FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM

恶性疟原虫对磷米霉素的耐药性

• 批准号: 10058237
• 负责人: Audrey Ragan Odom John
• 金额: $ 42.3万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058237
• 关键词: Anabolism; Antimalarials; Biological Process; Biology; Carbon; Catalysis; Cells; Cessation of life; Chemicals; Combined Modality Therapy; Data; Development; Drug Targeting; Drug resistance; Enzymes; Eubacterium; Family; Future; Genes; Genetic; Genetic Screening; Glycolysis; Goals; Growth; Homeostasis; Human; Infection; Investigation; Life; Malaria; Mediating; Metabolic; Metabolic Control; Metabolism; Molecular; Nucleotidases; Organism; Parasites; Pathway interactions; Phase II Clinical Trials; Phosphoric Monoester Hydrolases; Phosphorylation; Plants; Plasmodium falciparum; Protein Dephosphorylation; Proteins; Regulation; Resistance; Role; Structure; Substrate Specificity; Transgenic Organisms; Variant; base; clinical development; drug development; drug metabolism; fosmidomycin; genetic approach; global health; improved; inhibitor/antagonist; innovation; isoprenoid; metabolomics; molecular marker; mutant; next generation sequencing; novel therapeutics; pathogen; sugar; sugar-phosphatase; tool

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. This pathway is the target of an antimalarial agent, fosmidomycin, which is currently in Phase II clinical trials in combination therapies for malaria. We have used forward genetic screening to identify fosmidomycin-resistant malaria parasites, in order to investigate the genetic mechanisms of fosmidomycin resistance and advance our basic understanding of isoprenoid biology. We have thus identified a new family of metabolic regulators in malaria, the HAD proteins. Our approach consists of two specific aims: (1) Establish the mechanisms of HAD-mediated drug resistance, and (2) Characterize the genetic and metabolic mechanisms that underlie enhanced drug resistance in malaria strains lacking HADs. We will identify P. falciparum genes and pathways that genetically interact with the essential MEP pathway and our strong preliminary results support this approach. Our results will identify molecular biomarkers of fosmidomycin resistance and identify new targets for much needed antimalarial drug development.

项目摘要 恶性疟原虫感染引起的严重疟疾是对全球的严重威胁 健康，每年死亡超过一百万。由于 对现有疗法的广泛抵抗。有希望的抗疟药靶标是 类异丙生素生物合成的MEP途径，在人类中找不到。这条路是 抗疟药Fosmidomycin的靶标，该剂目前处于II期临床中 疟疾组合疗法的试验。我们已经使用了前遗传筛选 鉴定抗霉素耐药疟疾寄生虫，以研究遗传 fosmidomycin耐药性的机制，并提高了我们对 类异丙生素生物学。因此，我们已经确定了一个新的代谢调节剂家族 疟疾，有蛋白质。我们的方法包括两个具体目标：（1）建立 脱介导的耐药性的机制，（2）表征了遗传和 缺乏疟疾菌株的耐药性增强的代谢机制 hads。我们将确定恶性疟原虫基因和与遗传相互作用的途径 基本的MEP途径和我们强大的初步结果支持这种方法。 我们的结果将确定fosmidomycin耐药性的分子生物标志物，并确定 急需抗疟药的新目标。