MEP pathway resistance in Plasmodium falciparum

恶性疟原虫中的 MEP 途径耐药性

• 批准号: 10653457
• 负责人: Audrey Ragan Odom John
• 金额: $ 47.24万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653457
• 关键词: Anabolism; Anopheles Genus; Antimalarials; Biochemical; Biological Process; Biology; Carbon; Cessation of life; Chemicals; Culicidae; Data; Dedications; Development; Drug Targeting; Drug resistance; Enzymes; Eubacterium; Family; Genes; Genetic; Genetic Markers; Genetic Screening; Genetic study; Glycerol; Glycerol-3-Phosphate Dehydrogenase; Glycolysis; Goals; Homeostasis; Homologous Gene; Human; Infection; Investigation; Label; Life; Life Cycle Stages; Liver; Malaria; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Molecular; Organism; Orthologous Gene; Parasite resistance; Parasites; Pathway interactions; Persons; Phosphoric Monoester Hydrolases; Plants; Plasmodium falciparum; Predisposition; Protein Dephosphorylation; Proteins; Regulation; Resistance; Role; Source; Stress; alpha-glycerophosphoric acid; asexual; clinical development; drug development; drug sensitivity; fitness; fosmidomycin; global health; humanized mouse; improved; in vivo; inhibitor; innovation; inorganic phosphate; isoprenoid; metabolomics; next generation sequencing; novel therapeutics; pathogen; resistance mechanism; resistance mutation; tool; transmission process

PROJECT SUMMARY Severe malaria due to infection by Plasmodium falciparum is a serious threat to global health with over a million deaths per year. New antimalarial agents are needed due to widespread resistance to existing therapies. A promising antimalarial drug target is the MEP pathway of isoprenoid biosynthesis, which is not found in humans. We have used forward genetic screening to identify malaria parasites resistant to MEP pathway inhibition. We have thus identified a new family of metabolic regulators in malaria, the HAD proteins. We now propose to determine the mechanism by which loss of HAD phosphatases confers drug resistance (Aim 1); establish the biological functions of HADs in parasite development (Aim 2); and use a new MEP pathway inhibitor to identify and characterize additional mechanisms of resistance (Aim 3). We will identify P. falciparum genes and pathways that genetically interact with the essential MEP pathway and our strong preliminary results support this approach. In addition, our results will inform our understanding of the basic biology of the HAD family of metabolic regulators and will determine whether HAD-mediated drug resistance can be transmitted.

项目摘要 由恶性疟原虫感染引起的严重疟疾是对全球健康的严重威胁， 每年有一百万人死亡由于对现有抗疟药物的广泛耐药性， 治疗一个有希望的抗疟疾药物靶点是类异戊二烯生物合成的MEP途径， 在人类中是找不到的。我们已经使用正向遗传筛选来鉴定疟疾寄生虫的抗药性 MEP通路抑制。因此，我们确定了一个新的疟疾代谢调节因子家族， 有蛋白质。我们现在建议确定HAD磷酸酶的损失的机制， 赋予抗药性（目标1）;确定HADs在寄生虫发育中的生物学功能 (Aim 2）;并使用新的MEP通路抑制剂来鉴定和表征 阻力（目标3）。我们将识别恶性疟原虫基因和与恶性疟原虫基因相互作用的途径 重要的MEP途径和我们强有力的初步结果支持这种方法。此外，我们的结果 将告知我们对代谢调节剂的HAD家族的基础生物学的理解，并将 确定HAD介导的耐药性是否可以传播。