Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB

耐多药-广泛耐药结核病新突变的进化和功能意义

基本信息

  • 批准号:
    9980263
  • 负责人:
  • 金额:
    $ 67.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-19 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

In 2015, there were 10.4 million cases of active tuberculosis (TB) and 1.4 million deaths due to TB. While we have effective TB treatment, the incidence of drug resistant cases is increasing and threatens TB control efforts. In 2015, 480,000 new cases of multi drug-resistant TB (MDR-TB) were reported. Among these, nearly 60,000 were extensively drug-resistant TB (XDR-TB). The scenario is much worse in some regions. In Belarus, close to one of each two cases (48%) are MDR-TB (35.3% in new and 76.5% in previously treated TB-patients). Since the global cure rate of MDR-TB is still well below the target set by WHO for 2015 (exceedingly low in many parts of the world), and since XDR-TB treatment success rates are even lower (20% in Belarus), there is an urgent need for improved understanding of the problem and to identify/evaluate new drugs/combinations of drugs as the situation in Belarus is likely to spread. Two trials for combinatorial treatment involving four new and repurposed drugs bedaquiline, linezolid, clofazimine, and delamanid are underway thanks to funding from the World Health Organization and the Global Fund. As part of these two trials, monthly sputum samples will be collected for six months from all patients. Unfortunately, in the first trial with 30 patients having completed the combinatorial treatment, in six the treatment has failed, and one death has been recorded. This project aims to leverage the resources created by the two trials in order to uncover previously unknown mechanisms of drug resistance, evolutionary path to resistance, and timeline to resistance to the four new/repurposed drugs. Our approach will be to use in silico comparative genomic and epigenetic (methylome and transcriptomic) analysis in order to curate a comprehensive catalog of uncharacterized (epi)genomic changes in failed treatment cases. In silico functional characterization of genes and regulatory elements associated with resistance to the five study drugs will then elucidate the mechanism of resistance. A subsequent phylogenomic analysis and MIC characterization of time-course samples will allow us to understand the evolutionary path to resistance, and the change in resistance level after each evolutionary event. This will allow us to understand for example whether resistance emerges in steps with increasing levels, or spontaneously at a high level. In the case of the former, we will be able to identify the stepwise genetic and methylation markers associated with each resistance level. This allows the clinician to decide whether increasing the drug dosage or change of the drug regimen is the best course of action.
2015年,有1040万活动性结核病病例,140万人死于结核病

项目成果

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Faramarz Valafar其他文献

Faramarz Valafar的其他文献

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{{ truncateString('Faramarz Valafar', 18)}}的其他基金

Undetected Drug resistance and Tolerance in lesions of recurrent TB
复发性结核病灶中未检测到的耐药性和耐受性
  • 批准号:
    10454640
  • 财政年份:
    2022
  • 资助金额:
    $ 67.07万
  • 项目类别:
Undetected Drug resistance and Tolerance in lesions of recurrent TB
复发性结核病灶中未检测到的耐药性和耐受性
  • 批准号:
    10656341
  • 财政年份:
    2022
  • 资助金额:
    $ 67.07万
  • 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
  • 批准号:
    8596784
  • 财政年份:
    2013
  • 资助金额:
    $ 67.07万
  • 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
  • 批准号:
    8704446
  • 财政年份:
    2013
  • 资助金额:
    $ 67.07万
  • 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
  • 批准号:
    9109555
  • 财政年份:
    2013
  • 资助金额:
    $ 67.07万
  • 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
  • 批准号:
    10212921
  • 财政年份:
    2013
  • 资助金额:
    $ 67.07万
  • 项目类别:

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