The increase in opportunistic fungal infections such as candidiasis, zygomycosis, cryptococcosis, histoplasmosis, and Aspergillus and Fusarium infections in immunocompromised individuals, including AIDS patients, the elderly, surgical patients, and burn victims, has demonstrated that these infections are frequently fatal if untreated. In addition, the two accepted therapies, amphotericin B and the azoles, have limited effectiveness and toxic side-effects. There is a clear need for more effective antifungal agents. To address this need, we plan to exploit the opportunity to discover antifungal compounds with a novel mechanism of action by targeting drug discovery efforts on a microtubule motor essential for mitotic progression in Aspergillus. Using a high-throughput screen developed by Cytokinetics, we will isolate inhibitors of this molecule's activity from chemical libraries totaling 230,000 compounds. We will test hits for antifungal activity against a panel of fungi and determine mammalian toxicity using cell-based assays. We have isolated homologs of the Aspergillus target from several pathogens, which we will use in in vitro assays to support our efforts to develop broad-spectrum antifungal compounds. In addition to their anticipated use in treating a number of opportunistic fungal diseases in humans, we expect inhibitors of these targets to have agricultural and animal health applications. PROPOSED COMMERCIAL APPLICATION: There has been a dramatic increase in opportunistic fungal infections in immunocompromised individuals, including AIDS patients, the elderly, transplant patients, and burn victims. The two accepted therapies, amphotericin B and the azoles, have limited effectiveness and toxic side effects. We seek to identify new antifungal agents with a novel mechanism of action. Current antifungals have potential market sales of $6.5 billion annually. Clearly, a novel, broad-spectrum antifungal will have significant commercial value, and will increase the quality of life for infected individuals
