Inhibition of the Nonmevalonate pathway to Kill Mycobacterium tuberculosis

抑制非甲羟戊酸途径杀死结核分枝杆菌

• 批准号: 7820987
• 负责人: Cynthia Schieck Dowd
• 金额: $ 37.44万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820987
• 关键词: Active Sites; Address; Affinity; Anabolism; Area; Bacillus (bacterium); Bacteria; Binding; Binding Sites; Biochemical Process; Bridged Compounds; Carrier Proteins; Cell Survival; Cell Wall; Cells; Chemicals; Commit; Communicable Diseases; D-xylulose-5-phosphate; Data; Development; Diagnostic; Drug Resistant Tuberculosis; Drug Transport; Drug resistance; Enzymes; Escherichia coli; Essential Genes; Extreme drug resistant tuberculosis; Future; Genus Mycobacterium; Goals; Growth; HIV; Human; Hydrolysis; Infection; Isomerase; Isoprene; Knock-out; Lead; Learning; Metabolic Pathway; Metabolism; Mutation; Mycobacterium tuberculosis; NADP; Organism; Pathway interactions; Penetration; Pharmaceutical Preparations; Population; Positioning Attribute; Process; Prodrugs; Relative (related person); Resistance; Role; Route; Series; Structure; Therapeutic; Therapeutic Intervention; Thick; Translational Research; Tuberculosis; Validation; Vitamin K 2; Work; analog; base; cell killing; chemotherapy; design; fosmidomycin; inhibitor/antagonist; isoprenoid; killings; mycobacterial; next generation; novel; public health relevance; research study; resistant strain; small molecule; tool; tuberculosis drugs

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-AI-102: Develop diagnostics and drugs for multiple or extensively drug-resistant tuberculosis (MDR/XDR TB). Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's deadliest infectious diseases. Co-infection with HIV plus the emergence of drug resistant strains have made TB both difficult and expensive to treat. In order to eradicate tuberculosis, new drugs are needed that will kill wild-type and drug-resistant strains of Mycobacterium tuberculosis. The major challenge in developing new TB drugs is to identify metabolic processes that are required for viability of the bacteria. The long-term goal of our work is to understand which processes are essential for survival of Mycobacterium tuberculosis. We will achieve this through the development of small molecule chemical tools which inhibit specific enzymes thought to be important and then examine their effect on bacterial survival. As we, and others, develop small molecule inhibitors of specific biochemical processes, we will begin to learn which pathways are essential for bacterial survival. These pathways can then become targets for therapeutic intervention. This proposal centers on developing inhibitors of the nonmevalonate pathway, the initial steps in isoprenoid biosynthesis. This pathway is essential in Mtb, but absent in humans. We focus on Dxr, or 1-deoxy-D-xylulose 5-phosphate reducto-isomerase, which is the first committed step in the nonmevalonate pathway. Our hypothesis is that small molecule inhibitors of Dxr will be effective in killing Mycobacterium tuberculosis. Dxr inhibitor development will be based on two approaches: (I) synthesis of lipophilic prodrugs and bioisosteres to enhance cell penetration and (II) structure-based design of Dxr inhibitors using the recent co-crystal structure of Mtb Dxr and fosmidomycin, a known Dxr inhibitor. The activity of compounds will be assessed through inhibition of Mtb Dxr activity, as well as efficacy against intact Mtb bacilli. From these studies, we will determine the role of Dxr, and thereby the nonmevalonate pathway, in mycobacterial survival and provide a platform for further lead molecule development. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is one of the world's deadliest infectious diseases, and co-infection with HIV plus the emergence of drug-resistance have made TB both difficult and expensive to treat. In order to create new TB drugs, we need to understand how best to kill the organism that causes TB, Mycobacterium tuberculosis. This proposal outlines experiments that will help us understand if a particular pathway (the nonmevalonate pathway) can be used to kill this organism and help to cure TB.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定挑战主题，15-AI-102：开发多种或广泛耐药性结核病（MDR/XDR TB）的诊断和药物。结核分枝杆菌（MTB）引起的结核病（TB）仍然是世界上最致命的传染病之一。与艾滋病毒的共同感染加上耐药菌株的出现使结核病既困难又昂贵。为了消除结核病，需要新药，以杀死结核分枝杆菌的野生型和抗药性菌株。开发新结核病药物的主要挑战是确定细菌生存能力所需的代谢过程。我们工作的长期目标是了解哪些过程对于结核分枝杆菌的生存至关重要。我们将通过开发小分子化学工具来实现这一目标，这些化学工具抑制被认为很重要的特定酶，然后检查它们对细菌存活的影响。当我们和其他人会发展出特定生化过程的小分子抑制剂，我们将开始学习哪些途径对于细菌生存至关重要。然后，这些途径可以成为治疗干预的目标。该建议集中于发展非层甲烯酸途径的抑制剂，这是类异型生物合成的初始步骤。该途径在MTB中至关重要，但在人类中不存在。我们专注于DXR或1-脱氧-D-氧基5-磷酸异构酶，这是非层状途径中的第一个投入步骤。我们的假设是，DXR的小分子抑制剂将有效地杀死结核分枝杆菌。 DXR抑制剂开发将基于两种方法：（i）亲脂性前药和生物膜体的合成，以增强细胞渗透率，以及（ii）使用最近使用MTB DXR和Fosmidomycin的MTB DXR和Fosmidomycin的共晶结构的DXR抑制剂的结构设计，是一种已知的DXR抑制剂。化合物的活性将通过抑制MTB DXR活性以及对完整MTB杆菌的功效来评估。从这些研究中，我们将确定DXR的作用，从而确定非层状途径在分枝杆菌生存中，并为进一步的铅分子发育提供了一个平台。 公共卫生相关性：结核病（结核病）是世界上最致命的传染病之一，与HIV的共同感染加上耐药性的出现使结核病既困难又昂贵。为了创建新的结核病药物，我们需要了解如何最好地杀死导致结核分枝杆菌结核病的生物体。该提案概述了实验，这些实验将有助于我们了解特定的途径（非层状途径）是否可以用于杀死这种生物并有助于治愈结核病。