Lactic Acid Bacteria that Detect & Inhibit Enterococci in the Mammalian GI Tract

检测的乳酸菌

基本信息

批准号：
8747170
负责人：
GARY M DUNNY
金额：
$ 35.3万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2014-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747170
关键词：
Address Animal Experiments Animal Model Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Bacteriophages Benchmarking Bile fluid Bioavailable Biological Metamorphosis Blood Circulation Cell Wall Cells Chloride Ion Chlorides Cleaved cell Cloning Communicable Diseases Communication Cytolysis Detection Development Disease Engineering Enterococcus Enterococcus faecalis Enterococcus faecium Environment Enzymes Feedback Future Gastrointestinal tract structure Gene Expression Genes Genetic Genetic Engineering Goals Health Care Costs Healthcare Systems Heart Hospitals Human Incidence Individual Infection Intervention Intestines Lactobacillus Lactococcus Lactococcus lactis Lead Length of Stay Liver Mammals Membrane Membrane Proteins Methods Modeling Modification Morbidity - disease rate Mus Nosocomial Infections Operon Organism Patients Peptide Hydrolases Peptides Peptidoglycan Pheromone Plasmids Probability Probiotics Production Protein Engineering Proteins Reporter Genes Reporting Resistance Resistance development Resort Severities Signal Transduction Skin Spleen Stomach Structure Surface System Technology Testing Therapeutic Vacuum Vancomycin Vancomycin resistant enterococcus Virulence Work antimicrobial antimicrobial peptide bile salts biophysical properties cost directed evolution endolysin enterocin fighting gastrointestinal improved in vivo insight killings lactic acid bacteria mathematical model microorganism mortality multi-scale modeling pathogen peptide pheromone cCF10 promoter protein expression public health relevance research study response screening spatiotemporal therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Enterococci are bacteria that grow naturally inside human intestines. Over the last few decades, these pathogens have developed resistance to our most potent antibiotics, including vancomycin, an antibiotic of last resort for infectious disease. Vancomycin-resistant Enterococcus (VRE) does not cause illness to healthy individuals. But it does cause severe illness to hospital patients, especially the ones who have undergone antibiotic therapy. Antibiotic therapy eliminates a lot of the "good" bacteria in the gut of humans. VRE grab and fill this vacuum, spreading quickly from the intestines to the bloodstream and from there to the spleen, the liver, the heart. There they grow and cause disease that can no longer be easily treated with antibiotics. We genetically engineer lactic acid bacteria (LAB) to specifically target enterococcus inside gastrointestinal (GI) tracts. We propose to administer these cellbots to mice and examine if enterococcus vanishes from mouse GI tracts. We pursue three specific aims: First we engineer "smart" LAB that can detect enterococci. Upon detection, engineered LAB produce and release proteins. In the second aim, we engineer these proteins to be lethal to enterococci. In the third aim, we will examine the efficacy of our modified LAB in mice. We will infect mice with enterococcus and then administer LAB to them. The main hypothesis is that engineered LAB kill enterococci and stop their colonization inside animal GI tracts. If successful, these experiments can lead to the development of a promising therapeutic strategy against enterococcal infections.

描述（由申请人提供）：肠球菌是在人类肠内天然生长的细菌。在过去的几十年中，这些病原体已经对我们最有效的抗生素产生了抗性，包括万古霉素，瓦诺霉素是一种传染病的抗生素。抗性霉素肠球菌（VRE）不会引起健康的个体疾病。但这确实会给医院患者，尤其是接受抗生素治疗的患者。抗生素疗法消除了肠道中的许多“好”细菌人类。 VRE抓住并填充这种真空，从肠道迅速传播到血液，从那里到脾脏，肝脏，心脏。它们在那里生长并引起不再容易用抗生素治疗的疾病。我们在基因工程乳酸上细菌（实验室）特异性靶向胃肠道（GI）内部的肠球菌。我们建议对小鼠进行这些细胞机器人，并检查肠球菌是否从小鼠胃肠道中消失。我们追求三个具体目标：首先我们设计可以检测肠球菌的“智能”实验室。检测后，工程实验室生产并释放蛋白质。在第二个目标中，我们将这些蛋白质设计为致命的肠球菌。在第三个目标中，我们将检查我们改良实验室在小鼠中的功效。我们将用肠球菌感染小鼠，然后对它们进行实验。主要的假设是工程实验室杀死肠球菌并停止在动物胃肠道内的定殖。如果成功，这些实验可能会导致针对肠球菌感染的有希望的治疗策略。