Targeting the sphingolipid pathway for the R&D of new antifungals

ABSTRACT The goal of this project is to discover and develop a new therapeutic smore potent than current antifungals for the treatment of invasive fungal infectionsAmong invasive fungal infectionscryptococcosiscandidiasisand aspergillosis are the most life threateningThe incidence of these infections has risen more thanfold over the lastyearswith a mortality rate ofyearWe recently discovered a fungal enzymeceramide synthaseCeressential for fungal growth at neutralalkaline and acidic environmentsThusa fungal mutant lacking Ceris not pathogenic in animal models becauseupon infectionit cannot survive in host neutrallung and other organsalkalinebloodand acidicinflammatory tissueenvironmentsThusCeris an ideal target for the development of new antifungals because any compound blocking Cerwill be fungicidalWe have optimized a high throughput assay that allows the screen for selective and specific inhibitors of fungal CerThuswe will screen ChemBridge DIVERSet libraries for compounds inhibiting fungal Cerbut not human ceramide synthases and select potent hit molecule sto move forward for medicinal chemistry and preclinical studiesWe do have the experience and expertise to perform these studies NARRATIVE Fungal infections have dramatically increased during the last decade and new treatment strategies are neededThis proposal focuses on developing new compounds targeting the fungal but not the mammalian sphingolipid pathway