Alternative Respiratory Chains of M. tuberculosis

结核分枝杆菌的替代呼吸链

• 批准号: 6846083
• 负责人: Dirk Schnappinger
• 金额: $ 33.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846083
• 关键词: Mycobacterium tuberculosis; bacteria characteristic; bacterial proteins; bioenergetics; cellular respiration; gene expression; gene targeting; genetically modified animals; hypoxia; laboratory mouse; macrophage; microarray technology; multidrug resistance; oxidoreductase; polymerase chain reaction; tissue /cell culture; transposon /insertion element

DESCRIPTION (provided by applicant): About a third of the world's population is infected with Mycobacterium tuberculosis (MTB). In a stand off that may last decades during the period of clinical latency, a population of MTB persists in a state of apparent bacteriostasis until the host's ability to restrict growth of the pathogen is reduced by declining cell-mediated immunity. Then bacterial replication can resume and reactivation of latent foci leads to clinical disease in about 10% of the immune-competent individuals infected with MTB. Drug therapy of active TB takes 6 to 9 months. Premature termination of therapy decreases its success rate and leads to the development and spread of drug resistant and multi-drug resistant MTB. Drugs for treating active TB are relatively ineffective against MTB in the latent phase of the infection and against non-replicating MTB. New drugs that are active against non-replicating MTB might shorten drug therapy of active TB and also allow the treatment of latently infected individuals that are at high risk to develop active TB. Respiration is fundamental for growth of most bacterial species and also for survival during bacteriostasis. Respiratory chains that occur in MTB but not in humans might be suitable targets for the development of novel anti-mycobacterial drugs that are active against persisting as well as growing bacteria. The goal of this project is to determine the importance of these (alternative) respiratory chains for MTB pathogenesis. We will determine how the energy metabolism of MTB adapts to environments encountered within the host with experiments that monitor the expression levels of genes encoding respiratory enzymes. Using transposon mutants we will test whether alternative respiratory chains are important for pathogenesis of MTB in mice. We will also investigate whether respiratory chains with a low bioenergetic efficiency are important for the pathogen's ability to metabolize highly reduced carbon sources like fatty acids and whether anaerobic respiration is essential for MTB to survive hypoxia.

描述（由申请人提供）：世界上大约三分之一的人口感染结核分枝杆菌（MTB）。在可能持续数十年的临床潜伏期中，结核分枝杆菌群体持续处于明显的抑菌状态，直到宿主限制病原体生长的能力因细胞介导的免疫力下降而降低。然后，细菌复制可以恢复，潜伏灶的重新激活导致大约10%的免疫功能正常的感染MTB的个体出现临床疾病。活动性结核病的药物治疗需要6至9个月。过早终止治疗降低了其成功率，并导致耐药和多重耐药MTB的发展和传播。治疗活动性结核的药物对感染潜伏期的结核分枝杆菌和非复制性结核分枝杆菌相对无效。对非复制性结核分枝杆菌具有活性的新药可能缩短活动性结核的药物治疗时间，并允许治疗潜伏感染的高危活动性结核患者。呼吸是大多数细菌生长的基础，也是抑菌期生存的基础。在结核分枝杆菌中存在但在人类中不存在的呼吸链可能是开发新型抗分枝杆菌药物的合适靶标，这种药物对持续存在的细菌和生长的细菌都有活性。该项目的目的是确定这些（替代）呼吸链对结核分枝杆菌发病机制的重要性。我们将通过监测编码呼吸酶的基因表达水平的实验来确定MTB的能量代谢如何适应宿主内遇到的环境。利用转座子突变体，我们将测试替代呼吸链在小鼠MTB发病机制中是否重要。我们还将研究低生物能量效率的呼吸链是否对病原体代谢高度还原的碳源（如脂肪酸）的能力很重要，以及厌氧呼吸是否对结核分枝杆菌在缺氧中生存至关重要。