Biotin synthesis and biotin ligation in Mtb

Mtb 中的生物素合成和生物素连接

• 批准号: 8204466
• 负责人: Dirk Schnappinger
• 金额: $ 60.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-03 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204466
• 关键词: Acquired Immunodeficiency Syndrome; Antibiotics; Binding; Biochemical; Biological; Biotin; Biotin Metabolism Pathway; Biotinylation; Carbon; Cause of Death; Cell Death; Cessation of life; Chronic; Communicable Diseases; Development; Disease; Drug Design; Drug resistance; Enzymes; Eukaryotic Cell; Evaluation; Event; Generations; Goals; Growth; Homologous Gene; Human; In Vitro; Infection; Infectious Agent; Lead; Ligase; Ligation; Measures; Metabolism; Molecular; Mus; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Physiological Processes; Population; Property; Protein Inhibition; Proteins; Public Health; Research; Resistance; Series; Source; Starvation; Structure; Structure-Activity Relationship; Testing; Tuberculosis; Work; auxotrophy; base; drug biological activity; global health; inhibitor/antagonist; insight; metabolic abnormality assessment; metabolomics; mouse model; mutant; nucleoside analog; premature; prevent; public health relevance; resistant strain; response; transcriptomics; tuberculosis drugs

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains the second leading cause of human death from a single infectious agent. Mycobacterium tuberculosis strains that are resistant against multiple drugs (MDR) or are extremely drug resistant (XDR) continue to emerge and spread. New drugs are needed limit the impact of TB on global public health. We demonstrated that biotin metabolism is essential for growth and persistence of M. tuberculosis during infections, that biotin starvation can cause bacterial cell death, and we identified inhibitors of the biotin protein ligase of M. tuberculosis. In the proposed research we will (i) measure vulnerability of M. tuberculosis towards inhibition of different enzymes participating in biotin metabolism, (ii) identify triggers of biotin-starvation-induced cell death in M. tuberculosis, (iii) use structure-based drug design to further develop available lead compounds that inhibit biotin metabolism in M. tuberculosis, and (iv) study the mechanism of action of these inhibitors. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the world's second leading cause of premature human death from an infectious disease. Work outlined in this proposal will directly contribute to the development of new TB drugs and ultimately help reducing the impact of this disease on global health.

描述（由申请人提供）：结核病（TB）仍然是单一感染因子导致人类死亡的第二大原因。耐多药（MDR）或极端耐药（XDR）的结核分枝杆菌菌株继续出现和传播。需要新的药物来限制结核病对全球公共卫生的影响。 我们证明了生物素代谢是必不可少的生长和持久的M。结核杆菌感染期间，生物素饥饿可导致细菌细胞死亡，我们确定了M.结核在拟议的研究中，我们将（i）测量M的脆弱性。结核病对抑制不同的酶参与生物素代谢，（ii）确定触发生物素饥饿诱导的细胞死亡M。结核病，（iii）使用基于结构的药物设计，以进一步开发可用的先导化合物，抑制生物素代谢的M。结核病，和（iv）研究这些抑制剂的作用机制。 公共卫生相关性：结核病（TB）是世界上第二大传染病导致人类过早死亡的原因。本提案中概述的工作将直接有助于开发新的结核病药物，并最终有助于减少这种疾病对全球健康的影响。