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

子项目3 治疗和预防抗生素耐药感染的新方法

• 批准号: 9151288
• 负责人: Michael S Gilmore
• 金额: $ 33.84万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151288
• 关键词: Acute; Address; Advisory Committees; Agriculture; Antibiotic Resistance; Antibiotics; Chromosome Mapping; Collaborations; Collection; Crowding; Data; Ecology; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Evolution; Genes; Genus staphylococcus; Goals; Government; Growth; Health; Hospitals; Human; In Vitro; Infection; Infection prevention; Libraries; Medicine; Multi-Drug Resistance; Mus; National Security; Nosocomial Infections; Operon; Pathway interactions; Patients; Prevention; Production; Reading; Resources; Services; Staphylococcus aureus; System; Technology; Testing; Urbanization; Work; anthropogenesis; comparative genomics; design; improved; in vivo; insight; membrane synthesis; methicillin resistant Staphylococcus aureus; new therapeutic target; next generation; novel strategies; novel therapeutics; prevent; programs; promoter; prototype; screening; tool

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.

概括 抗生素耐药性是美国医院的一个严重问题，威胁着医学的每一个分支 目前正在实践中。抗生素耐药性现在甚至成为国家安全问题。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耐受性，这些疾病尤其难以治疗。这 该提案与所有其他子项目合作和协同，试图响应国家 挑战是在上一支持期间取得的进展的基础上再接再厉，并将重点放在这些方面 大量资源用于推进这场危机的切实解决方案。我们的总体目标是 提高现有抗生素类别的效用，并探索新的治疗范例 用于多重耐药感染。为了实现这一目标，在本子项目中，我们将追求 2 个具体目标 目标：1) 确定 MRSA/MSSA 和 VRE/VSE 对抗生素活性的障碍，以及 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，包括众包菌株 收集新信息，从中获得新的更好的预防和预防方法 可以设计治疗多重耐药 MRSA 和 VRE 感染。我们开创了 应用比较基因组学来了解抗生素耐药性的起源和传播 肠球菌；前期数据显示，人为因素如 人类的城市化和抗生素的应用达到前所未有的水平，推动了它们的发展 进化;并与其他子项目合作，应用Tn-seq来鉴定所需的基因 金黄色葡萄球菌的体外和体内生长以及新的药物靶点。每一项都开创了先例 适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，并为新抗生素的设计和 抗生素增效剂。此外，还将探索新的治疗模式来预防 VRE 定植和感染。这些结果将为优化设计提供关键信息 新药和抗生素增效剂；以及改善生态管理的新工具 患者减少多重耐药感染的可能性和数量。我们相信这个数据 对于直接解决目前存在的抗生素耐药性危机具有重大价值。