Antifungal Activity of the Lipophilic Antioxidant Ferrostatin-1 |
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Authors: | Michael C Horwath Prof Tiffany R Bell-Horwath Victor Lescano Dr Karthik Krishnan Prof Edward J Merino Prof George S Deepe Jr |
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Affiliation: | 1. Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, 333 Burnet Avenue, Cincinnati, OH, 45229 USA;2. Department of Chemistry, University of Cincinnati McMicken College of Arts and Sciences, 2600 Clifton Court, Cincinnati, OH, 45221 USA;3. Department of Clinical and Health Information Sciences, University of Cincinnati College of Allied Health Sciences, 3202 Albert Sabin Way, Cincinnati, OH, 45267 USA;4. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 234 Goodman Street, Cincinnati, OH, 45219 USA;5. Division of Infectious Diseases, University of Cincinnati College of Medicine, 3230 Eden Avenue, Cincinnati, OH, 45267 USA |
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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 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. |
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Keywords: | antifungal ferrostatin Histoplasma capsulatum lipophilic antioxidant structure–activity relationship |
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