Targeting NAD biosynthesis in Mycobacterium tuberculosis

靶向结核分枝杆菌的 NAD 生物合成

• 批准号: 8873087
• 负责人: Konstantin V Korotkov
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873087
• 关键词: Address; Adverse effects; Anabolism; Animal Model; Anti-Bacterial Agents; Antibiotics; Antitubercular Agents; Bacillus anthracis; Bacillus subtilis; Biochemical Pathway; Biological Assay; Cell Death; Cell physiology; Communicable Diseases; Complex; Data; Databases; Development; Drug Targeting; Drug resistance in tuberculosis; Effectiveness; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Escherichia coli; Extreme drug resistant tuberculosis; Fingerprint; Genus Mycobacterium; Goals; Growth; Homologous Gene; Human; In Vitro; Inhibitory Concentration 50; Intervention; Lead; Ligands; Metabolic Pathway; Methodology; Methods; Molecular Weight; Multi-Drug Resistance; Mycobacterium smegmatis; Mycobacterium tuberculosis; Nicotinamide adenine dinucleotide; Nicotinamide-Nucleotide Adenylyltransferase; Nicotinate-nucleotide adenylyltransferase; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Property; Public Health; Publishing; Recycling; Reporting; Research; Roentgen Rays; Role; Staging; Structure; Testing; Time; Tuberculosis; antimicrobial; base; chemotherapy; combat; design; drug development; drug discovery; improved; in vivo; inhibitor/antagonist; innovation; insight; mycobacterial; next generation; nicotinate mononucleotide; nicotinic acid adenine dinucleotide; novel; pathogen; programs; public health relevance; research study; resistant strain; scaffold; screening; small molecule; small molecule libraries; structural biology; success; treatment duration; treatment strategy; tuberculosis treatment; virtual

 DESCRIPTION (provided by applicant): Emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), represents a major threat to TB control. There is an urgent need for development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of antimicrobial compounds active against Mtb. Nicotinamide mononucleotide adenylyltransferase (NadD), an essential enzyme of NAD biosynthesis, represents a highly promising target for drug development against bacterial pathogens. In recent years there have been a number of NadD inhibitors developed and validated against Escherichia coli, Bacillus subtilis and B. anthracis. Published data indicate tha NadD is required for the growth and survival of mycobacteria. Thus, this recent progress provides a starting point for pursuing this enzyme as a target for the development of novel anti-tubercular drugs. The experiments in this proposal are designed to find inhibitors of Mtb NadD using a combination of structural biology approach and our recently developed virtual screening (VS) methodology. We propose to use our crystal structure of Mtb NadD and previously identified scaffolds active against E. coli and B. anthracis NadD, to apply an iterative ligand- an structure-based VS approach to discover the NadD inhibitors. The VS method will exploit databases with approved drugs that have already been shown to be safe in humans. Upon successful completion of this project we will obtain a number of potent and safe lead compounds that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant targets.

 描述（由申请人提供）：结核病（TB）的病原体——结核分枝杆菌（Mtb）的多重耐药和广泛耐药菌株的出现，对结核病控制构成了重大威胁。迫切需要开发针对以前未探索的细胞过程的新的、更有效的抗结核药物。该提案的目标是寻找一类新型抗菌化合物，对 Mtb 具有活性。烟酰胺单核苷酸腺苷酸转移酶 (NadD) 是 NAD 生物合成的必需酶，是针对细菌病原体药物开发的一个非常有前景的靶标。近年来，针对大肠杆菌、枯草芽孢杆菌和炭疽芽孢杆菌开发并验证了许多 NadD 抑制剂。已发表的数据表明 NadD 是分枝杆菌生长和存活所必需的。因此，这一最新进展为追求这种酶作为开发新型抗结核药物的靶点提供了起点。本提案中的实验旨在结合结构生物学方法和我们最近开发的虚拟筛选 (VS) 方法来寻找 Mtb NadD 抑制剂。我们建议使用 Mtb NadD 的晶体结构和先前鉴定的对大肠杆菌和炭疽芽孢杆菌 NadD 有活性的支架，应用迭代配体 - 基于结构的 VS 方法来发现 NadD 抑制剂。 VS 方法将利用数据库，其中包含已被证明对人类安全的批准药物。该项目成功完成后，我们将获得许多有效且安全的先导化合物，这些化合物将在体内研究中得到进一步验证。拟议研究中制定的策略也将适用于其他医学相关目标。