Chemical Mycobateriology

结核病是由结核分枝杆菌引起的一种慢性肺部疾病。 感染了大约四分之一的世界人口。已经发现了多种药物， 在体外迅速杀死结核分枝杆菌及其亲属，但临床治疗需要至少6个月的联合治疗 治疗和抵抗是猖獗的。此外，目前检测结核分枝杆菌感染的最新技术 使用80多年前开发的繁琐方法。在此，我们建议 开发可在低资源环境下使用的检测结核分枝杆菌的新方法，并开发 筛选潜在的结核病药物，以及对分枝杆菌的作用进行基础研究 毒力中的脂类。 在R37 AI051622题为“化学分枝杆菌学”的续期申请中，我们建议 以下四个目标：(1)开发基于荧光尼罗红和3-羟色酮染料的探针， 它可以用低功率、低成本的显微镜来检测结核杆菌；(2)建立一种磁珠- 基于浓缩平台，可部署在护理地点，以增强荧光检测 标记的结核分枝杆菌细胞；(3)部署代谢标记作为高通量药物筛选的读数 减少发现新的结核病药物的时间和费用；以及(4)采用生物正交标记和 化学生物学方法阐明邻苯二甲酸甘油酯(PDIM)脂类在 分枝杆菌毒力。 相关性(请参阅说明)： 结核病是一种全球性的健康危机，它阻碍了治疗和控制结核病的努力，而且与其他疾病不同 可以用一种抗生素治疗一周的细菌感染，结核病治疗需要 几种药物联合使用至少6个月，而且通常情况下，即使这种疗法也不起作用。在这 项目我们将：(1)开发一种更好的检测患者痰标本中活动性结核病的方法 与南非一个治疗结核病感染者和艾滋病毒/结核病混合感染者的小组合作；(2) 开发一种更好的方法，以快速、经济有效地筛选潜在的结核病新药；以及(3)进行 基础研究，以确定引起结核病的病原体外层如何允许感染 会发生的。我们临床诊断结核病的新方法应该会更容易确定结核病药物 在病人身上起作用；此外，如果他们工作不好，从这项工作中收集到的新见解可能 帮助我们更好地理解其中的原因。

Tuberculosis (TB) is a chronic pulmonary disease caused by Mycobacterium tuberculosis (Mtb), which infects approximately one quarter of the world’s population. A variety of drugs have been identified that rapidly kill Mtb and its relatives in vitro, yet clinical treatment requires at least 6 months of combination therapy and resistance is rampant. Furthermore, the current state-of-the-art for detection of Mtb infection employs cumbersome methods that were developed more than 80 years ago. Herein we propose to develop new methods for detection of Mtb that can be employed in low resource settings, and to develop new screens for potential TB drugs, as well as to perform fundamental studies on the role of mycobacterial lipids in virulence. In this renewal application of R37 AI051622 entitled “Chemical Mycobacteriology”, we propose the following four Aims: (1) to develop probes based on the fluorogenic Nile Red and 3-hydroxychromone dyes, which can be used to detect Mtb with low-power, low-cost microscopes; (2) to establish a magnetic bead- based enrichment platform that can be deployed at the point-of-care to enhance detection of fluorescently labeled Mtb cells; (3) to deploy metabolic labeling as a readout for high-throughput drug screens to decrease time and expense in discovery of new TB drugs; and (4) to employ bioorthogonal labeling and chemical biology approaches to elucidate the role of phthiocerol dimycocerosates (PDIM) lipids in mycobacterial virulence. RELEVANCE (See instructions): Tuberculosis (TB) is a global health crisis that has frustrated efforts to treat and contain, and, unlike other bacterial infections that can be treated with a week-long course of a single antibiotic, TB therapy requires several drugs in combination for at least 6 months and often even this regimen does not work. In this project we will: (1) develop a better detection method for active TB in patient sputum samples through collaboration with a group in South Africa that works with TB-infected and HIV/TB-coinfected patients; (2) develop a better method for quickly and cost-effectively screening potential new TB drugs; and (3) conduct fundamental studies to determine how the outer layer of the pathogen that causes TB allows infection to happen. Our new method for clinical TB diagnosis should make it easier to determine whether TB drugs are working in patients; additionally, if they are not working well, new insight gleaned from this work may help us to better understand why.