4.7 Article

Pseudomonas aeruginosa Oligoribonuclease Controls Tolerance to Polymyxin B by Regulating Pel Exopolysaccharide Production

Journal

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 66, Issue 3, Pages -

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.02072-21

Keywords

Pel; Pseudomonas aeruginosa; eDNA; polymyxins

Funding

  1. National Key Research and Development Project of China [2021YFE0101700, 82061148018]
  2. National Science Foundation of China [32170177, 32170199, 31970179, 31970680, 31900115]
  3. Fundamental Research Funds for the Central Universities [63213121]
  4. Tianjin Municipal Science and Technology Commission [19JCYBJC24700]

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Polymyxins are last-resort antibiotics for treating infections caused by multidrug-resistant Gram-negative pathogens. Pseudomonas aeruginosa, an opportunistic pathogen, has proteins that contribute to bacterial resistance to polymyxins by modifying lipopolysaccharides and maintaining membrane integrities. The study found that a mutation in the oligoribonuclease gene increased bacterial survival after polymyxin B treatment in P. aeruginosa. Pel, a protein that binds to extracellular DNA, was also shown to trap polymyxin B and protect bacterial cells.
Polymyxins are considered as the last resort antibiotics to treat infections caused by multidrug-resistant Gram-negative pathogens. Pseudomonas aeruginosa is an opportunistic pathogen that causes various infections in humans. Proteins involved in lipopolysaccharide modification and maintaining inner and outer membrane integrities have been found to contribute to the bacterial resistance to polymyxins. Polymyxins are considered as the last resort antibiotics to treat infections caused by multidrug-resistant Gram-negative pathogens. Pseudomonas aeruginosa is an opportunistic pathogen that causes various infections in humans. Proteins involved in lipopolysaccharide modification and maintaining inner and outer membrane integrities have been found to contribute to the bacterial resistance to polymyxins. Oligoribonuclease (Orn) is an exonuclease that regulates the homeostasis of intracellular (3 '-5 ')-cyclic dimeric GMP (c-di-GMP), thereby regulating the production of extracellular polysaccharide in P. aeruginosa. Previously, we demonstrated that Orn affects the bacterial resistance to fluoroquinolone, beta-lactam and aminoglycoside antibiotics. In this study, we found that mutation of orn increased the bacterial survival following polymyxin B treatment in a wild-type P. aeruginosa strain PA14. Overexpression of c-di-GMP degradation enzymes in the orn mutant reduced the bacterial survival. By using a fluorescence labeled polymyxin B, we found that mutation of orn increased the bacterial surface bound polymyxin B. Deletion of the Pel synthesis genes or treatment with a Pel hydrolase reduced the surface bound polymyxin B and bacterial survival. We further demonstrated that Pel binds to extracellular DNA (eDNA), which traps polymyxin B and thus protects the bacterial cells. Collectively, our results revealed a novel defense mechanism against polymyxin in P. aeruginosa.

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