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
• 负责人: Faramarz Valafar
• 金额: $ 61.97万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596784
• 关键词: Amikacin; Antibiotic Therapy; Bacillus (bacterium); Biochemical; Bioinformatics; Candidate Disease Gene; Capromycin; Cessation of life; Classification; Code; Collection; Computer Simulation; Country; Databases; Development; Diagnostic; Diagnostic tests; Drug Resistant Tuberculosis; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Epidemic; Etiology; Evolution; Extreme drug resistant tuberculosis; Fluoroquinolones; Funding; Future; Gene Mutation; Gene Proteins; Genes; Genetic Markers; Genome; Goals; India; Injectable; Kanamycin; Laboratories; Lead; Lesion; Light; Location; Lung; Microbe; Modeling; Moldova; Moxifloxacin; Multi-Drug Resistance; Mutation; Mycobacterium tuberculosis; Patients; Pharmaceutical Preparations; Philippines; Phylogenetic Analysis; Phylogeny; Proteins; Public Health; Publishing; Recombinants; Regulatory Element; Reporting; Resistance; Resources; Rifampin; Role; Route; Sequence Alignment; Site; South Africa; Technology; Treatment Failure; Work; bacterial resistance; base; deep sequencing; falls; gene interaction; improved; isoniazid; mutant; novel; protein protein interaction; public health relevance; resistance mechanism; resistance mutation; trend; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Last year over 9 million cases of active TB and 1 million deaths due to TB were reported. The development of drug-resistant Mtb is increasing and threatens TB control efforts. Global Consortium for Drug-resistant TB and Diagnostics (GCDD) has identified over 100 (out of 419) resistant Mtb isolates without known resistance-causing mutations. Additionally, GCDD has identified distinct regional genotypic-phenotypic relationships at its four study sites (India, Moldova, the Philippines, and South Africa) for seven first and second line drugs, suggesting that Mtb is taking a different evolutionary route to resistance at each site. This could also mean that Mtb is using different mechanisms for producing resistance at these study sites and therefore could soon require new set of anti-TB drugs for each evolutionary path/study site. While the emergence of the distinct evolutionary paths are probably due to variable availability of anti-TB drugs, the emergence of this distinctiveness is alarming and if continued, Mtb can evolve into different states of total drug resistance (TDR- TB) causing an epidemic that requires region-specific treatment and public health strategy. This project aims to uncover previously-unknown mechanisms of drug resistance through in silico functional characterization of newly identified gene and regulatory elements associated with drug resistance. This will explain the unexplained cases of resistance. The functional characterization will allow the identification of the mechanism of resistance for each drug involving these novel mutations, identification of "keystone" mutations that can cause resistance to multiple drugs, and identify central loci in the functional interaction network that can serve as new drug targets. This project will also perform a phylogenetic analysis of all 400+ GCDD Mtb genomes. The combination of functional characterization of novel and known mutations and the evolutionary analysis of drug resistance will answer whether distinct evolutionary paths and mechanisms of resistance are a reality or not. If so, the model can be extended to predict future regional evolutionary trends. Experimental recombinant technology will be used to confirm the significant the keystone mutations responsible for resistance in the laboratory.

描述（由申请人提供）：据报道，去年有超过900万例活跃结核病和100万例死亡。耐药的MTB的发展正在增加，并威胁着结核病控制工作。全球抗药性结核病和诊断剂（GCDD）的全球财团已确定100多个（在419个）耐药的MTB分离株中，没有已知的抗性突变。此外，GCDD在其四个研究地点（印度，摩尔多瓦，菲律宾和南非）确定了不同的区域基因型 - 表型关系 第一线和第二行药物，表明MTB在每个部位采取不同的进化途径来阻力。这也可能意味着MTB使用不同的机制在这些研究地点产生抗性，因此很快可能需要每个进化路径/研究地点的新型抗TB药物。虽然不同的进化路径的出现可能是由于抗TB药物的可用性可变，但这种独特性的出现令人震惊，如果继续，MTB可以演变为总体耐药性（TDR-TB）的不同状态，导致流行病，需要地区特异性治疗和公共健康策略。该项目的目的是在新近鉴定的基因和与耐药性相关的调节元件的硅函数表征中揭示以前未知的耐药性机制。这将解释无法解释的抵抗案例。功能表征将允许鉴定涉及这些新型突变的每种药物的耐药机制，鉴定可能引起多种药物抗性的“基石”突变，并确定可以用作新药物靶标的功能相互作用网络中的中央基因座。该项目还将对所有400+ GCDD MTB基因组进行系统发育分析。新颖突变和已知突变的功能表征以及耐药性的进化分析的结合将回答不同的进化路径和抗药性的机制是否是现实。如果是这样，则可以扩展该模型以预测未来的区域进化趋势。实验重组技术将用于确认负责实验室耐药性的重大基石突变。