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Targeting ceramide synthases for the development of new antifungals
Deveney Dasilva1, Nivea Pereira de Sa1, Kathryn Takemura2
1Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA.
Abstract:
Invasive fungal infections (IFIs) caused by pathogenic fungi are a major public health concern, particularly across various immunocompromised populations. Effective clinical management is currently hindered by limited treatment options. Fungal sphingolipids have emerged as potential antifungal targets based on cumulative evidence demonstrating that fungal sphingolipid metabolism is key to the virulence of pathogenic fungi. This study focuses on the sphingolipid metabolizing enzyme ceramide synthase. We developed an enzymatic assay to examine ceramide synthase activity and devised a high-throughput screening platform. Two synthetic compounds were identified that preferentially inhibit the fungal vs. the mammalian ceramide synthase activity. Further studies indicate that these compounds block fungal growth, with in silico and mutagenesis investigations revealing insights into the interactions between the inhibitors and the ceramide synthase active site. Together, our study establishes fungal ceramide synthase as a promising antifungal target and paves the way for new structure-activity relationship studies leveraging fungal sphingolipid metabolism.
Insights
Researchers identified novel compounds that inhibit fungal ceramide synthase, a key enzyme in fungal virulence. This discovery offers a promising new strategy for developing treatments against invasive fungal infections (IFIs) in immunocompromised patients.
Area of Science:
- Medical Mycology
- Biochemistry
- Drug Discovery
Background:
- Invasive fungal infections (IFIs) pose a significant threat, especially to immunocompromised individuals.
- Current antifungal treatments are limited, necessitating the exploration of novel therapeutic targets.
- Fungal sphingolipid metabolism is crucial for the virulence of pathogenic fungi, making it a potential target.
Purpose of the Study:
- To investigate fungal ceramide synthase as a potential antifungal target.
- To develop and utilize a high-throughput screening platform to identify inhibitors of fungal ceramide synthase.
Main Methods:
- Development of an enzymatic assay to measure ceramide synthase activity.
- Implementation of a high-throughput screening platform to identify inhibitory compounds.
- In silico and mutagenesis studies to elucidate inhibitor-enzyme interactions.
Main Results:
- Two synthetic compounds were identified that selectively inhibit fungal ceramide synthase over mammalian forms.
- These compounds demonstrated efficacy in blocking fungal growth.
- Structural insights into inhibitor binding at the ceramide synthase active site were obtained.
Conclusions:
- Fungal ceramide synthase is validated as a promising molecular target for antifungal drug development.
- The identified inhibitors provide a foundation for structure-activity relationship studies.
- This research opens new avenues for combating invasive fungal infections through sphingolipid metabolism modulation.
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