Copper ions induces ferroptosis in Staphylococcus aureus and promotes healing of MRSA-induced wound infections

Abstract

The emergence of multidrug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), poses a significant threat to public health, necessitating new antimicrobial strategies. Here, we demonstrate that low doses of copper sulfate (CuSO₄) exhibit potent bactericidal effects against both S. aureus and MRSA by inducing ferroptosis. CuSO₄ treatment causes bacterial cell membrane perforation, increases intracellular free copper (Cu⁺) and ferrous ions (Fe²⁺), elevates reactive oxygen species (ROS) production and lipid peroxidation, and triggers the intracellular Fenton reaction. The use of ROS scavengers, copper chelators, iron chelators, and iron oxidase inhibitors attenuated ROS levels and lipid peroxidation, reducing Cu²⁺-mediated cell death, confirming the role of ferroptosis. Proteomic analysis revealed that Cu²⁺ enhances the expression of Fur protein, mediates iron release from intracellular stores, and inhibits glutathione biosynthesis. Furthermore, we developed a sodium alginate hydrogel loaded with CuSO₄ (Cu-SA), which significantly improved wound healing and reduced inflammation and organ damage in an MRSA-infected mouse skin model. Our findings suggest that Cu²⁺-induced ferroptosis offers a promising alternative to traditional antibiotics for treating MRSA infections, providing a novel strategy to combat antibiotic resistance in S. aureus.