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

描述(由申请人提供)：广泛的长期目标：这项工作的广泛的长期目标是确定(I)新的抗真菌药物靶标和(Ii)这些抗真菌药物靶标的抑制剂。具体目标：这项工作的具体目标1是确定真菌特有的氨基酸和维生素途径中的突变体，这些突变体经历营养特定的杀伤性饥饿和/或由于有毒中间体的积累而高度有害。具体目标2将涉及白色念珠菌和新生念珠菌相应突变体的构建和特征。 相关性：由于抗真菌药物相对较少，以及现有抗真菌药物的副作用和疗效，因此非常需要新的抗真菌药物。该项目与健康的相关性在于对新的抗真菌药物靶点的遗传鉴定。由于靶标将位于真菌特有的途径中，因此抑制剂的副作用应该最小。由于抑制靶标会导致有毒中间体在真菌中积累，因此抑制剂应该是有效的抗真菌药物。 这项研究与公共卫生的相关性：这项工作的公共卫生相关性的重点是确定具有杀菌作用的新的抗真菌药物靶标。抗真菌药物的鉴定是一个长期的目标，将极大地改善人类健康。

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.