Harvard-wide Program on Antibiotic Resistance

总结 抗生素耐药性是全世界最重要的公共卫生问题。哈佛大学范围内的项目 抗生素耐药性是专门为应对这一全球紧迫性而设计的。它作为其 主题和总体目标“制定治疗和预防多种毒品 耐药MRSA和VRE感染。”一个高度协作和富有成效的科学家团队， 从医学到分子遗传学再到生物化学， 努力上一个资助期的成果丰硕，主要成果包括： 鉴定和开发用于抑制壁磷壁酸的先导化合物的新颖和独特的方法 生物合成S.金黄色葡萄球菌; 2）鉴定和追求新的细胞壁靶向活性; 3）使用 独特的筛选策略，以识别靶向细菌膜的无毒化合物， 包括重新利用已在使用的药物; 4）鉴定S.金黄色葡萄球菌， 在感染部位存在和增殖的能力; 5）开发用于靶向的领域领先的工具 鉴定;和6）确定阻碍细胞内抗生素的外排泵的特征 积累在这些成功的基础上，该团队确定了最有前途的增长途径， 从上一个时期，并设计了研究路线沿着最短的途径，以解决 抗生素耐药性问题。这些措施包括：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）使用新的药物治疗方法 利用初期开发的新型屏幕的发现，并将顶部 导线;以及3）开发新的患者管理模式，降低 高度抗生素耐药性感染的发展。上述目标将通过4个分项目实现 作为一个互动的网络，利用和最大限度地利用所有 程序资产。随着项目的共同发展，协同作用源于智力和 物质贡献。财务和职能管理将由一位经验丰富的 管理核心，这也有助于促进数据共享，并将项目与更大的 学术界和制药界通过组织年度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.