Nano-decocted ferrous polysulfide coordinates ferroptosis-like death in bacteria for anti-infection therapy

Antibacterial nanomaterials provide promising alternative strategies to combat the global challenge of bacterial infection due to deteriorating resistance. However, few have been applied for intracellular bacteria killing or in vivo therapy due to potential cytotoxicity and poor biocompatibility. Here we present a strategy to generate formula suitable for in vivo anti-infective therapy by decocting antibacterial nanomaterial. An aqueous formula containing ferrous iron and polysulfide (Fe(II)Snaq) is prepared by a decoction procedure using nano-iron sulfide (nFeS) as raw substance. Theoretical calculation indicated that replacement of a sulfur atom by an oxygen atom occurred, resulting in polysulfide release and iron dissolution. The Fe(II)Snaq decocted from nFeS induced bacterial death with ferroptosis-like hallmarks, including iron enrichment, lipid peroxidation, and glutathione (GSH) depletion. The antibacterial action of Fe(II)Snaq was dependent on ferrous iron, which could be inhibited by iron chelators, ferroptosis inhibitors, and GSH, while the polysulfide prevented ferrous iron oxidation and counteracted GSH. Furthermore, Fe(II)Snaq not only killed up to 99 % of planktonic bacteria within 5 min, but also suppressed up to 90 % of intracellular Staphylococcus aureus without triggering cytotoxicity to host cell. Administration of Fe(II)Snaq achieved equivalent therapeutic effect to vancomycin for infectious pneumonia treatment and significantly prolonged the survival period of septic mice. These results indicate that aqueous ferrous polysulfide can induce ferroptosis- like death in bacteria and may be formulated as an antibacterial alternative for anti-infection therapy.