Metabolic determinants of barrier function in rifampin-sensitive and -resistant Mtb

利福平敏感和耐药结核分枝杆菌屏障功能的代谢决定因素

• 批准号: 10612039
• 负责人: Kyu Y Rhee
• 金额: $ 47.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612039
• 关键词: Affect; Anabolism; Anti-Infective Agents; Antibiotic Resistance; Antimycobacterial Agents; Bacteria; Bacterial Infections; Biology; CRISPR interference; Cell Wall; Cell Wall Alteration; Cells; Chemicals; Collaborations; Complex; Crowns; Cytosol; DNA-Directed RNA Polymerase; Data; Drug resistance in tuberculosis; Ethambutol; Evolution; Extreme drug resistant tuberculosis; Goals; Knowledge; Measures; Mediating; Membrane Lipids; Metabolic; Modeling; Modernization; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Organism; Penetration; Peptidoglycan; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Property; Regulation; Research; Research Personnel; Resistance; Rifampin; Role; Structure; Structure-Activity Relationship; System; Technology; Therapeutic; Tuberculosis; Vancomycin; Variant; Virulence; Whole Organism; acquired drug resistance; arabinofuranose; arabinogalactan; cell envelope; chemotherapy; combat; common treatment; drug action; drug-sensitive; genome-wide; improved; individualized medicine; innovation; lens; lipidomics; p-Aminosalicylic Acid; programs; response; tool; tuberculosis chemotherapy; tuberculosis drugs; tuberculosis treatment; virtual

Project 2 - Metabolic determinants of barrier function in rifampin-sensitive and -resistant Mtb Project Leader: Kyu Rhee Co-investigator: Valerie Mizrahi Collaborating investigators: Jeremy Rock (Core D), D. Branch Moody (Core B) ABSTRACT The overarching goal of this project is to elucidate specific cell envelope structure-activity relationships mediating barrier function. A key and quite literal barrier to safer and simpler drugs and treatments for TB is its highly unusual cell envelope. Improved knowledge of the barrier function of the Mtb envelope thus represents a potential blueprint to developing better safer drugs. Unlike most bacteria, the Mycobacterium tuberculosis (Mtb) envelope consists in a unique multilayered structure whose physico-chemical properties are widely believed to mediate an intrinsic mechanism of antibiotic resistance. Using newly developed whole organism chemical profiling and genome scale CRISPRi technologies, we challenge the longstanding view of Mtb cell wall as a static and impermeant chemical barrier. Preliminary studies indicate that the Mtb cell envelope is chemically selective, and its barrier activity is not a simple product of its bulk physico-chemical properties. These data further show that both its composition and barrier function are dynamically regulated. This project specifically focuses on Mtb barrier function through the therapeutic lens of the frontline TB drug rifampicin. We focus on rifampicin because of its unique treatment shortening and sterilizing activities against drug-sensitive TB, and its defining role in the biology of drug-resistant TB. In addition, because rifampicin has a single, well understood target of action, the b subunit of RNA polymerase, which is located in the cytosol, it serves as a potential model that could elucidate general principles that apply to any drug with cytosolic targets.

项目 2 - 利福平敏感和耐药 Mtb 屏障功能的代谢决定因素 项目负责人：李奎 联合研究员：瓦莱丽·米兹拉希 合作调查员：Jeremy Rock（核心 D）、D. Branch Moody（核心 B） 抽象的 该项目的总体目标是阐明特定的细胞包膜结构-活性关系 介导屏障功能。更安全、更简单的结核病药物和治疗方法的一个关键且相当明显的障碍是它 非常不寻常的细胞包膜。因此，对 Mtb 包膜屏障功能的了解加深代表了 开发更好更安全药物的潜在蓝图。与大多数细菌不同，结核分枝杆菌 (Mtb) 信封由独特的多层结构组成，其物理化学特性被广泛认为 介导抗生素耐药性的内在机制。采用新开发的全有机化学物质 通过分析和基因组规模 CRISPRi 技术，我们挑战了 Mtb 细胞壁作为 静态且不渗透的化学屏障。初步研究表明 Mtb 细胞包膜具有化学性质 选择性，其屏障活性并不是其大量物理化学性质的简单产物。这些数据 进一步表明其成分和屏障功能都是动态调节的。本项目具体 通过一线结核病药物利福平的治疗视角关注结核分枝杆菌屏障功能。我们专注于 利福平因其对药物敏感结核病具有独特的治疗缩短和灭菌活性， 在耐药结核病生物学中的决定性作用。此外，由于利福平具有单一的、易于理解的 作用目标，RNA 聚合酶的 b 亚基，位于细胞质中，它可以作为潜在的模型 这可以阐明适用于任何具有胞质靶点的药物的一般原则。