Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1
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 inv...
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Published in | Chembiochem : a European journal of chemical biology Vol. 18; no. 20; pp. 2069 - 2078 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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18.10.2017
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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.
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. |
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AbstractList | 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 10µm. 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. 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. 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 μ m . 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. 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. |
Author | Deepe, George S. Lescano, Victor Bell‐Horwath, Tiffany R. Merino, Edward J. Horwath, Michael C. Krishnan, Karthik |
Author_xml | – sequence: 1 givenname: Michael C. orcidid: 0000-0002-0128-9147 surname: Horwath fullname: Horwath, Michael C. organization: University of Cincinnati College of Medicine – sequence: 2 givenname: Tiffany R. surname: Bell‐Horwath fullname: Bell‐Horwath, Tiffany R. organization: University of Cincinnati McMicken College of Arts and Sciences – sequence: 3 givenname: Victor surname: Lescano fullname: Lescano, Victor organization: University of Cincinnati College of Allied Health Sciences – sequence: 4 givenname: Karthik surname: Krishnan fullname: Krishnan, Karthik organization: University of Cincinnati Medical Center – sequence: 5 givenname: Edward J. surname: Merino fullname: Merino, Edward J. organization: University of Cincinnati McMicken College of Arts and Sciences – sequence: 6 givenname: George S. orcidid: 0000-0001-6158-6461 surname: Deepe fullname: Deepe, George S. email: george.deepe@uc.edu organization: Cincinnati VA Medical Center |
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Keywords | ferrostatin Histoplasma capsulatum antifungal lipophilic antioxidant structure-activity relationship |
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Snippet | Ferrostatin‐1 (Fer‐1) is a lipophilic antioxidant that effectively blocks ferroptosis, a distinct non‐apoptotic form of cell death caused by lipid... Ferrostatin-1 (Fer-1) is a lipophilic antioxidant that effectively blocks ferroptosis, a distinct non-apoptotic form of cell death caused by lipid... Abstract Ferrostatin‐1 (Fer‐1) is a lipophilic antioxidant that effectively blocks ferroptosis, a distinct non‐apoptotic form of cell death caused by lipid... |
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SubjectTerms | 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 |
Title | Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1 |
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