The Role of Cell Wall Lipids in Pathogenesis of Rifampin-Resistant TB

细胞壁脂质在利福平耐药结核病发病机制中的作用

基本信息

批准号：
8889625
负责人：
Petros C Karakousis
金额：
$ 28.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2013-08-19 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889625
关键词：
Actinobacteria class Acute Anabolism Animal Model Attenuated Baltimore Biological Assay C3HeB/FeJ Mouse Cell Wall China Clinical Collaborations Country DNA Sequence DNA Sequence Alteration DNA-Directed RNA Polymerase Data Defect Development Drug Targeting Environment Exhibits Gene Activation Gene Cluster Gene Mutation Genes Genetic Goals Growth Health Histologic Human Image Imaging Techniques In Vitro Individual Infection Laboratories Lesion Lipids Liquid Chromatography Lung Lung Inflammation Mediating Metabolic Metabolic Pathway Methods Microbiology Missense Mutation Molecular Target Morphology Multidrug-Resistant Tuberculosis Mus Mutation Mycobacterium tuberculosis Necrosis Nutrient Operon Organism Other Genetics PET/CT scan Parents Pathogenesis Pathway interactions Permeability Pharmaceutical Preparations Polymerase Gene Pulmonary Tuberculosis Relative (related person)Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Rifampicin resistance Rifampin Role Scanning Transmission Electron Microscopy Procedures Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Techniques Testing Thick Thin Layer Chromatography Time Universities Virulence Virulence Factors Work base clinically relevant cost cytokine experience fitness innovation interdisciplinary approach isoniazid laser capture microdissection liquid chromatography mass spectrometry macrophage medical schools mouse model mutant novel pathogen polyketide synthase protein expression resistant strain tandem mass spectrometry treatment duration tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis (Mtb) resistant to the two first-line drugs isoniazid and rifampin, has emerged as a major threat to global TB control. The situation is particularly acute in China, which is one of 27 high-burden MDR-TB countries. In >95% of clinical MDR-TB isolates, rifampin resistance is mediated by mutations in a relatively short segment of the rpoB gene, which encodes the molecular target of rifampin. Although laboratory-derived mutants with a variety of different rpoB gene mutations show slower growth under nutrient-rich conditions, Mtb clinical strains isolated from individuals with TB who developed rifampin resistance during treatment show normal growth compared to their rifampin-susceptible counterparts, despite harboring the same mutation as some of the laboratory-derived strains. Recently, we have found evidence that a known lipid virulence factor, phthiocerol dimycocerosate (PDIM), accumulates in the cell wall of rifampin-resistant TB organisms. Studies using laboratory-generated double mutant strains revealed that PDIM is required for the normal survival of rifampin-resistant strains in activated mouse macrophages. The central hypothesis of this proposal is that the induction of pathways involved in biosynthesis and transport of cell wall-associated lipid virulence factors is a compensatory metabolic adaptation, which serves to enhance the virulence of rifampin-resistant clinical isolates in the infected host. This proposal represents a unique collaboration between investigators at Jiao Tong University School of Medicine in Shanghai, China and Johns Hopkins University School of Medicine in Baltimore, U.S.A. Using a multidisciplinary approach, including the use of a novel mouse model, which develops TB lung lesions resembling their human counterparts, in combination with transcriptional, lipidomic, genetic, and imaging techniques, we will investigate whether PDIM accumulation compensates for the fitness cost associated with Mtb rpoB mutation during host infection. Our data are expected to yield novel drug targets, with the ultimate goal of shortening the duration of MDR-TB treatment in China and worldwide.

描述（由申请人提供）：多药耐药性结核病（MDR-TB），定义为对两种一线药物异烟肼和利福平的抗性结核分枝杆菌（MTB），已成为对全球TB控制的主要威胁。这种情况在中国尤为严重，这是27个高负责人MDR-TB国家之一。在> 95％的临床MDR-TB分离株中，利福平抗性是由相对较短的RPOB基因的突变介导的，该突变编码了利福平的分子靶标。尽管具有多种不同RPOB基因突变的实验室衍生突变体在营养丰富的条件下的生长较慢，但MTB的临床菌株从TB的个体中分离出来，在治疗过程中产生利福平的人与利福平相比具有正常的生长，尽管其可易感性敏感性也与实验室菌株相同的突变。最近，我们发现了证据表明，已知的脂质毒力因子苯二甲苯二氧化碳（PDIM）积聚在利福平耐药TB生物的细胞壁中。使用实验室生成的双重突变菌株的研究表明，在活化小鼠巨噬细胞中抗利福平抗性菌株的正常存活需要PDIM。该提案的中心假设是，诱导与细胞壁相关的脂质毒力因子的生物合成和转运的途径是补偿性代谢适应，该适应性旨在增强感染宿主中对利福平抗fifampin耐药的临床分离株的毒力。该提议代表了上海的若昂大学医学院研究人员与美国巴尔的摩的约翰·霍普金斯大学医学院的研究人员之间的独特合作补偿与MTB RPOB突变相关的适应性成本。我们的数据有望产生新的药物靶标，其最终目标是缩短中国和全球的MDR-TB治疗持续时间。