Inhibition of MEP pathway Isoprenoid Biosynthesis

抑制 MEP 途径类异戊二烯生物合成

基本信息

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
项目类别：
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

项目摘要

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（由适用的）描述：结核分枝杆菌（MTB）引起的结核病（TB），由恶性疟原虫引起的疟疾仍然是世界上最致命的传染病之一。与其他疾病（如艾滋病毒）共同感染，以及全世界许多抗药性菌株的出现，使这些感染变得困难且昂贵。需要新药，这将杀死两个组织的野生型和抗药性菌株。开发新的抗微生物剂的主要挑战是鉴定可活力所必需的代谢过程，并且能够被小分子靶向。我们的总体目标工作是要发现和开发新颖的，潜在的抗结核病和抗疟疾药物。我们将通过耦合潜在的小分子抑制剂与下游药代动力学和动物实验的合成来实现这一目标。该建议集中在1-脱氧-D-氧基5-磷酸盐还原酶（DXR）作为抗菌药物靶标。 DXR是第一个投入的人，并且是磷酸甲基智能的速率一步（MEP，当前的抗菌药物不通过DXR（或MEP）机制起作用。DXR抑制剂的发展是针对TB和疟疾的铅化合物的开发，这将是我们的先前有价值的工作。恶性菌感染的细胞在细胞内作用，并杀死小鼠的疟原虫感染，旨在进一步改善我们化合物的有效性，验证DXR抑制的细胞内影响，并根据我们的最先验抑制剂的成功率，以评估我们的成功率。磷酸为了改善细胞的渗透率，第二次抑制作用将评估化合物的抑制作用和对纯化的重组DXR的模式。第三，我们将测量化合物对野生型和耐药菌株的抗菌活性。我们将确认化合物的细胞内靶向效应。最有希望的化合物将在药代动力学（PK）和动物有效性评估中进行评估。总体而言，该提案中概述的实验将导致对MTB和恶性疟原虫的潜在抗菌化合物，并可能为进一步的铅分子发展提供一个平台。