A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa...

Area of Science:

• Microbiology
• Immunology
• Genetics

Background:

• Antibiotic resistance in Pseudomonas aeruginosa during chronic cystic fibrosis infections correlates with severe outcomes.
• Mechanisms of increased virulence in antibiotic-resistant strains remain poorly understood.

Purpose of the Study:

• To investigate the virulence mechanisms of aztreonam-resistant Pseudomonas aeruginosa.
• To identify specific genetic mutations and their functional consequences.

Main Methods:

• Utilized a macrophage infection model.
• Performed genomic and transcriptomic analyses.
• Investigated the role of RNase E mutations and siderophore production.

Main Results:

• A mutation in the rne gene (encoding RNase E) increased pyoverdine and pyochelin siderophore expression.
• Iron-bound pyochelin induced macrophage ferroptosis and lysis, while other siderophore forms did not.
• Gallium, an iron mimetic, eliminated macrophage killing.
• RNase E variants and their associated functions were observed in clinical cystic fibrosis isolates.

Conclusions:

• Pseudomonas aeruginosa RNase E variants enhance virulence through increased siderophore production, leading to host cell ferroptosis.
• These findings suggest potential therapeutic strategies targeting siderophore-mediated damage in cystic fibrosis.
• Gallium presents a potential precision therapy for infections caused by these resistant strains.