FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM

恶性疟原虫对磷米霉素的耐药性

• 批准号: 10005586
• 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/10005586
• 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.

项目总结