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

耐多药（莫尔）结核病（TB）被认为是一种新兴的传染病， 全球公共卫生的主要问题。44. hot water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。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目前的抗结核药物产生抗药性的结核病爆发， 这是一个令人担忧的情况，因为未经治疗（或无法治疗）的结核病携带40- 60%的死亡率。公共 为难治性结核病做好卫生准备，需要开发新的化疗药物， M.结核病或削弱其毒力或在宿主中的生长。为此，对M.结核 生物学是最重要的优先事项，因为它们可以照亮开发新的 化疗本项目的长期目标是阐明分枝杆菌的生物合成 铁载体（铁清除化合物）是M.结核病内 宿主的巨噬细胞，具有（0.结核病需要产生疾病。我们将奉行 通过两个具体目标实现这一目标：（1）在体外探索MbtABCDEF的酶功能 铁载体生物合成中的酶系统;（2）研究铁载体生物合成中的基因参与。 使用遗传方法在铁载体生产中的mbt基因簇。这两个目标高度 互补，但独立的，并代表生化和遗传方法，分别， 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探索方面。该项目将揭示潜在的新 抗结核药物开发的目标，因此它可能会照亮新的途径， 可能在治疗和/或预防性多药物治疗中找到特别重要的利基的药物 针对MDRIXDR M的治疗。结核病是全球公共卫生的主要威胁， 用于生物恐怖主义的潜在制剂

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.