Mechanistic basis of bacteriophages for the decolonization of vancomycin resistant enterococci in the intestine.

噬菌体对肠道内万古霉素耐药肠球菌去定植的机制基础。

基本信息

批准号：
10456852
负责人：
Breck A Duerkop
金额：
$ 37.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2023-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456852
关键词：
Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteremia Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacteriophages Binding Biological Products Blood Circulation Cell Wall Clinic Communities Development Drug resistance Enterococcus Enterococcus faecalis Environment Evolution Future Genome Genome Stability Genomics Germ-Free Goals Gram-Positive Bacteria Habitats Hospitals Human In Vitro Incidence Individual Infection Intestines Knowledge Lead Mediating Modeling Molecular Molecular Genetics Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Mutation Natural Immunity Nosocomial Infections Oral Administration Outcome Phage Receptors Physiological Population Predatory Behavior Process Resistance Resort Sepsis Site Specificity Therapeutic Therapeutic Intervention Tissues Vancomycin Vancomycin resistant enterococcus Virus bacterial fitness bacterial resistance base combat experience experimental study genome sequencing gut colonization gut microbiota in vivo insight microbiota novel novel therapeutic intervention novel therapeutics opportunistic pathogen pathogenic bacteria plasmid DNA pressure receptor receptor function resistant strain standard of care trait treatment strategy whole genome

Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteremia Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacteriophages Binding Biological Products Blood Circulation Cell Wall Clinic Communities Development Drug resistance Enterococcus Enterococcus faecalis Environment Evolution Future Genome Genome Stability Genomics Germ-Free Goals Gram-Positive Bacteria Habitats Hospitals Human In Vitro Incidence Individual Infection Intestines Knowledge Lead Mediating Modeling Molecular Molecular Genetics Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Mutation Natural Immunity Nosocomial Infections Oral Administration Outcome Phage Receptors Physiological Population Predatory Behavior Process Resistance Resort Sepsis Site Specificity Therapeutic Therapeutic Intervention Tissues Vancomycin Vancomycin resistant enterococcus Virus bacterial fitness bacterial resistance base combat experience experimental study genome sequencing gut colonization gut microbiota in vivo insight microbiota novel novel therapeutic intervention novel therapeutics opportunistic pathogen pathogenic bacteria plasmid DNA pressure receptor receptor function resistant strain standard of care trait treatment strategy whole genome

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项目摘要

Project Summary/Abstract The incidence of multidrug resistant (MDR) bacterial infections is rising. This is particularly relevant for the Gram- positive bacterium Enterococcus faecalis, an opportunistic pathogen and leading cause of nosocomial bacteremia. The rise in MDR E. faecalis infections is largely attributed to their ability to resist many antibiotics including antibiotics of “last resort”, such as vancomycin. E. faecalis is a native inhabitant of the human intestinal tract which serves as a major reservoir of MDR E. faecalis. Antibiotic depletion of the intestinal microbiota can facilitate blooms of E. faecalis leading to their enhanced dissemination to the bloodstream and other tissue sites. In many cases overgrowth of intestinal enterococci is dominated by vancomycin resistant enterococci (VRE) which severely limits available treatment options. With increasing VRE infections worldwide, it is imperative that new strategies for therapeutic intervention are explored. An alternative to traditional antibiotics is the use of biological agents for the treatment of drug resistant bacterial infections. One approach is harnessing bacteriophages (phages) that infect and kill bacteria. Although phages may hold promise as next generation therapeutics, we know little of the basic principles of phage infection processes in vivo and how the mammalian host environment influences phage-bacteria interactions. This project investigates the use of phages for the decolonization of VRE within its natural intestinal habitat. Using a combination of mouse intestinal colonization models, molecular genetics and whole genome sequencing, we aim to gain mechanistic insight into how intestinal selective pressures influence the infectivity and genome evolution of phages during phage-mediated VRE decolonization. To achieve this goal we will execute three specific aims: 1) Define the intestinal selective pressures that dictate phage-mediated E. faecalis decolonization, 2) Determine the long-term stability and genomic evolution of E. faecalis phages in the intestine, and 3) Determine cognate receptors for diverse E. faecalis phages and delineate receptor function. Understanding intestinal selective pressures and molecular mechanisms of enterococcal phage infection in vivo will aid in the development of novel phage therapeutics for the decolonization of enterococci recalcitrant to conventional antibiotics.

项目摘要/摘要多药耐药（MDR）细菌感染的事件正在增加。这与革兰氏集特别相关 - 阳性细菌肠球菌粪便是机会性病原体，是医院的主要原因 MDR E.粪便感染的升高主要归因于它们抵抗许多抗生素的能力包括“最后的度假胜地”的抗生素，例如万古霉素。 E. Faecalis是人类肠道的本地居民作为MDR E.粪便的主要储藏室。肠道菌群的抗生素消耗可以促进粪肠球菌的血液，从而增强了对血液和其他组织部位的传播。在许多情况下哪些严重限制了可用的治疗选择。随着世界范围内VRE感染的增加，必须探索了热干预的新策略。传统抗生素的一种替代方法是使用用于治疗耐药细菌感染的生物学剂。一种方法是利用感染并杀死细菌的噬菌体（噬菌体）。虽然噬菌体可能有望作为下一代治疗剂，我们对体内噬菌体感染过程的基本原理几乎不知道宿主环境会影响噬菌体 - 细菌相互作用。该项目调查了噬菌体的使用 VRE在其自然肠栖息地内的非殖民化。结合小鼠肠道定殖模型，分子遗传学和整个基因组测序，我们旨在获取机械洞察力，以了解如何肠道选择压力影响噬菌体介导的噬菌体的感染和基因组进化 VRE非殖民化。为了实现这一目标，我们将执行三个具体目标：1）定义肠道选择性决定噬菌体介导的E.粪便非殖民化的压力，2）确定长期稳定性和肠道大肠杆菌噬菌体的基因组进化，3）确定多种多样的同源受体 E.粪便噬菌体和划定接收器功能。了解肠道选择性压力和体内肠噬菌体感染的分子机制将有助于发展新型噬菌体肠肠球菌顽固抗生素的非殖民化的治疗剂。