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
- 来源:
- 关键词:Antibiotic TherapyAntibioticsBacillusBacteriaBacteriologyBelarusCatalogsCessation of lifeClinicalCombined Modality TherapyCommunicable DiseasesContractsDNA MethylationDNA sequencingDrug CombinationsDrug resistanceEpigenetic ProcessEventEvolutionExposure toExpression ProfilingExtreme drug resistant tuberculosisFluoroquinolonesFundingGenesGeneticGenetic MarkersGenomeGenomicsGoalsGrantIncidenceInfectionInjectableInvestigationLaboratoriesLeadLinezolidMetabolicMissionModelingMolecularMultidrug-Resistant TuberculosisMutagenesisMutationMycobacterium tuberculosisPatientsPharmaceutical PreparationsPlayPopulationPrevalenceProcessPyrazinamideRegimenRegulatory ElementReportingResistanceResourcesRifampinRoleSamplingSputumTestingTimeTimeLineTreatment FailureTreatment ProtocolsTreatment outcomeTuberculosisVariantWorld Health Organizationbacterial resistancecase controlcombinatorialcomparative genomicsdifferential expressiondosageepigenomicsgenome analysisgenome annotationgenome wide association studygenome-wide analysisimprovedin silicoinsightisoniazidmethylation biomarkermethylomemethylomicsnetwork modelsnovelnovel drug combinationnovel therapeuticspressureresistance mechanismresponsesample collectionstressorsuccesstranscriptometranscriptome sequencingtranscriptomicstuberculosis drugstuberculosis treatment
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,全球有1040万例活动性结核病(TB)病例,140万人死于结核病。
TB.虽然我们有有效的结核病治疗,但耐药病例的发生率正在增加,
威胁到结核病控制工作。2015年,48万例新的耐多药结核病(MDR-TB)病例
本文报告其中,近6万人是广泛耐药结核病(XDR-TB)。的
在某些地区情况更糟。在白俄罗斯,几乎每两个病例中就有一个(48%)是
耐多药结核病(新发结核病患者占35.3%,既往接受过治疗的结核病患者占76.5%)。因为全球治愈率
耐多药结核病的发病率仍远低于世卫组织为2015年设定的目标(
由于广泛耐药结核治疗成功率甚至更低(白俄罗斯为20%),
迫切需要更好地了解问题,并确定/评估新的
因此,我们建议使用毒品/混合毒品,因为白俄罗斯的情况可能会蔓延。
两项联合治疗试验涉及四种新的和重新用途的药物贝达喹啉,
利奈唑胺、氯法齐明和delamanid正在世界卫生组织的资助下进行
作为这两项试验的一部分,每月的痰液样本将被
从所有患者中收集6个月。不幸的是,在第一次试验中,
完成联合治疗后,6例治疗失败,1例死亡
已经被记录下来了。该项目旨在利用这两项试验所创造的资源,
揭示以前未知的耐药性机制,耐药性的进化路径,
以及对四种新的/重新利用的药物产生耐药性的时间轴。我们的方法将是使用在
计算机比较基因组和表观遗传学(甲基化组和转录组)分析,
策划治疗失败的非特征性(epi)基因组变化的综合目录
例基因和调控元件的计算机功能表征
对五种研究药物的耐药性将阐明耐药性的机制。随后的
时间进程样本的基因组分析和MIC表征将使我们能够
了解抗性的进化路径,以及每次抗性水平的变化
进化事件这将使我们能够理解,例如,
逐步增加的水平,或自发地在高水平。对于前者,我们将
能够识别与每种抗性相关的逐步遗传和甲基化标记
水平这允许临床医生决定是否增加药物剂量或改变药物浓度。
药物疗法是最好的治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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