Exploiting membrane targets to overcome antibiotic resistance

利用膜靶标克服抗生素耐药性

基本信息

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
项目类别：
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

项目摘要

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。细菌）提案是为了应对这一紧迫的全球威胁而构思的，我们计划的主题是“利用”。克服抗生素耐药性的膜目标”解决了当前知识中的重要差距促进将发现转化为对抗抗生素耐药性感染的策略。来自不同领域（化学、生物化学、结构生物学和分子遗传学——细胞包膜，宿主和病原体之间的界面，共同努力。是细菌的一个主要弱点，干扰细胞包膜组装或功能可以抑制细菌。生长，促进裂解，降低对宿主免疫防御的抵抗力，并增加对其他物质的易感性识别和利用破坏组装的新方法。然而，实现治疗发现的途径一直是该领域的一个重要目标。生物合成和监管过程带来的许多挑战阻碍了这一进程。控制细胞被膜生物发生的蛋白质发生在膜界面，并且通常涉及含有以下成分的蛋白质：多个跨膜片段，在多蛋白复合物中发挥作用，并使用复杂的底物推进我们对这些细胞靶标的理解需要跨学科团队的共同努力，其专业知识涵盖化学和生物学广泛领域。最近的技术进步和生物学发现，其中许多是由 CARB 项目团队取得的，已经改变了我们对细胞包膜生物学的理解，并为全新方法打开了大门为了以这些成功为基础，我们创建了一个协作的、跨学科项目，旨在识别、表征和验证生物发生和三个拟议的项目不仅通过共同的重点联系在一起。细胞包膜生物学的研究人员，他们致力于分子机制作为基础转化研究，以及重叠的主题和目标，而且还通过多个机构之间的协同合作每个提案内部以及项目 1 之间的研究人员将定义酶促反应的结构基础。广泛保守的 SEDS 家族细胞壁聚合酶的活性并确定 SEDS 蛋白的功能项目 2 将重点关注大型大分子复合物的生长和分裂过程。利用革兰氏阳性包膜细胞中的漏洞项目 3 将重点关注表征和利用。简化的管理核心将协调革兰氏阴性细胞包膜中的漏洞。最大限度地发挥协同作用、数据共享和所有计划资产的使用，同时提供负责任的财政监督。