Antifungal Activity of the Lipophilic Antioxidant Ferrostatin-1

Abstract: Ferrostatin-1 (Fer-1) is a lipophilic antioxidant that effectively blocks ferroptosis, a distinct non-apoptotic form of cell death caused by lipid peroxidation. During many infections, both pathogens and host cells are subjected to oxidative stress, but the occurrence of ferroptosis has not been investigated. Ferroptosis was examined in macrophages infected with the pathogenic yeast Histoplasma capsulatum. Unexpectedly, Fer-1 not only reduced death of macrophages infected in vitro, but inhibited the growth of H. capsulatum and related species Paracoccidioides lutzii and Blastomyces dermatitidis at concentrations under 10 M. Other antioxidant ferroptosis inhibitors, including Liproxstatin-1, did not prevent fungal growth or reduce macrophage death. Structural analysis revealed potential similarity of Fer-1 to inhibitors of fungal sterol synthesis, and ergosterol content of H. capsulatum decreased over two-fold after incubation with Fer-1. Strikingly, additional Fer-1 analogs with slight differences from Fer-1 had limited impact on fungal growth. In conclusion, the ferroptosis inhibitor Fer-1 has unexpected antifungal potency distinct from its anti-ferroptotic activity.