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: 10438918
• 负责人: Kyu Y Rhee
• 金额: $ 46.32万
• 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/10438918
• 关键词: Affect; Anabolism; Anti-Infective Agents; Antibiotic Resistance; Bacteria; Bacterial Infections; Biology; CRISPR interference; Cell Wall; Cell Wall Alteration; Cells; Chemicals; Complex; Cytosol; DNA-Directed RNA Polymerase; Data; Dental crowns; Drug resistance; 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; arabinofuranose; arabinogalactan; cell envelope; chemotherapy; combat; common treatment; drug action; drug-sensitive; genome-wide; improved; individualized medicine; innovation; lens; lipidomics; mycobacterial; 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-利福平敏感和耐药的MTB的屏障功能的代谢决定因素 项目负责人：Kyu Rhee 共同投资者：瓦莱丽·米兹拉希（Valerie Mizrahi） 合作调查人员：Jeremy Rock（Core D），D。BranchMoody（Core 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动关系 中介屏障功能。对结核病的关键和字面上的障碍是它的更安全，更简单的药物和治疗方法 高度不寻常的细胞包膜。因此，改善了MTB信封的屏障功能的知识代表 潜在的蓝图以开发更好的安全药物。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是 介导抗生素耐药性的内在机制。使用新开发的整个生物化学 分析和基因组量表CRISPRI技术，我们挑战了MTB细胞壁的长期视图 静态和无形的化学屏障。初步研究表明，MTB细胞包膜是化学上的 选择性及其障碍活动并不是其大量物理化学特性的简单产物。这些数据 进一步表明其组成和屏障功能都受到动态调节。这个项目是专门的 通过前线TB药物利福平的治疗晶状体的侧重于MTB屏障功能。我们专注于 利福平因其独特的治疗方法缩短和对药物敏感性结核的灭菌活性，及其 定义在耐药结核病生物学中的作用。另外，因为利福平有一个，很了解 作用靶标，RNA聚合酶的B亚基，位于细胞质中，它是潜在模型 这可以阐明适用于具有胞质靶标的药物的一般原则。