The fungal cell wall protects the organism against a hostile environment and relays signals for invasion and infection of a likely plant, animal, or human host. The cell wall of fungi is synthesized at each hyphal apex in a complex assembly sequence. The fungal wall affords a clear and discernible difference between fungi and their human hosts, providing an experimental target for antifungal antibiotics. In this Phase I SBIR application, we propose to develop two novel screens that target the expression of each of two genes essential for cell-wall assembly, (1,3)beta-glucan synthase and Neurospora crassa os-1 histidine kinase. We will accomplish this in three Specific Aims: 1.
Specific Aim One : Develop a screen for inhibitors of expression of a gene essential for (1,3)beta-glucan synthase activity, the glucan synthase-1 gene. 2.
Specific Aim Two : Develop a screen for inhibitors of expression of an osmosensor histidine kinase, the osmotic sensitive-1 gene. 3.
Specific Aim Three : Screen natural samples on a pilot scale These assays will lead to the identification of novel antifungal compounds that inhibit essential steps in cell-wall biosynthesis. Such drugs are likely to be safe and effective human therapeutics.
Over the last four years the market for antifungal drugs has been one of the fastest growing markets for the pharmaceutical industry; 25% annual growth with the market total for 1995 of $4.2 Billion and the market is expected to grow to over $6 Billion by the year 2000. These assays will lead to the discovery of novel antifungal compounds that have significant market potential.
