Inhibition of MEP pathway Isoprenoid Biosynthesis

抑制 MEP 途径类异戊二烯生物合成

• 批准号: 9082987
• 负责人: Cynthia Schieck Dowd
• 金额: $ 55.58万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082987
• 关键词: Anabolism; Animal Experiments; Antibiotic Resistance; Antibiotics; Antimalarials; Antitubercular Agents; Area; Attention; Binding; Biological Assay; Cells; Cessation of life; Chemicals; Communicable Diseases; Contracts; Coupling; Development; Disease; Drug Kinetics; Drug Targeting; Drug resistance; Elements; Engineering; Enzyme Inhibition; Enzymes; Escherichia coli; Esters; Francisella tularensis; Generations; Goals; Growth; HIV; Human; In Vitro; Infection; Infectious Agent; Isoprene; Knowledge; Lead; Link; Malaria; Measures; Metabolism; Molecular Conformation; Mus; Mycobacterium tuberculosis; Organism; Pathway interactions; Penetration; Permeability; Pharmaceutical Preparations; Phosphonic Acids; Plasmodium falciparum; Process; Prodrugs; Public Health; Recombinants; Research; Resistance; Series; Structure; Structure-Activity Relationship; Therapeutic; Time; Tuberculosis; Work; Yersinia pestis; animal efficacy; antimicrobial; antimicrobial drug; base; co-infection; design; enzyme mechanism; experience; improved; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; isoprenoid; killings; lead series; metabolic profile; mutant; novel; novel therapeutics; pathogen; public health relevance; research study; resistant strain; small molecule; small molecule inhibitor; success; xylulose-5-phosphate

 DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), and malaria, caused by Plasmodium falciparum, remain amongst the world's deadliest infectious diseases. Co-infection with other diseases such as HIV plus the emergence of many drug-resistant strains worldwide have made these infections difficult and costly to treat. New drugs are needed that will kill wild-type and drug-resistant strains of both organisms. The major challenge in developing new antimicrobial agents is to identify metabolic processes that are both required for viability and able to be targeted by small molecules. The overall goal of our work is to discover and develop novel, potent antitubercular and antimalarial agents. We will achieve this by coupling the synthesis of potent small molecule inhibitors acting on-target intracellularly with downstream pharmacokinetic and animal experiments. This proposal centers on 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr) as an antimicrobial drug target. Dxr is the first committed, and a rate-limiting step in the methylerythritol phosphate (MEP, aka nonmevalonate) pathway of isoprenoid biosynthesis. Dxr and MEP are essential for Mtb and P. falciparum survival, and the pathway is absent in humans. Current antimicrobial drugs do not work through a Dxr (or MEP) mechanism. Development of Dxr inhibitors as lead compounds against TB and malaria would be therapeutically valuable. Our prior work has resulted in several compound series that potently inhibit Dxr, kill both Mtb and P. falciparum-infected cells, act on-target intracellularly, and kill Plasmodium infection in mice. The proposed experiments are designed to further improve the efficacy of our compounds, verify the intracellular effects of Dxr inhibition, and evaluate the therapeutic potential of the most potent inhibitors. First, based on the success in our prior work, we will synthesize a series of novel, rationally-designed phosphonic acids. To improve cell penetration, lipophilic prodrug esters will also be synthesized. Second, compounds will be assessed for inhibition and mode of binding against purified recombinant Dxr from Mtb and P. falciparum. Third, we will measure the antimicrobial activity of our compounds against wild-type and drug-resistant strains. We will confirm the intracellular, on-target effects of the compounds. The most promising compounds will be evaluated in pharmacokinetics (PK) and animal efficacy assays. Overall, the experiments outlined in this proposal will result in potent antimicrobial compounds against both Mtb and P. falciparum and may provide a platform for further lead molecule development.

 描述（由申请人提供）：由结核分枝杆菌（Mtb）引起的结核病（TB）和由恶性疟原虫引起的疟疾，仍然是世界上最致命的传染病，与艾滋病毒等其他疾病以及许多疾病的出现同时存在。世界范围内的耐药菌株使这些感染的治疗变得困难且昂贵，因此需要新的药物来杀死这两种生物的野生型和耐药菌株。开发新型抗菌剂的一个主要挑战是确定生存所需的代谢过程，并且能够被小分子靶向。我们的总体目标是。 我们的工作是发现和开发新型、有效的抗结核和抗疟药物，我们将通过将作用于细胞内的有效小分子抑制剂与下游药代动力学和动物实验相结合来实现这一目标。 5-磷酸还原异构酶（Dxr）作为抗菌药物靶点，Dxr 是甲基赤藓糖醇磷酸盐中第一个确定的限速步骤。类异戊二烯（MEP，又名非甲羟戊酸）途径 Dxr 和 MEP 对于 Mtb 和恶性疟原虫的生存至关重要，而目前的抗菌药物并不通过 Dxr（或 MEP）机制发挥作用。抑制剂作为抗结核病和疟疾的先导化合物将具有治疗价值，我们之前的工作已经产生了几种能有效抑制 Dxr 并杀死两者的化合物系列。 Mtb 和 P. falciparum 感染的细胞，在细胞内作用于靶点，并杀死小鼠体内的疟原虫感染。所提出的实验旨在进一步提高我们的化合物的功效，验证 Dxr 抑制的细胞内效果，并评估其治疗潜力。首先，基于我们之前工作的成功，我们将合成一系列新型的、合理设计的膦酸，以提高细胞渗透性，亲脂性前药酯也将被合成。其次，我们将评估化合物对来自 Mtb 和恶性疟原虫的纯化重组 Dxr 的抑制作用和结合方式。第三，我们将测量我们的化合物对野生型和耐药菌株的抗菌活性。总体而言，本提案中概述的实验将产生针对两种结核分枝杆菌的有效抗菌化合物。和恶性疟原虫，并可能为进一步的先导分子开发提供平台。