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
• 负责人: Faramarz Valafar
• 金额: $ 64.98万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212921
• 关键词: Antibiotic Therapy; Antibiotics; Bacillus; Bacteria; Bacteriology; Belarus; Catalogs; Cessation of life; Clinical; Combined Modality Therapy; Communicable Diseases; Contracts; DNA Methylation; DNA sequencing; Drug Combinations; Drug resistance; Epigenetic Process; Event; Evolution; Exposure to; Extreme drug resistant tuberculosis; Fluoroquinolones; Funding; Genes; Genetic; Genetic Markers; Genome; Genomics; Goals; Grant; Incidence; Infection; Injectable; Investigation; Laboratories; Lead; Linezolid; Metabolic; Mission; Modeling; Molecular; Multidrug-Resistant Tuberculosis; Mutagenesis; Mutation; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Play; Population; Prevalence; Process; Pyrazinamide; Regimen; Regulatory Element; Reporting; Resistance; Resources; Rifampin; Role; Sampling; Sputum; Testing; Time; TimeLine; Treatment Failure; Treatment Protocols; Treatment outcome; Tuberculosis; Variant; World Health Organization; bacterial resistance; case control; combinatorial; comparative genomics; differential expression; dosage; drug repurposing; epigenomics; genome analysis; genome annotation; genome wide association study; genome-wide analysis; improved; in silico; insight; isoniazid; methylation biomarker; methylome; methylomics; network models; novel; novel drug combination; novel therapeutics; pressure; resistance mechanism; response; sample collection; stressor; success; transcriptome; transcriptome sequencing; transcriptomics; tuberculosis drugs; tuberculosis treatment

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1040万例活动性结核病（TB）和140万例 TB。尽管我们进行了有效的结核病治疗，但耐药病例的发生率正在增加，并且 威胁结核病控制工作。 2015年，有480,000例新的耐药结核病（MDR-TB） 报道了。其中，将近60,000个是广泛的耐药结核病（XDR-TB）。这 在某些地区，场景更糟。在白俄罗斯，接近每两种情况之一（48％）是 MDR-TB（新的35.3％，在先前治疗的TB患者中为76.5％）。由于全球治愈率 MDR-TB的MDR仍远低于WHO 2015年WHO的目标（在许多地方的许多地方都非常低 世界），由于XDR-TB治疗成功率甚至更低（白俄罗斯为20％），因此 迫切需要改善对问题的理解并识别/评估新的 药物的药物/组合作为白俄罗斯的情况可能会传播。 两项合并治疗的试验，涉及四种新的和再利用的药物Bedaquiline， Linezolid，Clofazimine和Delamanid正在进行中，这要归功于World Health的资金 组织和全球基金。作为这两个试验的一部分，每月的痰液样本将是 从所有患者收集六个月。不幸的是，在第一次试验中，有30名患者 完成联合治疗后，六个治疗失败了，一人死亡 已记录。该项目旨在利用两个试验创造的资源按顺序 要发现以前未知的耐药性机制，抗性的进化途径， 和抵抗四种新/重新利用药物的时间表。我们的方法是在 硅比较基因组和表观遗传学（甲基甲基和转录组）分析，以便为了 策划失败治疗中未表征（EPI）基因组变化的全面目录 案例。在基因和调节元件的硅函数表征中 对五种研究药物的耐药性将阐明耐药机制。随后的 系统基础样品的系统基因分析和MIC表征将使我们能够 了解阻力的进化途径，以及每个之后的电阻水平的变化 进化事件。例如，这将使我们能够理解阻力是否出现 逐步增加水平，或自发自发。对于前者，我们将 能够识别与每种电阻相关的逐步遗传和甲基化标记 等级。这使临床医生可以决定增加药物剂量还是变化 药物方案是最好的行动方案。

项目成果

Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates.

• DOI: 10.7554/elife.58542
• 发表时间: 2020-10-27
• 期刊: eLife
• 影响因子: 7.7
• 作者: Modlin SJ;Conkle-Gutierrez D;Kim C;Mitchell SN;Morrissey C;Weinrick BC;Jacobs WR;Ramirez-Busby SM;Hoffner SE;Valafar F
• 通讯作者: Valafar F

Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG.

• DOI: 10.1016/j.tube.2017.11.007
• 发表时间: 2018-01
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Marney MW;Metzger RP;Hecht D;Valafar F
• 通讯作者: Valafar F

Pathogenesis of multi drug-resistant and extensively drug-resistant tuberculosis as a determinant of future treatment success.

多重耐药和广泛耐药结核病的发病机制是未来治疗成功的决定因素。

• DOI: 10.1016/j.ijmyco.2016.11.017
• 发表时间: 2016
• 期刊: International journal of mycobacteriology
• 影响因子: 1.2
• 作者: Valafar,Faramarz

Performance Comparison of Three Rapid Tests for the Diagnosis of Drug-Resistant Tuberculosis.

• DOI: 10.1371/journal.pone.0136861
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Catanzaro A;Rodwell TC;Catanzaro DG;Garfein RS;Jackson RL;Seifert M;Georghiou SB;Trollip A;Groessl E;Hillery N;Crudu V;Victor TC;Rodrigues C;Lin GS;Valafar F;Desmond E;Eisenach K
• 通讯作者: Eisenach K

Prognostic significance of novel katG mutations in Mycobacterium tuberculosis.

结核分枝杆菌中新型 katG 突变的预后意义。

• DOI: 10.1016/j.ijmyco.2014.11.043
• 发表时间: 2015
• 期刊: International journal of mycobacteriology
• 影响因子: 1.2
• 作者: Valafar,F;Ramirez-Busby,SM;Torres,J;Paul,LynthiaV;Rodwell,TC;Victor,TC;Rodrigues,C;Gler,MT;Crudu,V;Catanzaro,T
• 通讯作者: Catanzaro,T