Project Summary There is a worldwide need for improved treatment of systemic, life-threatening fungal infections. Current therapies are limited by the small number of approved drugs, toxicities, drug-drug interactions, mode of administration, and growing problems of drug resistance and emerging pathogens. Treatment also suffers from a lack of rapid clinical diagnoses, leading to dependence on broad-spectrum antifungal drugs. Moreover, existing antifungal drug classes target membrane and cell wall integrity, and there is a need to develop drugs with new modes of action. Essential genes are attractive antifungal drug targets because they are required for fungal pathogen growth and survival. C. albicans is the major human fungal pathogen and has the most robust genetic tools among the pathogenic fungi. We propose a “Redesigning Existing Drugs against Indispensable Targets” (ReEDIT) strategy that focuses on essential genes in C. albicans that have conserved human orthologs with known Chemically Tractable Inhibitors (CTIs) that are approved drugs or are in clinical or preclinical development. ReEDIT is an integrative approach using antifungal growth susceptibility, biochemical, structural, bioinformatic, and cheminformatic data, as well as molecular modeling studies to prioritize potential fungal targets. The specific aims of this Phase I proposal are to (1) identify essential genes in pathogenic fungi that encode druggable targets and (2) advance at least one essential target and drug series into lead optimization. The outcome will advance one or a small number of essential fungal targets and drug candidate(s) into a program for lead optimization and pre-clinical studies (Phase II). The long-term objectives are to develop inhibitors of novel essential fungal proteins into new classes of broad-spectrum antifungal drugs. To our knowledge, this is the first study to systematically assess a comprehensive set of conserved essential fungal genes and cognate inhibitors to be advanced for antifungal drug development.