Housekeeping Genes: Possible Antifungal Drug Targets?

DESCRIPTION (provided by investigator): The occurrence of fungal infections has escalated significantly in recent years. Increases in the number of patients presenting with candidiasis and aspergillosis in particular, has been profound, especially in those immunocompromised by disease or therapies. Unfortunately, only a limited number of antifungal drugs are available for treatment of these and other fungal infections. The paucity of effective agents is due in part to the high degree of relatedness between the biochemical machinery of fungi and the mammalian host. Thus, only a few targets, primarily those associated with fungal cell wall and memebrane biosynthesis, have been successfully exploited. In contrast, "housekeeping enzymes", those enzymes involved in the general biosynthetic and metabolic functions of the cell, have not been seriously considered as potential antifungal drug targets since counterpart proteins usually exist in the host. However, a number of amino acid and vitamin biosynthetic enzymatic pathways that are not present in mammalian cells occur in, and are presumed essential for, survival of certain pathogenic fungi. In this context, the primary aim of the proposed Phase I investigation is to provide proof of principle to validate the use of two such housekeeping enzymes as potential antifungal drug targets.