Exploiting membrane targets to overcome antibiotic resistance

利用膜靶标克服抗生素耐药性

• 批准号: 10699952
• 负责人: Suzanne Walker
• 金额: $ 251.52万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699952
• 关键词: Address; Anabolism; Antibiotic Resistance; Antibiotics; Area; Bacteria; Bacterial Antibiotic Resistance; Biochemical; Biochemistry; Biogenesis; Biological; Biological Assay; Biology; Cell Maintenance; Cell Wall; Cell physiology; Chemistry; Collaborations; Combating Antibiotic Resistant Bacteria; Complex; Creativeness; Cytolysis; Data; Development; Ensure; Environment; Family; Foundations; Genetic; Genetic Screening; Glycopeptide Antibiotics; Goals; Gram-Negative Bacteria; Growth; Immune; Individual; Infection; Investigation; Knowledge; Lipids; Macromolecular Complexes; Maintenance; Membrane; Membrane Proteins; Molecular; Molecular Genetics; Multiprotein Complexes; Natural Products; Organism; Pathway interactions; Peptidoglycan; Play; Polymerase; Polymers; Predisposition; Process; Productivity; Proteins; Public Health; Reagent; Research Personnel; Resistance; Role; Scientist; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Technology; Teichoic Acids; Testing; Therapeutic; Training; Translational Research; Translations; Validation; antibiotic resistant infections; antimicrobial; beta-Lactams; cell envelope; collaborative approach; combat; data sharing; design; drug resistant pathogen; experience; genetic approach; innovation; interdisciplinary collaboration; membrane assembly; membrane biogenesis; mortality; multidisciplinary; new therapeutic target; novel; novel strategies; pathogen; pathogenic bacteria; programs; protein function; reconstitution; resistant strain; response; structural biology; success; synergism; therapeutic target; tool

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.

项目摘要 - 总体 抗生素耐药性是全球主要的公共卫生问题。该碳水化合物（对抗抗生素耐药性 细菌）提出的提案是为了应对这种紧急的全球威胁。我们计划的主题是“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差距 促进将发现转化为打击抗生素耐药感染的策略。一个高度的团队 来自潜水领域的合作和产品科学家 - 化学，生物化学，结构生物学以及 分子遗传学 - 与这项努力联合起来。细胞包络，宿主和病原体之间的界面， 是细菌脆弱性的主要点。干扰细胞包络组件或功能可以抑制细菌 生长，促进裂解，降低对宿主免疫防御能力的抵抗力，并增加对其他的敏感性 抗生素以克服抗性。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重要目标。但是，在这个领域的进展 信封目标构成的许多挑战都受到了阻碍。生物合成和调节过程 控制细胞包膜生物发生在膜界面上发生，并且通常涉及包含的蛋白质 多个跨膜段，在多蛋白质复合物中的功能，并使用复杂的底物 无法商业上可用。促进我们对这些细胞信封目标的理解需要 一个跨学科团队的一致努力，其专业知识涵盖了广泛的化学和生物学领域。 CARB项目团队做出的许多技术进步和生物学发现， 改变了我们对细胞信封生物学的理解，并打开了从根本上开始新方法的大门 进行这种基本结构的热靶向。为了基于这些成功，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中的新脆弱性 维护途径。提出的三个项目不仅与 细胞包膜生物学的研究者，他们对分子机制的承诺作为基础 翻译研究，重叠的主题和目标，但也通过多个的协同合作 每个提案之间以及之间的调查人员。项目1将定义酶促的结构基础 广泛配置的SEDS系列细胞壁聚合酶的活性，并确定SEDS蛋白如何功能 在生长和分裂过程中大型大分子复合物中。项目2将专注于识别和 利用革兰氏阳性细胞包膜中的漏洞。项目3将集中于表征和利用 革兰氏阴性细胞包膜中的脆弱性。简化的行政核心将协调活动 在提供负责任的财政监督的同时，最大程度地提高协同作用，数据共享和使用所有计划资产。