The incidence of serious fungal infections has increased markedly in the last two decades and effective treatment options are increasingly compromised by the emergence of drug-resistant strains. The goal of the proposed work is to develop novel antifungal drugs that are safer and more effective than those currently available. The work will focus primarily on the dimorphic yeast, C. albicans, which is by far the leading cause of both life-threatening systemic fungal infections and more commonly occurring topical infections. A distinguishing feature of the drug-discovery strategy the applicants are pursuing is that it is based on target discovery, target prioritization and screening, all conducted with the pathogen itself, rather than with a surrogate model system. This strategy has been enabled by gene-identification and screen-configuration technologies developed at Elitra Pharmaceuticals, including important technologies developed under Phase I funding for this program. Under Phase I, an expression vector system was constructed that will allow screening for dominant-negative phenotypes. No such tools existed previously for C. albicans. Screens for dominant-negatives will identify new drug targets in C. albicans and help annotate essential physiological pathways in this important fungal pathogen. Critical functional features of the expression vector system have already been validated, a C. albicans complementary deoxyribonucleic acid (cDNA) library has been constructed in the vector, and pilot screening for dominant-negatives is in progress. Under Phase II funding, the investigators propose to implement the screen more broadly, characterize and prioritize the targets that are identified and conduct screening for drug leads. The dominant-negative phenotypes of the newly identified targets will be used to develop primary or secondary cell-based assays to screen chemical libraries for potential antifungal drugs and to facilitate the characterization of hits identified through other screening strategies. The proposed Phase II work will complement and enhance the value of internally funded target-identification and screening efforts at Elitra and will help promote the discovery of badly needed therapeutic agents in a medical area that generally receives insufficient attention from the pharmaceutical industry. ? ?
