Hasan, Chowdhury M, Pottenger, Sian 
ORCID: 0000-0002-5700-9693, Green, Angharad E ORCID: 0000-0002-8683-8191, Cox, Adrienne A, White, Jack S, Jones, Trevor, Winstanley, Craig, Kadioglu, Aras ORCID: 0000-0003-1137-6321, Wright, Megan H, Neill, Daniel R ORCID: 0000-0002-7911-8153 et al (show 1 more authors)
(2022)
Pseudomonas aeruginosa utilizes the host-derived polyamine spermidine to facilitate antimicrobial tolerance.
JCI INSIGHT, 7 (22).
e158879-.
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Animals, Mice, Pseudomonas aeruginosa, Cystic Fibrosis, Spermidine, Polyamines, Anti-Infective Agents, Microbial Sensitivity Tests |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 11 Oct 2022 07:58 |
| Last Modified: | 18 Jan 2023 20:37 |
| DOI: | 10.1172/jci.insight.158879 |
| Open Access URL: | https://insight.jci.org/articles/view/158879 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165231 |
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