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（MOR）结核病（TB）被认为是一种新出现的传染病和 MDR 44. 结核病也被列为 C 类优先事项。 生物防御研究的病原体 MDR 和广泛/极度耐药 (XDR) 的威胁。 由于自然出现或生物恐怖主义而对当前抗结核药物产生抗药性的结核病爆发， 这是一个令人震惊的情况，因为未经治疗（或无法治疗）的结核病公众死亡率为 40-60%。 顽固性结核病的卫生准备需要开发新的化疗方法来杀死 结核分枝杆菌或损害其在宿主中的毒力或生长为此，对结核分枝杆菌进行了研究。 生物学是最重要的优先事项，因为它们可以阐明开发新的途径 该项目的长期目标是阐明分枝杆菌的生物合成。 结核分枝杆菌在体内繁殖所需的铁载体（铁清除化合物） 宿主的巨噬细胞，具有（0.结核病产生疾病所需的能力。我们将追求 这一目标通过两个具体目标实现：（1）体外探测 MbtABCDEF 的酶功能 铁载体生物合成中的酶系统；以及（2）研究基因在铁载体生物合成中的参与。 使用遗传方法生产铁载体中的 mbt 基因簇这两个目标高度相关。 互补但独立，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阐明这一点。 该项目将揭示分枝杆菌铁载体生物合成的潜在新方面。 抗结核药物开发的目标，因此它可能会阐明开发新的途径 可能会在治疗和/或预防性多种药物中找到特别重要的药物利基 针对 MDRIXDR 结核分枝杆菌的治疗，这是对全球公共卫生的主要威胁，也是 用于生物恐怖主义的潜在制剂。