Mycobacterial Siderophores: Assembly, Assembly Inhibition, and Role in Virulence

分枝杆菌铁载体：组装、组装抑制和毒力中的作用

• 批准号: 7467066
• 负责人: LUIS E QUADRI
• 金额: $ 34.47万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467066
• 关键词: Anabolism; Antitubercular Agents; Base Sequence; Biochemical Genetics; Biology; Bioterrorism; Categories; Dental caries; Development; Disease; Disease Outbreaks; Drug resistance; Drug resistance in tuberculosis; Emerging Communicable Diseases; Enzymatic Biochemistry; Enzymes; Extreme drug resistant tuberculosis; Gene Cluster; Genes; Genetic; Goals; Growth; Hybrids; In Vitro; Iron; Knowledge; Light; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Peptides; Pharmaceutical Preparations; Production; Proteins; Public Health; Readiness; Research; Resistance; Role; Sequence Analysis; Siderophores; System; Testing; Therapeutic; Tuberculosis; Virulence; Work; biodefense; chemotherapy; drug development; killings; macrophage; mortality; mutant; mycobacterial; novel; pathogen; prophylactic; tuberculosis drugs

Multidrug-resistant (MOR) tuberculosis (TB) is recognized as an emerging infectious disease and a major problem in global public health. MDR 44. tuberculosis is also classified as a Category C Priority Pathogen for biodefense research. The threat of MDR and extensively/extremely drug-resistant (XDR) TB outbreaks that are resistant to current anti-TB drugs, either due to natural emergence or bioterrorism, is an alarming scenario since untreated (or untreatable) TB carries a mortality rate of 40-60%. Public health preparedness for intractable TB cases requires the development of new chemotherapies that kill M. tuberculosis or impair its virulence or growth in the host. To this end, studies on M. tuberculosis biology are priorities of utmost importance as they may illuminate avenues to develop new chemotherapies. The long-term goal of this project is to elucidate the biosynthesis of mycobacterial siderophores (iron-scavenging compounds) that are required for multiplication of M. tuberculosis inside the macrophages of the host, an ability of (0. tuberculosis needed to produáe disease. We will pursue this goal through two specific aims: (1) To probe in vitro the enzymatic functions of the MbtABCDEF enzyme system in siderophore biosynthesis; and (2) To investigate the involvement of the genes in the mbt gene cluster in siderophore production using a genetic approach. These two aims are highly complementary, yet independent, and represent biochemical and genetic approaches, respectively, to study the biosynthesis of mycobacterial siderophores. The knowledge gained will shed light on unexplored aspects of mycobacterial siderophore biosynthesis. This project will revealed potential new targets for anti-tuberculosis drug development and thus it may illuminate novel avenues for developing drugs that may find a particularly important niche in therapeutic and/or prophylactic multi-drug treatments against MDRIXDR M. tuberculosis, which is a major threat to global public health and a potential agent for use in bioterrorism.

耐多药结核病(TB)是公认的一种新发传染病。 全球公共卫生的主要问题。MDR 44。结核病也被列为C类优先事项 用于生物防御研究的病原体。多药耐药和广泛/极端耐药(XDR)的威胁 对当前抗结核药物具有抗药性的结核病爆发，要么是由于自然出现，要么是由于生物恐怖主义， 这是一个令人担忧的情况，因为未经治疗(或无法治疗)的结核病死亡率为40%-60%。公众 为顽固结核病病例做好健康准备需要开发新的化疗方法，以杀死 结核分枝杆菌或损害其在宿主中的毒力或生长。为此，对结核分枝杆菌的研究 生物学是最重要的优先事项，因为它们可能照亮开发新的 化疗。这个项目的长期目标是阐明分枝杆菌的生物合成。 铁载体(清除铁的化合物)是结核分枝杆菌在体内繁殖所必需的 宿主的巨噬细胞，一种能力(0。结核病是引发疾病的必需品。我们将继续追查 这一目标通过两个特定的目的：(1)在体外探索MbtABCDEF的酶功能 铁载体生物合成中的酶系统；以及(2)研究基因在生物合成中的作用。 使用遗传学方法在铁载体生产中的MBT基因簇。这两个目标是高度一致的 互补的，但独立的，分别代表生化和遗传方法 研究分枝杆菌铁载体的生物合成。所获得的知识将有助于 分枝杆菌铁载体生物合成的未知方面。该项目将揭示潜在的新的 抗结核药物开发的靶点，从而可能照亮开发的新途径 在治疗性和/或预防性多种药物中可能找到特别重要的利基市场的药物 对MDRIXDR结核分枝杆菌的治疗，这是对全球公共卫生和 可能用于生物恐怖主义的毒剂。