Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1

• Published in: Chembiochem : a European journal of chemical biology Vol. 18; no. 20; pp. 2069 - 2078
• Main Authors: Horwath, Michael C., Bell‐Horwath, Tiffany R., Lescano, Victor, Krishnan, Karthik, Merino, Edward J., Deepe, George S.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 18.10.2017
• Subjects: antifungal; Antifungal activity; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Apoptosis; Cell death; Cyclohexylamines - chemistry; Cyclohexylamines - pharmacology; Ergosterol; Ferroptosis; ferrostatin; Fungi; Fungicides; Histoplasma - drug effects; Histoplasma capsulatum; Hydrophobic and Hydrophilic Interactions; Incubation; Inhibitors; Lipid peroxidation; Lipophilic; lipophilic antioxidant; Macrophages; Mortality; Oxidative stress; Peroxidation; Phenylenediamines - chemistry; Phenylenediamines - pharmacology; Structural analysis; Structure-Activity Relationship; Yeast; ferrostatin; Histoplasma capsulatum; antifungal; lipophilic antioxidant; structure-activity relationship
• DOI: 10.1002/cbic.201700105
• ISSN: 1439-4227

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 had not been investigated. We examined ferroptosis in macrophages infected with the pathogenic yeast Histoplasma capsulatum. Unexpectedly, Fer‐1 not only reduced the 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 μm. Other antioxidant ferroptosis inhibitors, including liproxstatin‐1, did not prevent fungal growth or reduce macrophage death. Structural analysis revealed a potential similarity of Fer‐1 to inhibitors of fungal sterol synthesis, and ergosterol content of H. capsulatum decreased more than twofold after incubation with Fer‐1. Strikingly, additional Fer‐1 analogues 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 antiferroptotic activity. Unexpected antifungal: Ferrostatin‐1 (Fer‐1) is a lipophilic antioxidant and potent inhibitor of ferroptosis, a mammalian cell death process characterized by lipid peroxidation. We investigated whether ferroptosis could be occurring in macrophages infected with the pathogenic yeast H. capsulatum and made the unexpected discovery that Fer‐1 exhibits antifungal activity, distinct from its antioxidant function.