Chemical Mycobateriology

化学分枝杆菌学

• 批准号: 10117438
• 负责人: Carolyn Bertozzi
• 金额: $ 48.71万
• 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/10117438
• 关键词: Antibiotics; Bacterial Infections; Biology; Cells; Chemicals; Chronic; Clinical; Clinical Treatment; Collaborations; Combined Modality Therapy; Detection; Diagnosis; Dyes; Glean; HIV/TB; In Vitro; Infection; Instruction; Label; Lipids; Lung diseases; Metabolic; Methods; Microscope; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Population; Regimen; Resistance; Resources; Role; Sampling; South Africa; Sputum; Time; Tuberculosis; 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）引起的慢性肺部疾病， 感染了全球四分之一的人口已经鉴定出多种药物， 在体外快速杀死Mtb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，目前用于检测Mtb感染的最新技术 采用了80多年前开发的繁琐方法。在此，我们建议 开发可在资源匮乏环境中使用的结核分枝杆菌检测新方法，并开发 新的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， 脂质在毒力中的作用。 在标题为“化学分枝杆菌学”的R37 AI 051622的更新申请中，我们提出 以下四个目的：（1）开发基于荧光尼罗红和3-羟基色酮染料的探针， 其可用于用低功率、低成本的显微镜检测Mtb;（2）建立磁珠- 基于富集平台，可以部署在护理点，以增强荧光检测 标记的Mtb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， 化学生物学方法来阐明phthiocerol dimycerosates（PDIM）脂质在 分枝杆菌毒力 相关性（参见说明）： 结核病（TB）是一种全球性的健康危机，它使治疗和控制的努力受挫，并且与其他疾病不同， 细菌感染，可以用一个星期的疗程的单一抗生素治疗，结核病治疗需要 几种药物联合使用至少6个月，甚至这种方案也常常不起作用。在这 我们将：（1）开发一种更好的检测患者痰液样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/结核病合并感染者的小组合作;（2） 开发一种更好的方法，以快速和具有成本效益的方式筛选潜在的结核病新药;以及（3）开展 基础研究，以确定如何外层的病原体，导致结核病允许感染， 发生我们的临床结核病诊断新方法应该更容易确定结核病药物是否 在患者中起作用;此外，如果它们不起作用，从这项工作中收集到的新见解可能 帮助我们更好地理解为什么。