Novel Screen For Translation Inhibitory Antifungals

Fungal pathogens are responsible for a variety of diseases ranging from innocuous dermalmycoses to life-threatening systemic infections. In recent years the number of serious fungal infectionshas increased markedly as a result of the growing number of immunosuppressed and immunocompromis-ed individuals, such as AIDS patients, transplant recipients, and chemotherapy or radiotherapy patients.Efficacious and non-toxic antifungal therapeutics are difficult to identify, in part due to the fact that bothhumans and fungi are eukaryotes and share many potential molecular targets in common. Mostantifungals currently used act against a limited number of targets found primarily on the fungal cellsurface. An urgent need exists for more antifungal agents, especially those acting against additionaltargets. Translation-targeted therapeutics are particularly desirable because of their proven value intreating bacterial infections. This proposal describes a novel high-throughput screen for identifying newantifungal agents specifically targeted against protein translation. The assay identifies translationalinhibitors by their ability to stimulate the growth of a specially-designed test fungus on an indicatormedium. Secondary assays are used to verify specificity for fungal translation and to determine toxicityto human cells. Preliminary results with purified compounds of known activity support the proposal.