BEYOND BURDEN: NEW TOOLS FOR TUBERCULOSIS ANTIBIOTICREGIMEN DESIGN

超越负担：结核病抗生素方案设计的新工具

• 批准号: 10667002
• 负责人: MARTIN Inua VOSKUIL
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667002
• 关键词: Acceleration; Aerosols; Affect; Bacillus; Bacteriology; Benchmarking; Biological; Biological Assay; Cell physiology; Chronic; Clinical Trials; DNA biosynthesis; Development; Dose; Drug Combinations; Drug Design; Drug Evaluation; Drug Exposure; Drug Kinetics; Drug Tolerance; Epidemic; Foundations; Funding; Goals; In Vitro; Inbred BALB C Mice; Length; Lesion; Measures; Microscopic; Microscopy; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Penetration; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Physiological Processes; Population; RNA chemical synthesis; Regimen; Residual state; Ribosomal RNA; Role; Series; Standardization; Testing; Tuberculosis; bactericide; design; drug development; drug discovery; effective therapy; experimental study; in vivo; innovation; insight; lung lesion; mouse model; novel; pathogen; portability; preclinical development; response; tool; treatment response; tuberculosis drugs

Project Summary A key priority for combatting the global tuberculosis (TB) epidemic is shortening the length of treatment required to reliably cure TB. A critical impediment to drug and regimen development is the lack of metrics of effective treatment response for use in drug discovery and pre-clinical development. Two factors considered crucial to shortening treatment are the capacity of a drug to penetrate and accumulate in lung lesions and the inherent activity of a drug against residual drug-tolerant Mycobacterium tuberculosis (Mtb) populations that survive initial drug killing. This proposal focuses on the inherent treatment-shortening activity of drugs, independent of PK. Unfortunately, the bacteriological basis of why existing TB drugs and regimens vary in treatment-shortening activity remains unclear. This project evaluates the basis of drug treatment-shortening activity in TB, focusing particularly on the role of overall bacterial activity and replication during treatment. Conventionally, drugs are assessed based on the degree to which they lower Mtb burden. Our alternative approach evaluates how drugs affect fundamental bacterial cellular processes. Specifically, we developed an assay that quantifies how drugs affect ongoing ribosomal RNA synthesis called RS ratio. We found TB drugs and regimens that shorten treatment profoundly suppress rRNA synthesis; whereas drugs with high bactericidal activity but low treatment-shortening activity allow surviving Mtb populations to sustain rRNA synthesis. The RS ratio is already transforming drug development pipelines and clinical trials, but the physiological basis for the predictive power of the RS ratio needs to be fully elucidated. Since the rate of rRNA synthesis is fundamentally correlated with replication rate, we hypothesize that Mtb replication during treatment is an important unrecognized factor in treatment-shortening. Aim 1 will elucidate the effect of diverse drugs on replication while validating the RS ratio as a measure of Mtb replication and establishing a series of confirmatory molecular assays. Aim 2 will test the paradigm in vivo by evaluating pairwise combinations selected based on their potency on inhibiting Mtb replication. Collectively, our innovations are moving beyond crude measures of bacterial burden to a new era in which drugs and regimens are evaluated based on nuanced multifaceted molecular testing of their impact on fundamental physiologic processes of the pathogen.

项目摘要 抗击全球结核病流行的一个关键优先事项是缩短所需的治疗时间 to reliably可靠cure治愈TB结核.药物和方案开发的一个关键障碍是缺乏有效的指标， 用于药物发现和临床前开发的治疗反应。两个因素被认为是至关重要的， 缩短治疗时间的主要原因是药物渗透和积聚在肺部病变中的能力以及药物固有的 药物对在初始感染后存活的残余耐药结核分枝杆菌（Mtb）群体的活性 毒品杀人该提案重点关注药物的固有治疗缩短活性，与PK无关。 不幸的是，为什么现有的结核病药物和治疗方案在缩短治疗时间方面存在差异的细菌学基础 活动仍不清楚。该项目评估了结核病药物治疗的基础-缩短活动， 特别是在治疗过程中总体细菌活性和复制的作用。传统上，药物是 根据它们降低结核病负担的程度进行评估。我们的替代方法评估药物如何 影响基本的细菌细胞过程。具体来说，我们开发了一种检测方法， 影响核糖体RNA的合成，称为RS比率。我们发现了结核病药物和治疗方案， 深度抑制rRNA合成;而具有高杀菌活性但治疗缩短率低的药物 活性允许存活的Mtb群体维持rRNA合成。RS比率已经在改变药物 开发管道和临床试验，但生理基础的预测能力的RS比 需要充分阐明。由于rRNA的合成速率与复制速率基本相关， 我们假设在治疗期间Mtb复制是治疗缩短的一个重要的未被认识的因素。 目的1将阐明不同药物对复制的影响，同时验证RS比率作为Mtb的量度 复制并建立一系列确认性分子测定。目标2将通过以下方式在体内测试范例： 评价基于其抑制Mtb复制的效力选择的成对组合。总体而言，我们 创新正在超越细菌负荷的粗略测量，进入一个新的时代， 基于对它们对基本生理学影响的微妙的多方面分子测试进行评估 病原体的过程。