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.

项目概要-总体 抗生素耐药性是全球主要的公共卫生问题。CARB（Combating Antibiotic Resistant） 细菌）的建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“开发 克服抗生素耐药性的膜靶点”解决了当前知识的重要空白， 促进将发现转化为对抗抗药性感染的战略。有团队高 来自不同领域的合作和生产科学家-化学，生物化学，结构生物学， 分子遗传学-已经加入了这方面的努力。细胞被膜，宿主和病原体之间的界面， 是细菌的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，降低对宿主免疫防御的抵抗力，并增加对其他疾病的易感性。 抗生素来克服耐药性。识别和开发破坏包膜组装的新方法 能够发现治疗方法的途径一直是该领域的重要目标。然而，这方面的进展 受到了包络目标带来的许多挑战的阻碍。生物合成和调节过程 控制细胞被膜生物发生发生在膜界面，且通常涉及蛋白质，所述蛋白质包含 多个跨膜片段，在多蛋白复合物中起作用，并使用复杂的底物 这是不可商购的。为了进一步了解这些细胞包膜靶点， 跨学科团队的共同努力，拥有跨越化学和生物学广泛领域的专业知识。 最近的技术进步和生物学发现，其中许多是由CARB项目组完成的， 改变了我们对细胞包膜生物学的理解，并为全新的方法打开了大门。 到治疗靶向这个基本结构。为了在这些成功的基础上再接再厉，我们建立了一个合作， 跨学科项目，以确定，表征和验证信封生物成因和 维护路径。这三个拟议的项目不仅是由共同的重点， 研究人员对细胞包膜生物学，他们的承诺，分子机制的基础， 翻译研究，重叠的主题和目标，而且还通过多个之间的协同合作 调查人员在每一个提案之间。项目1将定义酶的结构基础 广泛保守的SEDS家族细胞壁聚合酶的活性，并确定SEDS蛋白如何发挥功能 在大分子复合体中生长和分裂。项目2将侧重于确定和 利用革兰氏阳性细胞包膜的漏洞项目3将侧重于描述和利用 革兰氏阴性细胞包膜的脆弱性一个精简的行政核心将协调各项活动， 最大限度地发挥协同作用，数据共享和使用所有计划资产，同时提供负责任的财政监督。