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: 7835659
• 负责人: LUIS E QUADRI
• 金额: $ 41.77万
• 依托单位: BROOKLYN COLLEGE
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835659
• 关键词: Address; Anabolism; Antibiotics; Antitubercular Agents; Attenuated; Base Sequence; Biochemical Genetics; Biological Products; Biology; Bioterrorism; Categories; Complement; Data; Development; Disease; Disease Outbreaks; Drug Delivery Systems; Drug resistance; Emerging Communicable Diseases; Enzymatic Biochemistry; Enzymes; Extreme drug resistant tuberculosis; Gene Cluster; Genes; Genetic; Goals; Growth; Human; In Vitro; Infection; Iron; Knowledge; Lead; Light; Link; Literature; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mutate; Mycobacterium tuberculosis; Organ; Personal Communication; Pharmaceutical Preparations; Production; Proteins; Public Health; Readiness; Research; Resistance; Rifampin; Role; Sequence Analysis; Siderophores; Surface; System; Testing; Therapeutic; Tuberculosis; Virulence; Work; antimicrobial; base; biodefense; chemotherapy; drug development; efficacy testing; insight; isoniazid; killings; macrophage; mortality; mouse model; mutant; mycobacterial; novel; pathogen; preclinical evaluation; prophylactic; scaffold; treatment effect; 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）被认为是紧急感染和A 全球公共卫生中的主要问题。 MDR 44。结核病也被归类为C类优先级 生物形式研究的病原体。 MDR和广泛/耐药的威胁（XDR） 由于自然出现或生物恐怖主义，对当前抗TB药物具有抗性的结核病暴发， 是一个令人震惊的情况，因为未经治疗（或不可治疗）的结核病的死亡率为40-60％。民众 针对顽固性结核病病例的健康准备需要开发杀死的新化学疗法 M.结核病或损害宿主中其病毒或生长。为此，对结核分枝杆菌的研究 生物学是最重要的优先事项，因为它们可能会阐明途径开发新的 化学疗法。该项目的长期目标是阐明分枝杆菌的生物合成 侧孔（铁扫除化合物）是在内部结核分枝杆菌所必需的 宿主的巨噬细胞，一种产生疾病需要的结核病的能力。我们将购买 通过两个特定目标的目标：（1）在体外探测MBTABCDEF的酶促功能 铁载体生物合成中的酶系统； （2）研究基因参与 MBT基因簇在铁载体中使用遗传方法产生。这两个目标高度 完全，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。获得的知识将阐明 分枝杆菌铁载体生物合成的未开发方面。该项目将揭示潜在的新 抗结核药物开发的靶标，因此可能会阐明发展的新途径 可能发现治疗和/或预防性多药的药物 针对Mdrixdr M.结核病的治疗方法，这是对全球公共卫生和A的主要威胁 生物恐怖主义使用的潜在药物。