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Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance
Chowdhury M Hasan1, Sian Pottenger1, Angharad E Green1
1Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.
Abstract:
Pseudomonas aeruginosa undergoes diversification during infection of the cystic fibrosis (CF) lung. Understanding these changes requires model systems that capture the complexity of the CF lung environment. We previously identified loss-of-function mutations in the 2-component regulatory system sensor kinase gene pmrB in P. aeruginosa from CF lung infections and from experimental infection of mice. Here, we demonstrate that, while such mutations lowered in vitro minimum inhibitory concentrations for multiple antimicrobial classes, this was not reflected in increased antibiotic susceptibility in vivo. Loss of PmrB impaired aminoarabinose modification of LPS, increasing the negative charge of the outer membrane and promoting uptake of cationic antimicrobials. However, in vivo, this could be offset by increased membrane binding of other positively charged molecules present in lungs. The polyamine spermidine readily coated the surface of PmrB-deficient P. aeruginosa, reducing susceptibility to antibiotics that rely on charge differences to bind the outer membrane and increasing biofilm formation. Spermidine was elevated in lungs during P. aeruginosa infection in mice and during episodes of antimicrobial treatment in people with CF. These findings highlight the need to study antimicrobial resistance under clinically relevant environmental conditions. Microbial mutations carrying fitness costs in vitro may be advantageous during infection, where host resources can be utilized.
Insights
Mutations in Pseudomonas aeruginosa that reduce antibiotic susceptibility in lab tests may not work in cystic fibrosis lungs. Host molecules like spermidine can protect bacteria, increasing resistance and biofilm formation.
Area of Science:
- Microbiology
- Infectious Diseases
- Cystic Fibrosis Research
Background:
- Pseudomonas aeruginosa diversifies during cystic fibrosis lung infections.
- Loss-of-function mutations in pmrB were previously identified in P. aeruginosa from CF infections.
- Understanding these bacterial adaptations requires complex model systems.
Purpose of the Study:
- To investigate the in vivo impact of PmrB mutations on antibiotic susceptibility in Pseudomonas aeruginosa.
- To explore the role of host factors in modulating bacterial response to antimicrobial pressure.
Main Methods:
- Analysis of pmrB loss-of-function mutants in Pseudomonas aeruginosa.
- In vitro minimum inhibitory concentration (MIC) testing for various antimicrobial classes.
- In vivo infection models (mice) and analysis of bacterial adaptation.
- Investigation of outer membrane modifications (LPS) and polyamine interactions (spermidine).
Main Results:
- PmrB mutations decreased in vitro antibiotic susceptibility but this was not observed in vivo.
- Loss of PmrB altered LPS, increasing outer membrane negative charge and cationic antimicrobial uptake.
- Host-derived spermidine coated PmrB-deficient P. aeruginosa, reducing susceptibility and promoting biofilm formation.
- Spermidine levels were elevated during P. aeruginosa infection and antimicrobial treatment in CF patients.
Conclusions:
- In vitro findings on antibiotic resistance do not always translate to the in vivo cystic fibrosis lung environment.
- Host-derived polyamines like spermidine can counteract bacterial mutations conferring antimicrobial resistance.
- Studying bacterial adaptation in clinically relevant conditions is crucial for understanding antimicrobial resistance.
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