Inhibition of methionine biosynthesis eliminates persistent M. tuberculosis.

抑制蛋氨酸生物合成可以消除持续存在的结核分枝杆菌。

• 批准号: 9214311
• 负责人: Michael Berney
• 金额: $ 20.88万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214311
• 关键词: Acute; Address; Amino Acids; Anabolism; Antibiotics; Appearance; Bacillus (bacterium); Bacteria; Biomedical Research; California; Cell Death; Cell physiology; Cells; Chemicals; Chronic; Collaborations; Complement; Data; Drug Targeting; Drug resistance; Essential Amino Acids; Extreme drug resistant tuberculosis; Failure; Future; Gene Silencing; Goals; Grant; Human; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Institutes; Luciferases; Mammals; Metabolic; Metabolic Pathway; Methionine; Methyltransferase; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Outcome; Pharmaceutical Preparations; Phase; Population; Preclinical Drug Evaluation; Probability; Proliferating; Publications; Publishing; Relapse; Reporter; Research; Research Institute; S-Adenosylmethionine; Seizures; Serum; Starvation; Sterilization; Supplementation; System; Time; Tissues; Tuberculosis; Validation; Virulence; aminoacid biosynthesis; base; cell envelope; chemotherapy; drug development; drug discovery; experimental study; extensive drug resistance; in vivo; inhibitor/antagonist; interdisciplinary approach; killings; macrophage; metabolomics; microbicide; mutant; new therapeutic target; novel; novel therapeutics; pathogen; protein degradation; public health relevance; screening; small molecule inhibitor; tool; transcriptomics; tuberculosis drugs

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is the most deadly bacterial pathogen in the world, killing 1.2 million people yearly and infecting over 8 million (WHO, 2013). Although chemotherapy against TB exists, a rapid global increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) cases makes new drugs with novel killing mechanisms an urgent need. A major drawback of current TB chemotherapy is its long duration, which increases the probability of relapse and the emergence of drug resistance. The underlying problem of this phenomenon is a population of non-replicating, drug-tolerant bacilli, the so-called persisters. However, current TB drugs are mainly effective against replicating and metabolically active bacteria. Preferably, new drugs kill fast (within weeks) and target actively growing as well as persister cells. Using a multidisciplinary approach, we have identified a novel drug target in methionine biosynthesis of M. tuberculosis. Our preliminary results are very promising, as they show rapid in vitro sterilization of a M. tuberculosis methionine auxotroph as well as complete lack of virulence in immunocompetent and immunocompromised mice. This is intriguing because most available TB antibiotics do not rapidly sterilize cultures. Metabolomics and transcriptomic analysis revealed a systemic metabolic shutdown by an unprecedented multi-target inhibition mechanism. The prospect of killing M. tuberculosis by causing rapid biosynthetic and metabolic seizure is very attractive for drug discovery. The goal of this proposal is to validate this drug target in vitro and in vivo and o develop a reporter strain for whole cell inhibitor screening. This will set the stage for a comprehensive high-throughput inhibitor screen against this target in the near future.

 描述（申请人提供）：结核分枝杆菌是世界上最致命的细菌病原体，每年导致120万人死亡，感染800多万人（WHO，2013）。尽管存在针对结核病的化疗，但全球多药耐药（MDR）和广泛耐药（XDR）结核病（TB）病例的快速增加使得迫切需要具有新的杀伤机制的新药。目前结核病化疗的一个主要缺点是持续时间长，这增加了复发的可能性和耐药性的出现。这种现象的根本问题是一群非复制的耐药杆菌，即所谓的持久菌。然而，目前的结核病药物主要对复制和代谢活性细菌有效。优选地，新药快速杀死（在几周内）并靶向活跃生长的细胞以及持续生长的细胞。利用多学科的方法，我们已经确定了一个新的药物靶点在蛋氨酸生物合成的M。结核我们的初步结果是非常有希望的，因为他们显示了快速的体外灭菌的M。结核病蛋氨酸营养缺陷型以及完全缺乏毒力的免疫活性和免疫功能低下的小鼠。这是有趣的，因为大多数可用的结核病抗生素不能迅速使培养物灭菌。代谢组学和转录组学分析揭示了前所未有的多靶点抑制机制导致的全身代谢关闭。杀死M的前景结核病通过引起快速的生物合成和代谢发作而对药物发现非常有吸引力。本提案的目的是在体外和体内验证该药物靶标，并开发用于全细胞抑制剂筛选的报告菌株。这将在不久的将来为针对该目标的全面高通量抑制剂筛选奠定基础。