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Published on: March 15, 2024
Antifungal Activity of the Lipophilic Antioxidant Ferrostatin-1
Michael C Horwath1,2, Tiffany R Bell-Horwath3, Victor Lescano4
1Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, 333 Burnet Avenue, Cincinnati, OH, 45229, USA.
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.
Insights
Ferrostatin-1, an antioxidant blocking cell death, unexpectedly inhibits fungal growth. This compound shows potent antifungal activity against Histoplasma capsulatum and related species, independent of its cell death-blocking properties.
Area of Science:
- Mycology
- Cell Biology
- Infectious Diseases
Background:
- Ferrostatin-1 (Fer-1) is a known inhibitor of ferroptosis, a form of cell death driven by lipid peroxidation.
- Oxidative stress occurs in host cells and pathogens during infections, but ferroptosis's role in this context was unexplored.
- The study investigates ferroptosis in macrophages infected with the pathogenic yeast Histoplasma capsulatum.
Purpose of the Study:
- To investigate the occurrence and role of ferroptosis in macrophages infected with Histoplasma capsulatum.
- To determine the effect of Ferrostatin-1 on infected macrophages and fungal growth.
- To explore the mechanism behind Fer-1's observed effects on fungal pathogens.
Main Methods:
- Macrophages were infected with Histoplasma capsulatum in vitro.
- Ferrostatin-1 and other ferroptosis inhibitors were used to treat infected macrophages.
- Fungal growth inhibition and ergosterol content were measured.
- Structural analysis of Fer-1 and its analogues was performed.
Main Results:
- Ferrostatin-1 reduced infected macrophage death and inhibited the growth of Histoplasma capsulatum, Paracoccidioides lutzii, and Blastomyces dermatitidis.
- Other ferroptosis inhibitors like liproxstatin-1 did not show similar antifungal effects.
- Fer-1 treatment led to a significant decrease in ergosterol content in H. capsulatum.
- Structural similarities suggested Fer-1 might inhibit fungal sterol synthesis.
Conclusions:
- Ferrostatin-1 exhibits potent antifungal activity against pathogenic yeasts, independent of its ferroptosis-inhibiting function.
- The antifungal mechanism of Fer-1 may involve the inhibition of fungal sterol synthesis.
- Fer-1 represents a potential lead compound for developing new antifungal therapies.
