Identification of factors that control Mycobacterium tuberculosis biofilm growth

控制结核分枝杆菌生物膜生长的因素的鉴定

基本信息

批准号：
8147487
负责人：
Anil Kumar Ojha
金额：
$ 14.24万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-29 至 2012-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8147487
关键词：
Address Affect Antibiotics Bacillus (bacterium)Bacteria Behavior Candida Cells Chronic Communities Defect Development Drug Exposure Drug Tolerance Environment Environmental Risk Factor Evaluation Exploratory/Developmental Grant Funding Gases Gene Mutation Generations Genes Genetic Genetic Determinism Grant Growth Growth and Development function Habitats In Vitro Infection Laboratories Microbe Microbial Biofilms Modeling Molecular Mycobacterium smegmatis Mycobacterium tuberculosis Mycolic Acid Nature Pharmaceutical Preparations Phenotype Physiological Postdoctoral Fellow Process Property Pseudomonas Regimen Resistance Rifampin Role Signal Transduction Streptococcus Structure Surface Suspension substance Suspensions Tuberculosis base chemotherapy design drug development effective therapy insight isoniazid killings microbial mutant mycobacterial pathogen planetary Atmosphere programs public health relevance research study tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Treatment of tuberculosis (TB) requires multi-drug regimen for a period of 6 to 9 months. One of the primary reasons for a long-term chemotherapy is the extraordinary ability of Mycobacterium tuberculosis, the causative agent of TB, to survive against drug exposure. Persistence of bacteria in their natural habitat is, in part, facilitated by their growth in multicellular structured community called biofilms. Persistence of chronic infections by several microbial pathogens such as Pseudomonas spp., Candida spp. or Streptococcus spp. has been attributed to their ability to form biofilms inside host. Therefore, in order to understand the persistence of M. tuberculosis against drug exposure we have been studying the development of its biofilms in an in vitro growth model. Our preliminary observation suggests that the biofilm formation by pathogen is controlled by both environmental and genetic factors. Upon evaluation of tolerance properties of M. tuberculosis biofilms against rifampicin and isoniazid we found that a significantly large number of bacilli in biofilms developed phenotypic resistance against both the antibiotics, whereas cells growing in planktonic suspension remained susceptible. This observation raises a fundamental question as to how these persisters develop within biofilms. One of the approaches in answering this question will be to understand the molecular basis of biofilm development by M. tuberculosis. I propose to investigate the environmental and genetic factors that control the biofilm development of M. tuberculosis. Identification of such factors will be very useful in understanding the development of persisters as wells as designing suitable strategies to targeting them. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB), caused by Mycobacterium tuberculosis, kills nearly 2 million people in the world every year and takes 6 to 9 months of intensive chemotherapy for the treatment. Long-term persistence of M. tuberculosis against chemotherapy is a key hurdle in an effective treatment of TB. In this project we are addressing the persistence issue of M. tuberculosis by studying its growth and development in biofilms- the surface attached multicellular structures with significantly more drug tolerant persisters than planktonic cultures.

描述（由申请人提供）：结核病治疗（TB）需要多药方案为6至9个月。长期化学疗法的主要原因之一是结核分枝杆菌（TB）的致病药物的非凡能力，可抵抗药物暴露。细菌在其自然栖息地中的持久性部分是由于它们在称为生物膜的多细胞结构社区中的增长而促进。几种微生物病原体（例如假单胞菌属，念珠菌属）的慢性感染持续性。或链球菌属。归因于它们在主机内形成生物膜的能力。因此，为了了解结核分枝杆菌对药物暴露的持久性，我们一直在研究其在体外生长模型中其生物膜的发展。我们的初步观察表明，病原体的生物膜形成受环境和遗传因素的控制。在评估结核分枝杆菌生物膜对利福平和异念珠菌的耐受性特性时，我们发现生物膜中的杆菌中有大量的杆菌对抗生素产生了表型抗性，而浮游物悬浮液中生长的细胞仍然是易感性的。这一观察结果提出了关于这些毅力如何在生物膜中发展的基本问题。回答这个问题的方法之一是了解结核分枝杆菌发育的分子基础。我建议研究控制结核分枝杆菌生物膜发展的环境和遗传因素。识别此类因素将在理解言论的发展以及设计适合目标的策略方面非常有用。公共卫生相关性：结核分枝杆菌引起的结核病（TB）每年杀死世界近200万人，需要6至9个月的治疗疗法进行6至9个月的强化化疗。结核分枝杆菌对化学疗法的长期持久性是有效治疗结核病的关键障碍。在这个项目中，我们通过研究生物膜中的生长和发育来解决结核分枝杆菌的持久性问题 - 表面附着的多细胞结构与浮游培养物相比，具有明显更多的药物耐受性持久性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Exposure to a cutinase-like serine esterase triggers rapid lysis of multiple mycobacterial species.

暴露于类角质酶丝氨酸酯酶会引发多种分枝杆菌物种的快速裂解。

DOI：
10.1074/jbc.m112.419754
发表时间：
2013
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Yang,Yong;Bhatti,Alexandra;Ke,Danxia;Gonzalez-Juarrero,Mercedes;Lenaerts,Anne;Kremer,Laurent;Guerardel,Yann;Zhang,Peijun;Ojha,AnilK
通讯作者：
Ojha,AnilK

Targeting drug tolerance in mycobacteria: a perspective from mycobacterial biofilms.