Biotin synthesis and biotin ligation in Mtb

Mtb 中的生物素合成和生物素连接

基本信息

批准号：
8586248
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
项目类别：
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/8586248
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

项目摘要

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.

描述（由申请人提供）：结核病（TB）仍然是单一传染病剂人类死亡的第二主要原因。抗多种药物（MDR）或极度耐药性（XDR）的结核分枝杆菌菌株继续出现并扩散。需要新药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对于感染过程中结核分枝杆菌的生长和持久性至关重要，生物素饥饿会导致细菌细胞死亡，我们确定了结核分枝杆菌的生物素蛋白连接酶的抑制剂。 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这些抑制剂。