Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance

Chowdhury M Hasan, Sian Pottenger, Angharad E Green, Adrienne A Cox, Jack S White, Trevor Jones, Craig Winstanley, Aras Kadioglu, Megan H Wright, Daniel R Neill, Joanne L Fothergill

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
18 Downloads (Pure)

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.

Original languageEnglish
Article numbere158879
Number of pages14
JournalJCI Insight
Volume7
Issue number22
DOIs
Publication statusPublished - 22 Nov 2022

Keywords

  • Mice
  • Animals
  • Pseudomonas aeruginosa/genetics
  • Polyamines/metabolism
  • Spermidine/metabolism
  • Microbial Sensitivity Tests
  • Cystic Fibrosis/drug therapy
  • Anti-Infective Agents/metabolism

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