Alternative Respiratory Chains of M. tuberculosis

结核分枝杆菌的替代呼吸链

基本信息

批准号：
7187436
负责人：
Dirk Schnappinger
金额：
$ 32.14万
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：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7187436
关键词：
Bacteria Bioenergetics Carbon Catabolism Cellular Immunity Clinical Cytochrome c Reductase Cytochromes Development Disease Disruption Drug resistance Drug resistance in tuberculosis Energy Metabolism Environment Fatty Acids Gene Structure Genes Genome Goals Growth Human Hypoxia Immune Individual Infection Liquid substance Lung Metabolic Metabolism Microbe Molecular Profiling Monitor Multi-Drug Resistance Mus Mycobacterium tuberculosis NOS2A gene Natural regeneration Outcome Oxidases Oxidoreductase Oxygen Pathogenesis Phagosomes Pharmaceutical Preparations Pharmacotherapy Phase Physiological Polymerase Chain Reaction Population Production Rate Respiration Respiratory Chain Risk Role Sentinel Source Testing Time Work fatty acid oxidation gene induction human NOS2A protein in vivo macrophage mutant mycobacterial novel pathogen research study respiratory respiratory enzyme success

项目摘要

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）：大约三分之一的人口感染了结核分枝杆菌（MTB）。在临床潜伏期期间可能持续数十年的一个立场中，MTB的人口持续到明显的细菌性状态，直到宿主通过下降细胞介导的免疫力来降低宿主限制病原体的生长的能力。然后，细菌复制可以恢复潜在灶，导致大约10％感染了MTB的免疫能力的个体，导致临床疾病。活性结核病的药物治疗需要6到9个月。治疗的过早终止降低了其成功率，并导致耐药和耐药MTB的发展和扩散。在感染的潜在阶段和对非重复的MTB的药物相对对MTB的治疗药物相对无效。活跃于非重复MTB的新药可能会缩短活性结核病的药物疗法，还可以治疗受到高风险的潜在感染者，而这些个体患有高风险。呼吸对于大多数细菌物种的生长以及在抑菌症中生存至关重要。在MTB中而不是在人类中发生的呼吸链可能是开发新型抗细菌药物的合适靶标，这些药物活跃于持续存在和生长的细菌。该项目的目的是确定这些（替代性）呼吸链对MTB发病机理的重要性。我们将确定MTB的能量代谢如何适应宿主在宿主中遇到的环境，并通过监测编码呼吸酶的基因的表达水平的实验。使用转座子突变体我们将测试替代呼吸链对于小鼠MTB的发病机理是否重要。我们还将研究生物能效率低的呼吸链对于病原体代谢高度降低的碳源（如脂肪酸）的能力以及厌氧呼吸对MTB的生存至关重要。