Carbon monoxide resistance in Mycobacterium tuberculosis pathogenesis

结核分枝杆菌发病机制中的一氧化碳耐药性

• 批准号: 8438755
• 负责人: MICHAEL SHILOH
• 金额: $ 39.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438755
• 关键词: Accounting; Acids; Active Sites; Aerosols; Affinity Chromatography; Amino Acids; Antibiotics; Antimicrobial Resistance; Attenuated; Bacteria; Biochemical; Biochemistry; Biological Assay; Carbon Monoxide; Cell Survival; Cells; Cessation of life; Communicable Diseases; Data; Development; Disease; Drug Delivery Systems; Drug resistance; Electron Transport; Environmental Risk Factor; Enzymes; Epidemic; Gases; Genes; Glycine; Goals; Growth; Heme; Histopathology; Homeostasis; Host Defense; Human; Hypoxia; Immune response; Incidence; Infection; Kinetics; Knowledge; Libraries; Mediating; Metabolic; Metabolism; Microbiology; Modeling; Molecular; Molecular Models; Morbidity - disease rate; Mus; Mutate; Mutation; Mycobacterium tuberculosis; NADH; Nitric Oxide; Nucleotides; Organ; Outcome; Oxygen; Oxygenases; Pathogenesis; Pathway interactions; Peroxonitrite; Pharmaceutical Preparations; Phenotype; Physiology; Population; Predisposition; Proteins; Proteomics; Pyruvate Metabolism Pathway; Research; Resistance; Role; Screening procedure; System; Testing; Therapeutic Intervention; Tuberculosis; Virulence; Work; antimicrobial; base; genetic analysis; global health; heme oxygenase-1; in vivo; inhibitor/antagonist; killings; knowledge base; macrophage; metabolomics; microbial; molecular modeling; mortality; mutant; mycobacterial; novel; novel strategies; overexpression; pathogen; reactive oxygen intermediate; research study; resistance mechanism; response; transcriptomics; tuberculosis treatment

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world's population. As an intracellular pathogen adapted to long-term survival, M. tuberculosis has evolved mechanisms to resist killing by host antimicrobial pathways. Targeting those resistance mechanisms has recently emerged as a powerful new approach to treating M. tuberculosis infection by enhancing the host's ability to eradicate the bacteria. However, the full repertoire of mycobacterial resistance genes is not known, and expanding this knowledge base provides additional avenues for the development of new drugs. We demonstrated the M. tuberculosis induces an enzyme, heme oxygenase, that produces carbon monoxide (CO) gas, and that M. tuberculosis both adapts to and resists killing by CO. We hypothesized that M. tuberculosis evolved genes for CO resistance, and our preliminary data indicate that M. tuberculosis encodes one such gene that when mutated results in attenuated virulence. We will apply metabolomic, transcriptomic, proteomic, and biochemical approaches to determine the function of the newly discovered CO resistance protein. Thus, in the proposed research we will (1) identify the molecular mechanism of CO resistance, (2) determine the interacting partners of the CO resistance gene and their role in CO resistance and (3) characterize the pathogenic effects of mutants in the CO resistance gene and its interacting partners. The proposed work will extend the current knowledge on M. tuberculosis's antimicrobial resistance mechanisms and reveal a novel microbial survival strategy. PUBLIC HEALTH RELEVANCE: Tuberculosis is a major human pathogen, accounting for significant morbidity and mortality worldwide. Work outlined in this proposal will investigate a novel mechanism that allows M. tuberculosis to survive and persist within humans. We expect that this work will help identify new potential drug targets for the treatment of tuberculosis. PUBLIC HEALTH RELEVANCE: The mechanisms used by Mycobacterium tuberculosis to survive within the host are incompletely understood. We propose to study how M. tuberculosis survives exposure to carbon monoxide, a toxic gas produced by host macrophages, focusing on the mycobacterial gene Rv1829 that we identified in a screen for CO resistance mutants. This approach is novel because it represents the first description of a CO resistance gene in a major human pathogen.

描述（由申请人提供）：结核分枝杆菌仍然是最具破坏性的人类传染病之一，每年造成200万人死亡，并延伸到世界三分之一的人口中。作为适合长期生存的细胞内病原体，结核分枝杆菌具有抵抗宿主抗菌途径杀死的机制。靶向这些抗性机制最近已成为一种强大的新方法，可以通过增强宿主消除细菌的能力来治疗结核分枝杆菌感染。但是，分枝杆菌抗性基因的全部曲目尚不清楚，扩大该知识库为开发新药提供了更多途径。我们证明了结核分枝杆菌会诱导产生一氧化碳（CO）气体的酶，血红素氧酶，并且结核分枝杆菌均​​适应并抵抗CO的杀伤。我们将采用代谢组学，转录组，蛋白质组学和生化方法来确定新发现的CO耐药性蛋白的功能。因此，在拟议的研究中，我们将（1）确定CO抗性的分子机制，（2）确定CO耐药基因的相互作用伙伴及其在CO抗性中的作用，以及（3）表征突变体在CO抗性基因及其相互作用伴侣中的致病作用。拟议的工作将扩展有关结核分枝杆菌抗菌抗性机制的当前知识，并揭示出一种新型的微生物生存策略。公共卫生相关性：结核病是一种主要的人类病原体，涉及全球的大量发病率和死亡率。该提案中概述的工作将研究一种新型机制，该机制使结核分枝杆菌能够在人类内生存并持续存在。我们预计这项工作将有助于确定治疗结核病的新潜在药物靶标。 公共卫生相关性：分枝杆菌在宿主内生存的机制尚不完全了解。我们建议研究结核分枝杆菌如何在宿主巨噬细胞产生的一种有毒气体中幸存下来，重点是我们在CO耐药性突变体筛选中鉴定出的分枝杆菌基因RV1829。这种方法是新颖的，因为它代表了主要人类病原体中CO抗性基因的第一个描述。