Fungal-specific drug targets: static vs. cidal starvation & toxic intermediates

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DESCRIPTION (provided by applicant): Broad long-term objectives: The broad long-term objectives of this work are to identify (i) novel antifungal drug targets and (ii) inhibitors of these antifungal drug targets. Specific Aims: Specific Aim 1 of this work is to identify mutants in fungal-specific amino acid and vitamin pathways that undergo nutrient-specific cidal starvation and/or are highly deleterious due to the accumulation of toxic intermediates. Specific Aim 2 will involve the construction and characterization of the corresponding mutants in C. albicans and C. neoformans. Relevance: Because there are relatively few antifungal drugs and because of the side effect profiles / efficacy of the available antifungal drugs, there is a great need for novel antifungal drugs. The health relatedness of this project lies in the genetic identification of novel antifungal drug targets. Because the targets will be in fungal-specific pathways, inhibitors should have minimal side effects. Because inhibition of the targets will result in the accumulation of toxic intermediates in the fungus, inhibitors should be effective antifungal drugs. Relevance of this research to public health: The public health relevance of this work is in its focus on the identification of novel antifungal drug targets that are fungicidal. The identification of fungicidal antifungal drugs, which is a long-term goal, will greatly improve human health.