Dataset Information

Metabotypes of Pseudomonas aeruginosa Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections.

ABSTRACT: Pseudomonas aeruginosa (P.a) is one of the most critical antibiotic resistant bacteria in the world and is the most prevalent pathogen in cystic fibrosis (CF), causing chronic lung infections that are considered one of the major causes of mortality in CF patients. Although several studies have contributed to understanding P.a within-host adaptive evolution at a genomic level, it is still difficult to establish direct relationships between the observed mutations, expression of clinically relevant phenotypes, and clinical outcomes. Here, we performed a comparative untargeted LC/HRMS-based metabolomics analysis of sequential isolates from chronically infected CF patients to obtain a functional view of P.a adaptation. Metabolic profiles were integrated with expression of bacterial phenotypes and clinical measurements following multiscale analysis methods. Our results highlighted significant associations between P.a "metabotypes", expression of antibiotic resistance and virulence phenotypes, and frequency of clinical exacerbations, thus identifying promising biomarkers and therapeutic targets for difficult-to-treat P.a infections.

SUBMITTER: Moyne O

PROVIDER: S-EPMC7909822 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Metabotypes of Pseudomonas aeruginosa Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections.

Moyne Oriane O Castelli Florence F Bicout Dominique J DJ Boccard Julien J Camara Boubou B Cournoyer Benoit B Faudry Eric E Terrier Samuel S Hannani Dalil D Huot-Marchand Sarah S Léger Claire C Maurin Max M Ngo Tuan-Dung TD Plazy Caroline C Quinn Robert A RA Attree Ina I Fenaille François F Toussaint Bertrand B Le Gouëllec Audrey A

Metabolites 20210121 2

Pseudomonas aeruginosa (P.a) is one of the most critical antibiotic resistant bacteria in the world and is the most prevalent pathogen in cystic fibrosis (CF), causing chronic lung infections that are considered one of the major causes of mortality in CF patients. Although several studies have contributed to understanding P.a within-host adaptive evolution at a genomic level, it is still difficult to establish direct relationships between the observed mutations, expression o ...[more]

PMID: 33494144

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Project description: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.

Project description:RationalePseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity.ObjectivesTo characterize the population genetic structure of transmissible P. aeruginosa Liverpool Epidemic Strain in chronic infections of nine patients with cystic fibrosis, and infer evolutionary processes associated with adaptation to the cystic fibrosis lung.MethodsWe performed whole-genome sequencing of P. aeruginosa isolates and pooled populations and used comparative analyses of genome sequences including phylogenetic reconstructions and resolution of population structure from genome-wide allele frequencies.Measurements and main resultsGenome sequences were obtained for 360 isolates from nine patients. Phylogenetic reconstruction of the ancestry of 40 individually sequenced isolates from one patient sputum sample revealed the coexistence of two genetically diverged, recombining lineages exchanging potentially adaptive mutations. Analysis of population samples for eight additional patients indicated coexisting lineages in six cases. Reconstruction of the ancestry of individually sequenced isolates from all patients indicated smaller genetic distances between than within patients in most cases.ConclusionsOur population-level analysis demonstrates that coexistence of distinct lineages of P. aeruginosa Liverpool Epidemic Strain within individuals is common. In several cases, coexisting lineages may have been present in the infecting inoculum or assembled through multiple transmissions. Divergent lineages can share mutations via homologous recombination, potentially aiding adaptation to the airway during chronic infection. The genetic diversity of this transmissible strain within infections, revealed by high-resolution genomics, has implications for patient segregation and therapeutic strategies.

Dataset Information

Metabotypes of Pseudomonas aeruginosa Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections.

Publications

Metabotypes of <i>Pseudomonas aeruginosa</i> Correlate with Antibiotic Resistance, Virulence and Clinical Outcome in Cystic Fibrosis Chronic Infections.

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