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Identification of novel DNA repair mechanisms in Mycobacterium tuberculosis

结核分枝杆菌新型 DNA 修复机制的鉴定

基本信息

批准号：
8223133
负责人：
Pallavi Ghosh
金额：
$ 18.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-04 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223133
关键词：
Alveolar Macrophages Antibiotics Antitubercular Agents Bacteria Base Excision Repairs DNA DNA Damage DNA Repair DNA Repair Enzymes DNA Repair Gene DNA Repair Pathway Data Disease Drug Delivery Systems Ensure Environment Escherichia coli Extreme drug resistant tuberculosis Gene Expression Gene Expression Regulation Generations Genes Genetic Screening Genetic Transcription Genome Genus Mycobacterium Goals Growth Homologous Gene Host Defense Mechanism Hydrogen Peroxide Hypersensitivity Infection Investigation Laboratories Methods Mismatch Repair Mitomycins Multi-Drug Resistance Mutation Mycobacterium smegmatis Mycobacterium tuberculosis Nitrogen Nonhomologous DNA End Joining Nucleotide Excision Repair Organism Oxidative Stress Oxygen Pathway interactions Phagocytosis Pharmaceutical Preparations Phase Population Reactive Oxygen Species Regimen Regulator Genes Resistance Respiratory Burst Role SOS Response System Techniques Testing Time Tuberculosis Work antimicrobial assault base biological adaptation to stress design effective therapy genetic regulatory protein genome-wide insight intein interest killings macrophage mutant mycobacterial novel pathogen pathogenic bacteria public health relevance recombinational repair repaired research study response success therapeutic target tuberculosis drugs tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Tuberculosis (TB), caused by Mycobacterium tuberculosis infects about 2 billion- a third- of the world's population. The success of the pathogen can be attributed to its extraordinary ability to survive indefinitely in the host. The treatment of TB requires a prolonged regimen of three anti-tuberculosis drugs to ensure complete eradication of a sub-population that continues to persist against antibiotics. The emergence of multi-drug resistant and extremely drug resistant TB is a tremendous concern as it completely eliminates all treatment options as well as overturns the effort made by WHO to control the spread of this disease. Therefore an understanding of the mechanism of persistence of M. tuberculosis inside the host is imperative for designing a short and effective treatment against the disease. During the course of infection M. tuberculosis is challenged with a variety of host defense mechanisms which the pathogen has to overcome. Of these, the challenges faced during the early phase of infection are perhaps the most critical for the pathogen to survive so as to establish a successful infection. This primarily constitutes the respiratory burst that occurs upon phagocytosis of the bacteria by alveolar macrophages and results in the generation of reactive oxygen and nitrogen intermediates. Whereas most pathogenic bacteria are cleared by these antimicrobial activities in the infected macrophages, M. tuberculosis has evolved mechanisms to subvert these challenges as well as to actively repair the damage caused. The bases in DNA are particularly susceptible to damage by these reactive oxygen and nitrogen species- the bacteria must therefore possess active mechanisms to repair the damage in order to ensure the survival of the pathogen. Previous work suggests that mycobacteria possess most of the DNA damage repair systems utilized by other bacteria; in addition it has a number of novel genes and pathways as well. This is not very surprising considering that M. tuberculosis resides in an environment rich in agents that can damage DNA. The project here proposes to identify novel DNA stress response pathways in the pathogen which will help in better understanding the mechanisms utilized by the bacteria to repair its DNA and are simultaneously very attractive as therapeutic targets. Our preliminary work has identified several novel genes that have previously not been shown to be involved in DNA damage repair in the surrogate host M. smegmatis. While the genes identified from M. smegmatis provide an invaluable insight into mycobacterial survival strategies against oxidative stress and strongly support the hypothesis that key repair pathways remain to be discovered, it is likely that M. tuberculosis could have additional genes for its survival because of its obligate intracellular growth requirement. In this revised submission we propose to identify novel DNA damage repair pathways in the pathogen, M. tuberculosis as well as study the involvement of regulatory proteins identified in the preliminary screen.) ) PUBLIC HEALTH RELEVANCE: Project)Narrative) ) Tuberculosis,)caused)by)M.)tuberculosis)infects)nearly)a)third)of)the)world's) population)and)kills)about)2)million)people)in)the)world)every)year.)Developing)new) drugs)for)the)disease)requires)a)better)understanding)of)the)mechanisms)the) pathogen)utilizes)to)persist)in)the)challenging)environment.)In)this)project)we)study) the)novel)mechanisms)used)by)bacteria)to)counter)the)constant)assault)on)its)DNA) by)the)reactive)oxygen)species)present)in)the)oxidizing)environment)of)macrophages) where)it)resides)for)prolonged)periods)of)time.))

描述（由申请人提供）：项目概述：结核病（TB），由结核分枝杆菌引起，感染了大约20亿-三分之一-世界人口。病原体的成功可以归因于其在宿主中无限期存活的非凡能力。结核病的治疗需要三种抗结核药物的长期方案，以确保完全根除继续坚持使用抗生素的亚群。耐多药和极端耐药结核病的出现令人极为关切，因为它完全消除了所有治疗选择，并推翻了世卫组织为控制这一疾病的传播所作的努力。因此，对M.宿主体内的结核病对于设计针对该疾病的短期和有效的治疗是必要的。在感染M.结核病受到病原体必须克服的多种宿主防御机制的挑战。其中，在感染的早期阶段所面临的挑战可能是病原体存活以建立成功感染的最关键的挑战。这主要构成呼吸爆发，其在肺泡巨噬细胞吞噬细菌时发生，并导致活性氧和氮中间体的产生。而大多数病原菌在感染的巨噬细胞中被这些抗菌活性清除，M。结核病已经形成了克服这些挑战以及积极修复所造成损害的机制。DNA中的碱基特别容易受到这些活性氧和氮物质的损伤-因此细菌必须具有修复损伤的主动机制，以确保病原体的存活。以前的工作表明，分枝杆菌拥有其他细菌所利用的大多数DNA损伤修复系统;此外，它还具有许多新的基因和途径。这并不奇怪，因为M。结核病存在于一个富含能破坏DNA的物质的环境中。该项目提出在病原体中识别新的DNA应激反应途径，这将有助于更好地理解细菌修复其DNA的机制，同时作为治疗靶点非常有吸引力。我们的初步工作已经确定了几个新的基因，以前没有被证明参与DNA损伤修复的替代宿主M。恶臭而从M. smegalloy提供了一个宝贵的洞察分枝杆菌的生存策略，对氧化应激和强烈支持的假设，关键的修复途径仍有待发现，很可能是M。结核病可能有额外的基因，因为它的专性细胞内生长的要求，它的生存。在这份修订后的报告中，我们提出了在病原体M中鉴定新的DNA损伤修复途径。以及研究参与初步筛选中确定的调节蛋白）。 ) 公共卫生相关性：项目）叙述））结核病，）引起））M.）结核病感染了世界上几乎三分之一的人口，每年在世界上杀死大约两百万人。为这种疾病开发新的药物需要更好地理解病原体在挑战性的环境中持续存在的机制。在这个项目中，我们研究了细菌使用的新机制，以对抗（活性氧）物质（存在于）巨噬细胞的（氧化）环境中）对其DNA的（持续）攻击。））