Ferric chloride induces ferroptosis in Pseudomonas aeruginosa and heals wound infection in a mouse model

Abstract

Background: Pseudomonas aeruginosa is one of the most common pathogens that lead to fatal human infection. This Gram-negative pathogen has evolved complex drug resistance, which poses significant challenges to the current antibiotic-dependent healthcare system. New therapeutic approaches are urgently required to treat infections caused by P. aeruginosa.

Methods: Inspired by ferroptosis, the antibacterial effects of iron compounds on P. aeruginosa via direct exposure were investigated. In addition, thermal-responsive hydrogels to carry FeCl₃ were developed as a wound dressing to treat P. aeruginosa-induced wound infection in a mouse model.

Results: The results showed that 200 µM FeCl₃ killed more than 99.9% of P. aeruginosa cells. FeCl₃-mediated cell death in P. aeruginosa was associated with hallmarks of ferroptosis in mammalian cells, including reactive oxygen species (ROS) burst, lipid peroxidation, and DNA damage. Catalase or Fe²⁺ chelator alleviated FeCl₃-mediated cell death, indicating that H₂O₂ and labile Fe²⁺ induced the Fenton reaction leading to cell death. Further proteomics analysis showed that proteins related to glutathione (GSH) synthesis and the glutathione peroxidase (GPX) family were significantly downregulated after FeCl₃ treatment, which is equivalent to GPX4 inactivation in mammalian cells. The therapeutic effect of FeCl₃ on P. aeruginosa was further evaluated in a mouse wound infection model using polyvinyl alcohol-boric acid (PB) hydrogels as a carrier of FeCl₃. FeCl₃-PB hydrogels completely cleared pus on wounds and promoted wound healing.

Conclusion: These results indicated that FeCl₃ induces microbial ferroptosis in P. aeruginosa and has high therapeutic potential for the treatment of P. aeruginosa wound infection.

Keywords: FeCl(3); Pseudomonas aeruginosa; ferroptosis; hydrogels; polyvinyl alcohol-boric acid hydrogels.