Novel antifungal therapeutics

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DESCRIPTION (provided by applicant): Significance and impact of proposed research. There are many associated with the management of blood stream infections caused especially by A. fumigatus and Candida species. It is clear from the literature that part of the problem is associated with the lack of new drug therapies that do not select for drug-resistant strains and that are free of toxicity or drug-drug interactions. There are two points of interest in regard to our proposal. First, there are no new classes of anti- fungals; the new drugs are remodeled triazoles or echinocandins, many still not evaluated clinically. Second, in spite of the problems associated with AmpB that include toxicity and increased cost of the less toxic liposomal preparations of AmpB, this drug remains as the major fall back choice to fluconazole or an echinocandin in the non-neutropenic patient with candidemia. In this regard, voriconazole offers little advantage over fluconazole. The same unfortunate rationale is used for treating patients that are neutropenic. The impact of our studies is focused upon preliminary data that indicate high susceptibilities to our compounds among several Candida species, Aspergillus fumigatus, and C. neoformans. In fact, the minimum fungicidal concentration (MFC) of our compounds is equivalent to the minimal inhibitory concentration (MIC). This feature is certainly important in drug discovery. Of utmost importance, our compounds are inhibitory to fluconazole- and micafungin-resistant Candida species and Cryptococcus neoformans. These new data strongly show that our compounds have a unique target(s). Furthermore, our approach to target discovery now focuses upon a genetic analysis using yeast knock-out and over expression libraries. Proof-of-principle studies by other groups provide confidence for our experiments. The point is that there are few choices among anti-fungal drugs, and urgency has been suggested recently by leaders in fungal disease research to develop new treatments. We propose in specific aim 3 that ADME/TOX studies be done to demonstrate that our compounds have low toxicity to human cells.