutable strains determines a biological cost for the colonization of secondary environments, the mutator phenotypes might confer a selective advantage under antibiotic treatment in a CF airways environment. Methods To test this hypothesis, the reference strain PAO1 and clonal pairs of CF clinical hypermutable and wild-type P. aeruginosa strains belonging to different genotypes were subjected to competition experiments in vitro and in a mouse model of chronic infection. Results Both in vitro and in vivo, under antibiotic selection pressure, clinical hypermutable P. aeruginosa strains and the reference PAO1ΔmutS outcompeted their wild-type strains, promoting P. aeruginosa hypermutable strains in the airways colonization. This advantage for the hypermutable strain did not occur in the absence of antibiotic treatments. Severe histopathological lesions were detected during chronic murine airways infection after antibiotic pressure, indicating that the advantage of the hypermutable population in the lungs may contribute to disease progression. Conclusions Overall, these results showed that P. aeruginosa hypermutability, previously associated with a biological cost, increases colonization potential under selection pressure in a context of CF chronic airways infection and can contribute to lung damage during long-term persistence.