Targeting Membrane Transport Steps in Cell Envelope Assembly

细胞包膜组装中的靶向膜运输步骤

• 批准号: 10027875
• 负责人: Daniel Kahne
• 金额: $ 73.44万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027875
• 关键词: ATP-Binding Cassette Transporters; Acinetobacter baumannii; Address; Affinity; Amino Acids; Amino Acyl-tRNA Synthetases; Antibiotics; Bacteria; Biochemical; Biochemistry; Biogenesis; Biological Assay; Biology; Carrier Proteins; Cell surface; Cells; Cellular Structures; Complex; Crystallization; Data; Development; Disaccharides; Drug resistance; Escherichia coli; Face; Family; Genus Mycobacterium; Glycolipids; Gram-Negative Bacteria; Health; Human; Impairment; Infection; Lead; Lipid A; Lipid Binding; Lipids; Lipopolysaccharides; Maps; Membrane; Methods; Molecular Conformation; Monitor; Mycobacterium tuberculosis; Mycolic Acid; Organism; Pathway interactions; Peptidoglycan; Permeability; Pharmaceutical Preparations; Polymers; Polysaccharides; Process; Proteins; Public Health; Pump; Research; Resistance; Role; Side; Structure; Surface; Therapeutic Uses; Toxic effect; Transmembrane Transport; Trehalose; Variant; Work; cell envelope; improved; inhibitor/antagonist; multidisciplinary; muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; novel; novel strategies; novel therapeutics; periplasm; resistance frequency; small molecule; structural biology; sugar; therapeutic development; tool; transport inhibitor; tuberculosis treatment

Project Summary/Abstract Infections due to Gram-negative bacteria and mycobacterium tuberculosis (Mtb) pose a serious threat to human health. These organisms produce especially complex cell envelopes consisting of a double layer of membranes that are essential for survival. This cell envelope also functions as a physical barrier to block entry of many classes of antibiotics and thereby render them ineffective. This research is directed towards understanding the structure and function of three protein transporters responsible for cell envelope assembly. Each of these transporters represents one of the three major transporter families, namely ABC transporters, MOPS transporters, and RND transporters. To understand how these transporters move their complex glycolipid cargo, biochemical and structural studies will be undertaken. Intermediates and inhibitors of transport and assembly of will be characterized structurally, biochemically, and in cells. A better understanding of these proteins’ roles in cell envelope assembly will lead to new therapies to treat resistant infections.

项目总结/摘要 革兰氏阴性菌和结核分枝杆菌（Mycobacteriumtuberculosis，Mtb）感染对人类健康构成严重威胁 健康这些生物体产生特别复杂的细胞被膜，由双层膜组成 对生存至关重要。这种细胞包膜也起到了物理屏障的作用， 抗生素的种类，从而使它们无效。本研究旨在了解 结构和功能的三种蛋白转运蛋白负责细胞包膜组装。这一切成功都 转运蛋白代表三大转运蛋白家族之一，即ABC转运蛋白、MOPS 转运蛋白和RND转运蛋白。为了了解这些转运蛋白是如何运输复杂的糖脂的， 将进行生物化学和结构研究。转运和组装的中间体和抑制剂 将在结构上、生物化学上和细胞中进行表征。更好地了解这些蛋白质在 细胞包膜组装将导致治疗耐药感染的新疗法。