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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(申请人提供)：肠球菌是在人体肠道内自然生长的细菌。在过去的几十年里，这些病原体已经对我们最有效的抗生素产生了抗药性，包括万古霉素，这是一种治疗传染病的最后手段。万古霉素耐药肠球菌(VRE)不会对健康个体造成疾病。但它确实会给医院的患者带来严重的疾病，特别是那些接受过抗生素治疗的患者。抗生素疗法消除了肠道中的许多“有益”细菌人类的生命。VRE抓住并填补这个真空，从肠道迅速传播到血液，然后从那里传播到脾、肝和心脏。在那里，它们生长并导致疾病，不再容易地用抗生素治疗。我们通过基因工程改造乳酸细菌(LAB)，专门针对胃肠道(GI)内的肠球菌。我们建议给小鼠使用这些蜂窝机器人，并检查肠球菌是否从小鼠的胃肠道中消失。我们追求三个具体目标：首先，我们设计了能够检测肠球菌的“智能”实验室。一旦检测到，工程实验室就会产生并释放蛋白质。在第二个目标中，我们将这些蛋白质改造成对肠球菌具有致命性。在第三个目标中，我们将检查我们改进后的实验室在小鼠身上的效果。我们将用肠球菌感染小鼠，然后对它们进行实验室治疗。主要的假设是，经过改造的实验室杀死了肠球菌，并阻止它们在动物胃肠道内定居。如果成功，这些实验可能导致开发一种有希望的治疗策略来对抗肠球菌感染。