Exploiting membrane targets to overcome antibiotic resistance

项目总结--总体 抗生素耐药性是世界范围内的一个主要公共卫生问题。这种CARB(抗击抗生素耐药性 (细菌)的提议是为了应对这一紧迫的全球威胁而构思的。我们节目的主题是“利用 克服抗生素耐药性的膜靶标“解决了当前知识中的重要空白 促进将发现转化为对抗抗生素耐药感染的战略。一支高素质的团队 来自不同领域的协作和多产的科学家-化学、生物化学、结构生物学和 分子遗传学--加入了这一努力。细胞膜，宿主和病原体之间的界面， 是细菌的一个主要弱点。干扰细胞被膜组装或功能可抑制细菌 生长，促进溶解，减少对宿主免疫防御的抵抗力，并增加对其他 用抗生素来克服耐药性。识别和利用破坏信封组件的新方法 实现治疗发现的途径一直是该领域的一个重要目标。然而，这一领域的进展 信封目标带来的许多挑战阻碍了这一进程。生物合成和调控过程 支配细胞膜的生物发生发生在膜的界面上，通常涉及含有 多个跨膜片段，在多蛋白质复合体中发挥作用，并使用复杂的底物 商业上买不到的东西。要推进我们对这些细胞包膜靶标的理解，需要 拥有跨越化学和生物广泛领域的专业知识的跨学科团队的共同努力。 最近的技术进步和生物发现，其中许多是由CARB项目组做出的， 改变了我们对细胞膜生物学的理解，打开了从根本上新方法的大门 针对这一重要结构的治疗靶点。为了在这些成功的基础上再接再厉，我们创建了一个协作、 跨学科项目，以识别、表征和验证包膜生物发生和验证中的新脆弱性 维护路径。拟议的三个项目不仅通过共同的重点 研究人员对细胞包膜生物学的研究，他们致力于以分子机制为基础 翻译研究，以及重叠的主题和目标，但也通过多个 调查人员在每个提案内部以及之间进行调查。项目1将确定酶的结构基础 广泛保守的SEDS家族细胞壁聚合酶的活性及其决定蛋白功能的研究 在生长和分裂过程中的大分子复合体中。项目2将侧重于确定和 利用革兰氏阳性细胞信封中的漏洞。项目3将专注于刻画和开发 革兰氏阴性细胞信封中的漏洞。精简的行政核心将协调各项活动，以 在提供负责任的财政监督的同时，最大限度地实现协同效应、数据共享和所有计划资产的使用。

PROJECT SUMMARY – Overall Antibiotic resistance is a major public health concern worldwide. This CARB (Combating Antibiotic Resistant Bacteria) proposal was conceived in response to this urgent global threat. The theme of our program, “Exploiting Membrane Targets to Overcome Antibiotic Resistance,” addresses important gaps in current knowledge to facilitate translation of discoveries into strategies to combat antibiotic-resistant infections. A team of highly collaborative and productive scientists from diverse fields – chemistry, biochemistry, structural biology, and molecular genetics – has joined forces in this effort. The cell envelope, the interface between host and pathogen, is a major point of vulnerability for bacteria. Interfering with cell envelope assembly or function can inhibit bacterial growth, promote lysis, decrease resistance to host immune defenses, and increase susceptibility to other antibiotics to overcome resistance. Identifying and exploiting new ways of disrupting envelope assembly pathways to enable therapeutic discovery has been an important goal in the field. However, progress in this area has been hampered by the many challenges posed by envelope targets. Biosynthetic and regulatory processes that govern cell envelope biogenesis take place at a membrane interface and often involve proteins that contain multiple membrane-spanning segments, function in multi-protein complexes, and use complicated substrates that are not commercially available. Advancing our understanding of these cell envelope targets requires the concerted efforts of an interdisciplinary team with expertise that spans broad areas of chemistry and biology. Recent technological advances and biological discoveries, many made by the CARB project team, have transformed our understanding of cell envelope biology and opened the door to fundamentally new approaches to therapeutic targeting of this essential structure. To build on these successes, we have created a collaborative, interdisciplinary project to identify, characterize, and validate novel vulnerabilities in envelope biogenesis and maintenance pathways. The three proposed projects are not only connected by the shared focus of the investigators on cell envelope biology, their commitment to molecular mechanism as the foundation of translational research, and overlapping themes and goals, but also by synergistic collaboration among multiple investigators within as well as between each proposal. Project 1 will define the structural basis for enzymatic activity of the broadly conserved SEDS family cell wall polymerases and determine how SEDS proteins function within large macromolecular complexes during growth and division. Project 2 will focus on identifying and exploiting vulnerabilities in the Gram-positive cell envelope. Project 3 will focus on characterizing and exploiting vulnerabilities in the Gram-negative cell envelope. A streamlined administrative core will coordinate activities to maximize synergies, data sharing, and use of all program assets while providing responsible fiscal oversight.