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

真菌特异性药物靶点：静态饥饿与杀菌饥饿

• 批准号: 7470634
• 负责人: John H. McCusker
• 金额: $ 22.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470634
• 关键词: Adverse effects; Amino Acids; Antifungal Agents; Attention; Candida albicans; Cryptococcus neoformans; Cytostatics; Drug Delivery Systems; Enzymes; Exhibits; Facility Construction Funding Category; Genetic; Goals; Growth; Health; Human; In Vitro; Industrial fungicide; Nutrient; Pathway interactions; Phenotype; Proteins; Public Health; Research; Saccharomyces cerevisiae; Starvation; Study Subject; Testing; Toxic effect; Validation; Virulence; Vitamins; Work; base; enzyme pathway; fungus; improved; in vivo; inhibitor/antagonist; mutant; novel; vitamin biosynthesis

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.

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)新的抗真菌药物靶点和（ii）这些抗真菌药物靶点的抑制剂。具体目的：本工作的具体目的1是鉴定真菌特异性氨基酸和维生素途径中的突变体，这些突变体经历营养特异性杀灭饥饿和/或由于有毒中间体的积累而具有高度毒性。特异性目标2将涉及白色念珠菌和新生念珠菌中相应突变体的构建和表征。

项目成果

Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2{Delta}) mutants is influenced by the carbon source and rapamycin.

• DOI: 10.1099/mic.0.034348-0
• 发表时间: 2010-03
• 期刊: Microbiology (Reading, England)
• 作者: Kingsbury JM;McCusker JH
• 通讯作者: McCusker JH