Interplay of M. tuberculosis trehalose metabolism and its pathogenesis and drug resistance

结核分枝杆菌海藻糖代谢及其发病机制和耐药性的相互作用

基本信息

批准号：
10585346
负责人：
Hyungjin Eoh
金额：
$ 66.19万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-16 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585346
关键词：
Aftercare Anabolism Antibiotics Antitubercular Antibiotics Bacillus Bacterial Infections C3HeB/FeJ Mouse CRISPR interference Carbon Cell Wall Clinical Cord Factors Cross-Sectional Studies Development Disaccharides Disease Drug Targeting Drug Tolerance Drug resistance Drug resistance in tuberculosis Dyes Exhibits Flow Cytometry Genomics Glycolipids Goals Health Heterogeneity Human Immune system In Vitro Infection Intrinsic factor Label Link Mediating Messenger RNA Metabolic Metabolism Microbial Biofilms Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis Outcome Pathogenesis Patients Pattern Periodicity Persons Phenotype Play Population Process Public Health Quantitative Reverse Transcriptase PCR Regimen Reporting Research Role Source Testing Therapeutic Therapeutic Intervention Treatment Protocols Trehalose Tuberculosis Variant Virulence Virulence Factors Work aged antibiotic tolerance bactericide base cost drug development drug resistance development drug-sensitive epidemiology study high risk in vivo inhibitor insight metabolomics mortality mouse model mutant novel therapeutic intervention novel therapeutics overexpression pathogen resistance mutation synergism tuberculosis drugs tuberculosis treatment validamycins

项目摘要

Research Summary Antibiotics have failed to control bacterial diseases typically due to the emergence of drug resistant (DR) mutants. Mycobacterium tuberculosis (Mtb) is one of the world’s most successful pathogens because of its capacity to develop DR mutants to withstand antibiotic effects. Treating DR-tuberculosis (TB) patients takes two years and costs nearly $393,000 per person, which is substantially more expensive than ~ $49,000 per person for treating a drug sensitive (DS)-TB patient. Despite this pressing human health problem, little is known about the mechanistic bases underlying the development of DR-TB. Given the low genomic mutation rates and slow replication of Mtb, intrinsic bacterial factors should play an important role in developing DR-TB, but they have been understudied. Accumulating evidence has shown that cyclic formation of Mtb persisters, a phenotypic variant transiently tolerant to TB antibiotics, can predispose TB patients to the emergence of permanent DR mutants. We recently reported untargeted metabolomics profiling of Mtb persisters and revealed that Mtb shifted its trehalose-mediated carbon flux towards the biosynthesis of central carbon metabolism (CCM) intermediates to avoid irreversible antibiotic damage, while decreasing its flux towards the biosynthesis of cell wall mycolyl glycolipids. This process was termed the “trehalose catalytic shift” and was identified to be essential for Mtb persister formation, viability, and drug tolerance. In this application, we hypothesize that the trehalose catalytic shift is an adaptive strategy executed by Mtb after treatment with TB antibiotics to achieve drug tolerance and also to facilitate the development of DR mutants, thus altering the TB disease course. In cross-sectional studies with 7 different clinical TB lineages, lineage 2 strains such as HN878 W-Beijing strain (HN878), have been associated with a high risk of developing multidrug resistant (MDR)-TB and high mortality. Thus, we will examine our hypothesis by demonstrating that HN878 is hypervirulent and more prone to develop drug resistance than other lineage strains because of its high level of trehalose catalytic shift activity. To this end, we will determine if the trehalose catalytic shift is an HN878 intrinsic factor responsible for its drug tolerance, DR mutation rates, and hypervirulence in vitro, ex vivo and then apply it in vivo using a TB murine model. A successful outcome of this application will aid in the development of new therapeutic interventions to cure DR-TB patients, including those infected with HN878.

研究总结抗生素未能控制细菌性疾病通常是由于耐药（DR）突变体的出现。结核分枝杆菌 (Mtb) 是世界上最成功的病原体之一，因为它能够开发 DR 突变体以抵抗抗生素的作用，治疗 DR 结核病 (TB) 患者需要两年的时间。每人花费近 393,000 美元，这比每人约 49,000 美元的治疗费用要贵得多药物敏感（DS）结核病患者尽管存在这一紧迫的人类健康问题，但人们对这种疾病知之甚少。耐药结核病发展的机制基础是基因组突变率低且缓慢。 Mtb 的复制、内在细菌因素在 DR-TB 的发展中应发挥重要作用，但它们越来越多的证据表明，结核分枝杆菌持续存在的循环形成是一种表型。对结核病抗生素短暂耐受的变体可能使结核病患者容易出现永久性 DR 我们最近报告了 Mtb 持续者的非靶向代谢组学分析，并揭示了 Mtb 发生了变化。海藻糖介导的碳通量用于中心碳代谢（CCM）中间体的生物合成避免不可逆的抗生素损伤，同时减少其细胞壁分枝菌基生物合成的通量这个过程被称为“海藻糖催化转变”，并被认为对于 Mtb 至关重要。在此应用中，我们采用了海藻糖的催化作用。转移是结核分枝杆菌在使用结核抗生素治疗后执行的一种适应性策略，以实现耐药性和在横断面研究中，还可以促进 DR 突变体的发展，从而改变结核病的病程。与7种不同的临床结核病谱系相比，谱系2株如HN878 W-北京株（HN878）已被与发展耐多药（MDR）结核病和高死亡率的高风险相关。因此，我们将进行检查。我们的假设是通过证明 HN878 具有高毒力并且比 HN878 更容易产生耐药性其他谱系菌株由于其高水平的海藻糖催化转变活性，为此，我们将确定是否。海藻糖催化转变是 HN878 的内在因素，决定其耐药性、DR 突变率和体外、离体高毒力，然后使用结核病小鼠模型将其应用于体内，这是一个成功的结果。应用将有助于开发新的治疗干预措施来治愈耐药结核病患者，包括那些感染HN878。