Establishing the Genetic Basis of Altered Drug Responses in Mycobacterium tuberculosis

建立结核分枝杆菌药物反应改变的遗传基础

基本信息

批准号：
10390301
负责人：
SARAH FORTUNE
金额：
$ 99.03万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-18 至 2024-03-31
项目状态：
已结题

项目摘要

Summary High-level drug resistance puts TB patients at increased risk of treatment failure. However, patients also fail treatment with apparently drug susceptible strains even in clinical trial settings where compliance is well monitored. We postulate that decades of drug exposure have selected for bacterial strains that have alterations in drug-mediated clearance that are not identified by conventional drug resistance testing and that these changes put compromise patient outcomes. In previous work, we identified mutations that alter bacterial drug susceptibility in ways that are not identified by conventional clinical resistance testing but are revealed by assaying bacterial drug responses using time-dependent killing assays under host-like environmental conditions. We hypothesize that these mutations predispose to treatment failure even as they also accelerate the emergence of high-level drug resistance. To test this hypothesis, we propose to test the hypothesis that mutations associated with resistance and treatment failure in clinical cohorts alter Mtb survival in the presence of antibiotics. For this aim, we will construct and phenotype a barcoded library of isogenic strains carrying mutations identified in our analyses of clinical strains as associated with drug resistance or treatment failure. We will test the hypothesis that the drug resistance-associated mutations and mutations associated with treatment failure cause treatment failure in a mouse model of infection. Finally, because many resistance associated mutations appear to cause multidrug tolerance, we will assess their effects on the efficacy of new antibiotics and small molecules in late stage development for Mtb.

概括高级耐药性使结核病患者的治疗衰竭风险增加。但是，患者也因药物易感性菌株的治疗而无法治疗临床试验环境得到了很好的监控。我们假设那几十年药物暴露已选择用于药物介导的改变的细菌菌株常规耐药性测试未识别的清除率变化使患者的结果妥协。在以前的工作中，我们确定了突变以常规的方式改变细菌药物的敏感性临床抗性测试，但通过使用细菌药物反应来揭示在类似宿主的环境条件下，时间依赖于时期的杀戮测定法。我们假设这些突变易于治疗失败，即使它们也加速了高级耐药性的出现。为了检验这一假设，我们建议测试假设与临床中抗药性和治疗失败相关的突变人群在存在抗生素的情况下改变MTB的存活。为此，我们将建造和表型在我们与耐药性或治疗失败有关的临床菌株的分析。我们将检验与耐药性相关突变和突变的假设与治疗失败相关的导致治疗失败的感染模型。最后，因为许多抗性相关的突变似乎会导致多饮宽容，我们将评估它们对新抗生素和小的疗效的影响 MTB晚期发育中的分子。