Chemical Mycobateriology

化学分枝杆菌学

• 批准号: 10434644
• 负责人: Carolyn Bertozzi
• 金额: $ 47.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434644
• 关键词: Antibiotics; Bacterial Infections; Biology; Cells; Chemicals; Chronic lung disease; Clinical; Clinical Treatment; Collaborations; Combined Modality Therapy; Detection; Dyes; Glean; HIV/TB; In Vitro; Infection; Instruction; Label; Lipids; Metabolic; Methods; Microscope; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Population; Regimen; Resistance; Resource-limited setting; Role; Sampling; South Africa; Sputum; Time; Tuberculosis; Tuberculosis diagnosis; Virulence; Work; active method; base; cost; detection method; global health; high-throughput drug screening; insight; magnetic beads; mycobacterial; nile red; pathogen; point of care; screening; tuberculosis drugs; tuberculosis treatment

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.

结核病（TB）是由结核分枝杆菌（MTB）引起的一种慢性肺疾病，该疾病 感染了世界人口的大约四分之一。已经确定了多种药物 迅速在体外杀死MTB及其亲戚，但是临床治疗需要至少6个月的组合 治疗和抗药性猖ramp。此外，目前检测MTB感染的最新目前 员工繁琐的方法是在80年前开发的。在此我们建议 开发可在低资源设置中进行的MTB检测的新方法，并开发 潜在的结核病药物的新屏幕，以及对分枝杆菌作用的基本研究 病毒中的脂质。 在这种续签R37 AI051622的续签应用中，题为“化学分生菌学”，我们提出了 以下四个目标：（1）基于荧光尼罗红色和3-羟基偶治剂染料而出现问题， 可用于检测具有低功率，低成本显微镜的MTB； （2）建立磁珠 可以在护理点上部署的基于富集的平台，以增强荧光的检测 标记为MTB细胞； （3）将代谢标签部署为高通量药物屏幕的读数 在发现新结核病药物时减少时间和费用； （4）采用生物正交标签和 化学生物学方法是阐明邻苯酚二氧化碳（PDIM）脂质在 分枝杆菌病毒。 相关性（请参阅说明）： 结核病（TB）是一种全球健康危机，对治疗和遏制的努力感到沮丧，并且与其他人不同 可以用单个抗生素的结核病治疗可以治疗的细菌感染需要 几种结合使用至少6个月的药物，甚至这种方案也无效。在这个 项目我们将：（1）通过通过 与南非的一个团体合作，该组织与感染了TB和HIV/TB可感染的患者合作； （2） 开发一种更好的方法来快速，成本效益筛选潜在的新结核药物； （3）行为 基本研究以确定导致结核病的病原体的外层如何允许感染 发生了。我们临床结核病诊断的新方法应该使确定是否更容易确定结核病药物 在患者中工作；此外，如果他们运作不佳，那么这项工作的新见解可能 帮助我们更好地理解原因。