The essential fungal cell wall protects the organism against a hostile external environment and is synthesized in a complex assembly sequence. Since the fungal wall affords a clear and discernible difference between fungi and their human hosts, it provides a prime target for antifungal antibiotics. In this Phase I SBIR application, we propose to identify inhibitors of beta1,3 glucan microfibril assembly, a key step in the synthesis of the fungal cell wall, as potential antifungal lead compounds. We will accomplish this in three specific aims:
Specific Aim One : To develop an existing assay to identify inhibitors of beta1,3 glucan microfibril assembly into a high-capacity assay.
Specific Aim Two : To identify inhibitors of beta1,3 glucan microfibril assembly and screen for inhibition of Candida albicans cell growth and protoplast regeneration activities.
Specific Aim Three : To test three beta1,3 glucan microfibril inhibitors for antifungal activity in an in vivo model of C.albicans infection. The identification of inhibitors of the assembly of beta1,3 glucan microfibrils will lead to the discovery of new classes of antifungal therapeutics for use in the treatment of human fungal infections.
Over the last few 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 1996 of greater than $4.5 billion. This antifungal target and assay will lead to the discovery of novel antifungal compounds that have significant market potential.
