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Outer Membrane Biogenesis: New Antibiotic Targets

外膜生物发生：新的抗生素靶点

基本信息

批准号：
10554382
负责人：
Daniel Kahne
金额：
$ 56.1万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554382
关键词：
3-Dimensional ATP-Binding Cassette Transporters Address Antibiotic Resistance Antibiotics Binding Biochemical Biogenesis Biological Assay Carrier Proteins Cell surface Cells Complex Crude Extracts Cryoelectron Microscopy Cytoplasm Face Fluorescent Probes Glycolipids Gram-Negative Bacteria Health Heterogeneity Human Image In Vitro Individual Infection Lipopolysaccharides Measures Mediating Membrane Membrane Proteins Methods Molecular Molecular Chaperones Molecular Structure Monitor Pharmaceutical Preparations Phospholipids Polymyxins Preparation Process Proteins Research Structure System Therapeutic Uses Variant Visualization Work beta barrel biochemical tools design in vivo inhibitor insight interest membrane assembly membrane biogenesis mutant novel therapeutics overexpression particle periplasm protein complex protein folding protein protein interaction proteoliposomes reconstitution reconstruction sugar tool transport inhibitor unpublished works

项目摘要

Project Summary/Abstract Antibiotic resistant Gram-negative infections pose a serious threat to human health. The outer membrane of Gram-negative bacteria is a unique structure essential for survival; it 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 two multi-protein machines responsible for the biogenesis of two major components of the outer membrane, lipopolysaccharide (LPS) and outer membrane proteins (OMPs). To understand the protein-protein interactions within each machine and their molecular structures, biochemical and structural studies will be undertaken. To dissect the functions of the individual components of these machines, intermediates in transport and assembly of LPS and OMPs will be characterized structurally, biochemically, and in cells. A better understanding of the protein machinery and the processes in which they are involved may lead to the discovery of inhibitors that could ultimately be developed to treat Gram-negative infections.

项目摘要/摘要耐药革兰氏阴性菌感染严重威胁人类健康。外膜的外膜革兰氏阴性菌是一种独特的生存所必需的结构；它也是阻止细菌生长的物理屏障许多种类的抗生素进入，从而使其无效。这项研究旨在了解两个多蛋白质机器的结构和功能，这些机器负责两个蛋白质的生物发生外膜的主要成分是脂多糖(LPS)和外膜蛋白(OMP)。至了解每台机器中的蛋白质-蛋白质相互作用及其分子结构、生化和将进行结构研究。为了剖析这些机器的各个部件的功能，内毒素和有机磷农药转运和组装的中间体将从结构、生化和在牢房里。更好地了解蛋白质的机制及其参与的过程可能会导致最终可能被开发出来治疗革兰氏阴性感染的抑制剂的发现。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct single-cell morphological dynamics under beta-lactam antibiotics.

DOI：
10.1016/j.molcel.2012.09.016
发表时间：
2012-12-14
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Yao, Zhizhong;Kahne, Daniel;Kishony, Roy
通讯作者：
Kishony, Roy

The assembly of β-barrel outer membrane proteins.

DOI：
10.1016/j.mib.2021.01.009
发表时间：
2021-04
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Tomasek D;Kahne D
通讯作者：
Kahne D

Membrane integration of an essential β-barrel protein prerequires burial of an extracellular loop.

必需的β-桶蛋白的膜整合需要埋藏细胞外环。

DOI：
10.1073/pnas.1616576114
发表时间：
2017
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Wzorek,JosephS;Lee,James;Tomasek,David;Hagan,ChristineL;Kahne,DanielE
通讯作者：
Kahne,DanielE

The Bacterial Cell Wall: From Lipid II Flipping to Polymerization.