2. Academic Validation
  3. Targeting ceramide synthases for the development of new antifungals

Targeting ceramide synthases for the development of new antifungals

  • Structure. 2025 Jun 12:S0969-2126(25)00213-8. doi: 10.1016/j.str.2025.05.016.
Deveney Dasilva 1,  Nivea Pereira de Sa 1,  Kathryn Takemura 2,  Kalani Jayanetti 2,  Jeehyun Karen You 1,  Nathalia Vieira de Sa 1,  Gabriel Soares Matos 1,  Andy Zhong 1,  Can E Senkal 3,  Yusuf Hannun 4,  Iwao Ojima 5,  John Mallamo 6,  John B McCarthy 6,  Maurizio Del Poeta 7
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA.
  • 2 Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.
  • 3 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
  • 4 Department of Medicine, Stony Brook University, Stony Brook, NY, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Veterans Affairs Medical Center, Northport, NY, USA.
  • 5 Department of Chemistry, Stony Brook University, Stony Brook, NY, USA; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
  • 6 MicroRid Technologies Inc., Dix Hills, NY, USA.
  • 7 Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA; Veterans Affairs Medical Center, Northport, NY, USA; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA; MicroRid Technologies Inc., Dix Hills, NY, USA; Division of Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY, USA. Electronic address: maurizio.delpoeta@stonybrook.edu.
PMID: 40555233 DOI: 10.1016/j.str.2025.05.016
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.

Keywords

Cryptococcus neoformans; antifungal; ceramide; ceramide synthase; docking; drug discovery; high-throughput screening; small molecule library; sphingolipid; sphingosine.

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