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

项目总结/摘要 多药耐药（MDR）细菌感染的发病率正在上升。这一点对于Gram来说尤为重要。 粪肠球菌是一种条件致病菌，是导致医院感染的主要原因。 菌血症MDR E.粪菌感染主要归因于它们抵抗许多抗生素的能力 包括抗生素的“最后手段”，如万古霉素。E.粪菌是人类肠道的原住民 作为MDR E的主要储存库的通道。粪便肠道菌群的抗生素消耗可以 促进E.粪便，导致其向血流和其他组织部位的传播增强。 在许多情况下，肠球菌的过度生长主要是万古霉素耐药肠球菌（VRE） 这严重限制了可用的治疗选择。随着全球VRE感染的增加，当务之急是 探索了治疗干预的新策略。传统抗生素的替代品是使用 用于治疗抗药性细菌感染的生物制剂。一种方法是利用 感染并杀死细菌的噬菌体。尽管作为下一代， 虽然我们对噬菌体体内感染过程的基本原理以及哺乳动物如何感染噬菌体的方法知之甚少， 宿主环境影响噬菌体-细菌相互作用。本项目研究了将生物柴油用于 VRE在其自然肠道栖息地内的非殖民化。利用小鼠肠道定植 模型，分子遗传学和全基因组测序，我们的目标是获得机制的洞察如何 肠道选择性压力影响噬菌体介导的大肠杆菌的感染性和基因组进化 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 压力决定噬菌体介导的E.粪便去殖民化，2）确定长期稳定性， E.肠中的粪肠球菌，和3）确定不同的同源受体 E.粪便排泄物和描绘受体功能。了解肠道选择性压力， 体内肠球菌噬菌体感染的分子机制将有助于开发新的噬菌体 用于使柠檬酸肠球菌对常规抗生素去殖民化的治疗剂。

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.