Targeting fungal ceramide synthases as new antifungals

ABSTRACT The goal of this project is to discover and develop a new therapeutic(s) more potent than current antifungals for the treatment of invasive fungal infections. Among invasive fungal infections, cryptococcosis, candidiasis, and aspergillosis are the most life-threatening.1-3 The incidence of these infections has risen more than 14-fold over the last 20 years,4-11 with a mortality rate of 1,300,000/year.12 We recently discovered a fungal enzyme, ceramide synthase 1 (Cer1), essential for fungal growth at neutral, alkaline and acidic environments. Thus, a fungal mutant lacking Cer1 is not pathogenic in animal models because, upon infection, it cannot survive in host neutral (lung and other organs), alkaline (blood) and acidic (inflammatory tissue) environments. Thus, Cer1 is an ideal target for the development of new antifungals because any compound blocking Cer1 will be fungicidal. We have optimized a high throughput assay that allows the screen for inhibitors of ceramide synthase activity and found few hits that selectively inhibit fungal Cer1. Thus, in this proposal we will continue the screening of the ChemBridge DIVERSet libraries to select a potent hit molecule(s) that ideally target fungal but not mammalian Ceramide synthases, to move it forward for medicinal chemistry and preclinical studies. We do have the experience and expertise to perform these studies.