Mycobacterial single cell drug susceptibility

分枝杆菌单细胞药物敏感性

基本信息

批准号：
8645267
负责人：
Elizabeth Hesper Rego
金额：
$ 5.33万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8645267
关键词：
Antibiotic Therapy Antibiotic susceptibility Antibiotics Bacteria Bacterial Physiology Behavior Biochemical Biological Assay Biosensor Cell Separation Cell physiology Cells Clinical Trials Disease Ethionamide Fluorescence Foundations Future Genetic Genus Mycobacterium Heterogeneity Human Individual Individuality Infection Lead Metabolic Metabolism Methods Microscopy Mycobacterium tuberculosis NADH Permeability Pharmaceutical Preparations Phenotype Physiological Population Predisposition Public Health Schools Reporter Reporting Research Personnel Stimulus System Testing Time Training Tuberculosis Variant Work adduct antineoplastic antibiotics bacterial genetics base design drug efficacy infectious disease treatment insight isoniazid light microscopy mortality mycobacterial novel pathogen physical property public health relevance research study response therapy development tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The ability of some bacteria to survive antibiotic treatment is a serious problem for the treatment of infectious diseases. This is especially true fo the pathogen Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB). Global TB mortality rates are increasing, despite the aggressive and lengthy antibiotic chemotherapy used to treat the disease. One of the reasons for failed treatment is that even in drug susceptible disease a considerable population of bacteria can survive antibiotic therapy. I intend to study this phenomenon of phenotypic tolerance, often referred to as persistence, in mycobacteria. Phenotypic tolerance is poorly understood and difficult to study since it requires looking at individual cells rather than populations. Here, I propose a novel method based on fluorescent biosensors and time-lapse microscopy to test my hypothesis that bacterial physiological state predetermines antibiotic susceptibility on a single-cell level and that this stte can fluctuate in response to endogenous and exogenous stimuli. The results will give insight into the mechanisms underlying phenotypic tolerance in mycobacteria, leading to future work that will focus on developing new strategies for treating TB infections more rapidly.

描述（由申请人提供）：某些细菌在抗生素治疗中生存的能力是治疗传染病的严重问题。这是病原体分枝杆菌结核病（MTB）的尤其正确，该病原体是人结核病（TB）的病原体。尽管用于治疗该疾病的侵略性且冗长的抗生素化学疗法，但全球结核病的死亡率仍在增加。治疗失败的原因之一是，即使在药物易感疾病中，大量细菌也可以在抗生素治疗中生存。我打算在分枝杆菌中研究这种表型耐受性的现象，通常称为持久性。表型耐受性知之甚少，很难研究，因为它需要查看单个细胞而不是人群。在这里，我提出了一种基于荧光生物传感器和延时显微镜的新方法，以检验我的假设，即细菌生理状态预先确定的单细胞水平上的抗生素易感性，并且该STTE可能会对内源性和外源性刺激而响应。结果将洞悉分枝杆菌中表型耐受性的机制，从而导致未来的工作，该工作将着重于制定新的策略来更快地治疗结核病感染。