Mucoidy, quorum sensing, mismatch repair and antibiotic resistance in Pseudomonas aeruginosa from cystic fibrosis chronic airways infections.
Survival of Pseudomonas aeruginosa in cystic fibrosis (CF) chronic infections is based on a genetic adaptation process consisting of mutations in specific genes, which can produce advantageous phenotypic switches and ensure its persistence in the lung. Among these, mutations inactivating the regulators MucA (alginate biosynthesis), LasR (quorum sensing) and MexZ (multidrug-efflux pump MexXY) are the most frequently observed, with those inactivating the DNA mismatch repair system (MRS) being also highly prevalent in P. aeruginosa CF isolates, leading to hypermutator phenotypes that could contribute to this adaptive mutagenesis by virtue of an increased mutation rate. Here, we characterized the mutations found in the mucA, lasR, mexZ and MRS genes in P. aeruginosa isolates obtained from Argentinean CF patients, and analyzed the potential association of mucA, lasR and mexZ mutagenesis with MRS-deficiency and antibiotic resistance. Thus, 38 isolates from 26 chronically infected CF patients were characterized for their phenotypic traits, PFGE genotypic patterns, mutations in the mucA, lasR, mexZ, mutS and mutL gene coding sequences and antibiotic resistance profiles. The most frequently mutated gene was mexZ (79%), followed by mucA (63%) and lasR (39%) as well as a high prevalence (42%) of hypermutators being observed due to loss-of-function mutations in mutL (60%) followed by mutS (40%). Interestingly, mutational spectra were particular to each gene, suggesting that several mechanisms are responsible for mutations during chronic infection. However, no link could be established between hypermutability and mutagenesis in mucA, lasR and mexZ, indicating that MRS-deficiency was not involved in the acquisition of these mutations. Finally, although inactivation of mucA, lasR and mexZ has been previously shown to confer resistance/tolerance to antibiotics, only mutations in MRS genes could be related to an antibiotic resistance increase. These results help to unravel the mutational dynamics that lead to the adaptation of P. aeruginosa to the CF lung.
Feliziani
Sofía
S
Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), CONICET, Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Luján
Adela M
AM
Moyano
Alejandro J
AJ
Sola
Claudia
C
Bocco
José L
JL
Montanaro
Patricia
P
Canigia
Liliana Fernández
LF
Argaraña
Carlos E
CE
Smania
Andrea M
AM
D000293:Adolescent; D000328:Adult; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000382:microbiology*; D053843:DNA Mismatch Repair; D004352:Drug Resistance, Microbial; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008297:Male; D009154:Mutation; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D053038:Quorum Sensing; D012137:Respiratory System / Q000382:microbiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D001426:Bacterial Proteins; C080365:LasR protein, Pseudomonas aeruginosa; C402792:MexZ protein, Pseudomonas aeruginosa; C063757:MucA protein, Bacteria; D015534:Trans-Activators