Subproject 3 New Approaches to Treatment and Prevention of Antibiotic Resistant Infection

总结 抗生素耐药性是美国医院的一个严重问题，并威胁着医学的每一个分支， 目前实行。抗生素耐药性现在甚至是一个国家安全问题。葡萄球菌 金黄色葡萄球菌（特别是MRSA）和肠球菌（特别是VRE）是医院感染的主要原因， 由于多重耐药性和内在的抗性，特别难以治疗。这 该提案与所有其他分项目合作并发挥协同作用， 在上一个支助期取得的进展的基础上再接再厉， 我们需要大量资源来推动切实解决这场危机。我们的首要目标是 提高现有抗生素类别的效用，并探索新的治疗模式 多药耐药感染为实现这一目标，在本次项目中，我们将实施2项具体措施， 目的：1）确定MRSA/MSSA和VRE/VSE对抗生素活性的阻碍，2）探索 VRE感染预防和治疗的新范式-肠道生态管理。这个项目 利用尖端技术和独特资产，包括众包应变 收集，以获得新的信息， 可以设计治疗多药耐药MRSA和VRE感染。我们开创了 应用比较基因组学了解抗生素耐药性的起源和传播 在肠球菌中;在前一时期，人为因素，如 人类的城市化和抗生素的应用达到了前所未有的水平， 进化;并与其他子项目合作，应用Tn-seq，以确定 S.金黄色葡萄球菌的体外和体内生长以及新的药物靶点。每一个都是先例 应用于葡萄球菌和肠球菌。这些技术现在将用于识别 抗生素靶向抑制的障碍，并告知新抗生素的设计， 抗生素增效剂。此外，将探索一种新的治疗模式来预防VRE 殖民和感染。这些结果将提供关键信息，优化设计的 新的药物和抗生素增效剂;和新的工具，以改善生态管理， 减少多药耐药感染的可能性和数量。我们相信这些数据 将直接解决目前存在的抗生素耐药性危机。

Summary Antibiotic resistance is an acute problem in US hospitals, and threatens every branch of medicine as currently practiced. Antibiotic resistance is now even a national security concern. Staphylococcus aureus (esp. MRSA) and the enterococci (esp. VRE) are among top causes of hospital infection that are especially difficult to treat, because of multiple drug resistances and intrinsic hardiness. This proposal, in collaboration and synergy with all other subprojects, attempts to respond to the national challenge by building on advances made in the previous period of support, and focusing those resources sharply on advancing tangible solutions to this crisis. Our overarching goals are to improve the utility of antibiotic classes that currently exist, and to explore new therapeutic paradigms for multidrug resistant infection. To achieve this goal, in this Subproject, we will pursue 2 Specific Aims: 1) Identify impediments in MRSA/MSSA and VRE/VSE to antibiotic activity, and 2) Explore a new paradigm for VRE infection prevention and treatment – Gut ecology management. This project takes advantage of cutting-edge technologies and unique assets, including a crowd sourced strain collection, to obtain new information from which new and better approaches for preventing and treating multidrug resistant MRSA and VRE infections can be designed. We have pioneered the application of comparative genomics to understand the origin and spread of antibiotic resistances among enterococci; showing in the previous period, that anthropogenic factors such as the urbanization of humans and the application of antibiotics in unprecedented levels, has driven their evolution; and in collaboration with other subprojects, applied Tn-seq, to identify genes required for S. aureus growth in vitro and in vivo as well as new drug targets. Each has been precedent-setting in application to staphylococci and enterococci. These technologies now will be used to identify impediments to target inhibition by antibiotics, and to inform the design of new antibiotics and antibiotic potentiators. Further, a new treatment paradigm will be explored for prevention of VRE colonization and infection. These results will provide critical information for optimizing the design of new drugs and antibiotic potentiators; and new tools for improving the ecological management of patients to reduce the likelihood and numbers of multidrug resistant infections. We believe this data will be of substantial value in directly addressing the antibiotic resistance crisis that now exists.