Harvard-wide Program on Antibiotic Resistance

摘要 抗生素耐药性是全球最重要的公共卫生问题。全哈佛范围的项目 抗生素耐药性是专门为应对这一全球紧迫性而设计的。它有作为它的 主题和总体目标：开发治疗和预防多种药物的新方法 耐药的耐甲氧西林金黄色葡萄球菌和VRE感染。一组高度合作和富有成效的科学家来自 从医学到分子遗传学再到生物化学的不同领域都被招募到这一领域。 努力。上一个供资期间卓有成效，主要成就包括：1)采取 鉴定和开发抑制壁磷壁酸的先导化合物的新的和独特的方法 金黄色葡萄球菌的生物合成；2)鉴定和寻找新的细胞壁靶向活性；3)使用 独特的筛选策略，以识别针对细菌膜的无毒化合物， 包括改变已在使用的药物的用途；4)确定对其具有重要意义的金黄色葡萄球菌的特征 在感染现场生存和扩散的能力；5)开发针对目标的现场领先工具 鉴定；以及6)确定阻碍细胞内抗生素的外排泵的特性 积累。为了在这些成功的基础上再接再厉，该团队确定了最有希望的增长途径 ，并沿着最短的路径设计了研究路线，以解决 抗生素耐药性问题。这包括1)以新颖的方式应用强大的新技术， 发现哪些因素限制了现有抗生素的有效性；2)使用新的药物方法 利用初期开发的新屏幕的发现，并推进顶部 以及3)开发新的患者管理模式，以降低 高度耐药感染的发生。上述目标将通过4个子项目来实现 协作发挥互动网络的作用，充分利用和最大限度地利用 计划资产。随着项目的共同发展，协同效应源于智力和 物质贡献。财务和职能管理将由经验丰富的 管理核心，它还用于促进数据共享并将项目与更大的 通过组织一年一度的Baarn会议和其他 活动。

Summary Antibiotic resistance is a foremost public health concern worldwide. The Harvard-wide Program on Antibiotic Resistance was specifically designed to be responsive to this global urgency. It has as its theme and overarching goal “Development of new approaches for treating and preventing multidrug resistant MRSA and VRE infection.” A team of highly collaborative and productive scientists from diverse fields – ranging from medicine to molecular genetics to biochemistry – was recruited to this effort. The previous funding period was highly productive, with major achievements including: 1) taking novel and unique approaches to identify and develop lead compounds for inhibition of wall teichoic acid biosynthesis by S. aureus; 2) identifying and pursuing new cell wall targeting activities; 3) using a unique screening strategy to identify non-toxic compounds that target the bacterial membrane, including repurposing drugs already in use; 4) identifying features of S. aureus that are important for its ability to exist and proliferate at the site of infection; 5) developing field-leading tools for target identification; and 6) determining the characteristics of efflux pumps that impede intracellular antibiotic accumulation. To build on these successes, the team identified the most promising avenues growing out of the previous period, and designed lines of research along the shortest pathway for solving the antibiotic resistance problem. These include 1) Applying powerful new technologies in novel ways, discover what factors limit the effectiveness of existing antibiotics; 2) Using new approaches to drug discovery that take advantage of novel screens developed in the initial period, and advance the top leads; and 3) Developing new paradigms for patient management that reduce the probability of development of highly antibiotic resistant infection. The above aims will be achieved by 4 subprojects functioning collaboratively as an interactive network that capitalizes on and maximizes the use of all program assets. As projects have grown together, synergy has stemmed from both intellectual and material contributions. Fiscal and functional management will be overseen by an experienced Administrative Core, which also serves to promote data sharing and connect the project to the greater academic and pharmaceutical communities through organizing the annual BAARN meeting and other activities.