Chemical Mycobateriology

化学分枝杆菌学

• 批准号: 10689101
• 负责人: Carolyn Bertozzi
• 金额: $ 47.2万
• 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/10689101
• 关键词: Antibiotics; Bacterial Infections; Biology; Cells; Chemicals; Chronic lung disease; Clinical; Clinical Treatment; Collaborations; Combined Modality Therapy; Detection; Dyes; Frustration; 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; 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）引起的一种慢性肺部疾病， 已发现多种药物导致世界上约四分之一的人口感染。 体外快速杀灭Mtb及其亲属，但临床治疗至少需要6个月的联合治疗 此外，目前检测 Mtb 感染的最先进技术也很普遍。 采用 80 多年前开发的繁琐方法。 开发可在资源匮乏环境中使用的 Mtb 检测新方法，并开发 潜在结核病药物的新筛选，以及对分枝杆菌作用的基础研究 脂质具有毒力。 在这个题为“化学分枝杆菌学”的 R37 AI051622 更新申请中，我们提出 以下四个目标：（1）开发基于荧光尼罗红和3-羟基色酮染料的探针， 可用于通过低功率、低成本显微镜检测 Mtb；(2) 建立磁珠- 基于富集平台，可部署在护理点以增强荧光检测 标记的 Mtb 细胞；(3) 将代谢标记用作高通量药物筛选的读数 减少新结核病药物披露的时间和费用；(4) 采用生物正交标记和 化学生物学方法阐明 phthiocerol dimycocerosates (PDIM) 脂质在 分枝杆菌毒力。 相关性（参见说明）： 结核病 (TB) 是一种全球性健康危机，它阻碍了治疗和遏制努力，并且与其他疾病不同 可以通过为期一周的单一抗生素疗程来治疗的细菌感染，结核病治疗需要 多种药物联合使用至少 6 个月，甚至这种治疗方案通常也不起作用。 项目我们将：（1）开发一种更好的患者痰样本中活动性结核病的检测方法 与南非的一个治疗结核病感染者和艾滋病毒/结核病合并感染患者的小组合作 (2)； 开发一种更好的方法来快速且经济有效地筛选潜在的新结核病药物；以及 (3) 进行 基础研究以确定导致结核病的病原体的外层如何允许感染 我们用于临床结核病诊断的新方法应该可以更容易地确定结核病药物是否有效。 正在对患者进行研究；此外，如果它们效果不佳，则可能会从这项工作中获得新的见解 帮助我们更好地理解原因。

项目成果

Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity.

• DOI: 10.7554/elife.60648
• 发表时间: 2020-11-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Cambier CJ;Banik SM;Buonomo JA;Bertozzi CR
• 通讯作者: Bertozzi CR

Differentially culturable tubercle bacteria as a measure of tuberculosis treatment response.

• DOI: 10.3389/fcimb.2022.1064148
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

The rv1184c locus encodes Chp2, an acyltransferase in Mycobacterium tuberculosis polyacyltrehalose lipid biosynthesis.

rv1184c 基因座编码 Chp2，这是结核分枝杆菌聚酰基海藻糖脂质生物合成中的一种酰基转移酶。

• DOI: 10.1128/jb.02015-14
• 发表时间: 2015
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Touchette,MeganH;Holsclaw,CynthiaM;Previti,MaryL;Solomon,VivenC;Leary,JulieA;Bertozzi,CarolynR;Seeliger,JessicaC
• 通讯作者: Seeliger,JessicaC

Toward Point-of-Care Detection of Mycobacterium tuberculosis: A Brighter Solvatochromic Probe Detects Mycobacteria within Minutes.

• DOI: 10.1021/jacsau.1c00173
• 发表时间: 2021-09-27
• 期刊: JACS Au
• 影响因子: 8
• 作者: Kamariza M;Keyser SGL;Utz A;Knapp BD;Ealand C;Ahn G;Cambier CJ;Chen T;Kana B;Huang KC;Bertozzi CR
• 通讯作者: Bertozzi CR

Organelle membrane proteomics reveals differential influence of mycobacterial lipoglycans on macrophage phagosome maturation and autophagosome accumulation.

• DOI: 10.1021/pr100688h
• 发表时间: 2011-01-07
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Shui, Wenqing;Petzold, Christopher J.;Redding, Alyssa;Liu, Jun;Pitcher, Austin;Sheu, Leslie;Hsieh, Tsung-yen;Keasling, Jay D.;Bertozzi, Carolyn R.
• 通讯作者: Bertozzi, Carolyn R.