Agmatine accumulation by Pseudomonas aeruginosa clinical isolates confers antibiotic tolerance and dampens host inflammation
| Autor: | Ryan C. Hunter, Adam J Gilbertsen, Bryan J. Williams, Clayton Evert, Jennifer L. McCurtain |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Agmatine Cystic Fibrosis Arginine Multidrug tolerance Hydrolases Neutrophils 030106 microbiology Virulence Microbial Sensitivity Tests Biology medicine.disease_cause Microbiology Mice 03 medical and health sciences chemistry.chemical_compound Drug Resistance Bacterial Pneumonia Bacterial medicine Tobramycin Animals Humans Pseudomonas Infections Arginine deiminase 030304 developmental biology Pathogenesis Virulence and Host Response Inflammation 0303 health sciences 030306 microbiology Pseudomonas aeruginosa Sputum Epithelial Cells General Medicine Adaptation Physiological Anti-Bacterial Agents 3. Good health Disease Models Animal Phenotype 030104 developmental biology chemistry Mutation Colistin Female medicine.drug |
| Zdroj: | J Med Microbiol |
| ISSN: | 1473-5644 0022-2615 |
| DOI: | 10.1099/jmm.0.000928 |
| Popis: | In the cystic fibrosis (CF) airways,Pseudomonas aeruginosaundergoes diverse physiological changes in response to inflammation, antibiotic pressure, oxidative stress and a dynamic bioavailable nutrient pool. These include loss-of-function mutations that result in reduced virulence, altered metabolism and other phenotypes that are thought to confer a selective advantage for long-term persistence. Recently, clinical isolates ofP. aeruginosathat hyperproduce agmatine (decarboxylated arginine) were cultured from individuals with CF. Sputum concentrations of this metabolite were also shown to correlate with disease severity. This raised the question of whether agmatine accumulation might also confer a selective advantage forP. aeruginosa in vivoduring chronic colonization of the lung. Here, we screened a library ofP. aeruginosaCF clinical isolates and found that ~5% of subjects harbored isolates with an agmatine hyperproducing phenotype. Agmatine accumulation was a direct result of mutations inaguA, encoding the arginine deiminase that catalyzes the conversion of agmatine into various polyamines. We also found that agmatine hyperproducing isolates (aguA-) had increased tolerance to the cationic antibiotics gentamicin, tobramycin and colistin relative to their chromosomally complemented strains (aguA+). Finally, we revealed that agmatine diminishes IL-8 production by airway epithelial cells in response to bacterial infection, with a consequent decrease in neutrophil recruitment to the murine airways in an acute pneumonia model. These data highlight a potential new role for bacterial-derived agmatine that may have important consequences for the long-term persistence ofP. aeruginosain the CF airways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|