Abstract
As one of the most common pathogens leading to fatal human infection, Pseudomonas aeruginosa has been evolving complex drug resistance, posing significant challenges to the current antibiotic-dependent healthcare system. New therapeutic approaches are urgently required to treat infections caused by P. aeruginosa. Inspired by ferroptosis, we investigated the antibacterial effects of iron compounds on P. aeruginosa via direct exposure, and developed thermal-responsive hydrogels to carry FeCl3 as a wound dressing to treat P. aeruginosa-induced wound infection in mice model. The results showed that 200 μM FeCl3 killed more than 99.9% P. aeruginosa cells. The FeCl3-mediated cell death in P. aeruginosa was associated with ferroptosis hallmarks of mammal cells, e.g., reactive oxygen species (ROS) burst, lipid peroxidation, and DNA damage. Either catalase or Fe2+ chelator alleviated the FeCl3-mediated cell death, indicating that H2O2 and labile Fe2+ facilitated the Fenton reaction leading to the cell death. Further proteomics analysis showed that proteins related to glutathione (GSH) synthesis and glutathione peroxidase (GPX) family were significantly down-regulated after FeCl3 treatment, equivalent to GPX4 inactivation in ferroptosis-occurring mammal cells. We further evaluated the therapeutic effect of FeCl3 on P. aeruginosa in a mouse wound infection model using polyvinyl alcohol-boric acid (PB) hydrogels as the carrier of FeCl3. Strikingly, FeCl3-PB hydrogels completely cleared pus on wounds and promoted the healing of wounds. These results indicated that FeCl3 facilitates microbial ferroptosis in the gram-negative pathogen P. aeruginosa and has high therapeutic potential in P. aeruginosa wound infection.
Published Version
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