Inhibition of the Essential TonB-ExbD Interaction in Escherichia coli

抑制大肠杆菌中必需的 TonB-ExbD 相互作用

基本信息

批准号：
9090004
负责人：
KATHLEEN POSTLE
金额：
$ 18.84万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090004
关键词：
Active Biological Transport Affinity Anti-Bacterial Agents Antibiotics Bacteroides Binding Biotechnology Cell membrane Cells Characteristics Chelating Agents Collaborations Communicable Diseases Couples Cyclic Peptides Development Diffusion Drug Targeting Energy-Generating Resources Escherichia coli Escherichia coli K12 Goals Gram-Negative Bacteria Harvest Health Heme Iron In Vitro Industry Iron Libraries Ligands Location Membrane Membrane Proteins Michigan Molecular Mutation N-terminal Neisseria gonorrhoeae Nutrient Peptides Pharmacologic Substance Plasmids Play Proteins Research Resistance development Role Siderophores Structure Surface Plasmon Resonance System Transferrin Transmembrane Domain Universities VDAC1 gene Vitamin B 12 War base biophysical techniques cell type high throughput screening in vivo inhibitor/antagonist medical schools nanomolar novel pathogen pathogenic Escherichia coli periplasm protein protein interaction screening small molecule uptake

项目摘要

DESCRIPTION (provided by applicant): The outer membranes of Gram-negative bacteria are barriers to diffusion of certain nutrients into the periplasmic space and subsequent transport into the cell. To acquire large, scarce, important nutrients such as iron-siderophores and vitamin B12, active transporters with sub-nanomolar affinities for their transport substrates are located in the outer membrane. Because the outer membrane lacks a conventional energy source, energy for active transport of iron-siderophores and vitamin B12 across the outer membrane and into the periplasmic space derives from the protonmotive force of the cytoplasmic membrane. The TonB-ExbB-ExbD system in the cytoplasmic membrane appears to harvest protonmotive force and transduce it in an unknown form to the outer membrane active transporters. Our long-term goal is to understand the mechanism of TonB-dependent energy transduction between the cytoplasmic and outer membranes of Escherichia coli. Mutations in tonB render many pathogenic species significantly less fit. Due to the role that iron availability plays in infectious disease, it is widely recognized the TonB system has potential as a novel target for the development of new antibiotics. We now understand the interaction between TonB and ExbD sufficiently to identify agents which interrupt that interaction and could potentially serve as antibacterials or guide antibacterial development.

描述（应用程序提供）：革兰氏阴性细菌的外膜是将某些营养物质扩散到外围简化空间的障碍，然后将其传输到细胞。为了获得大量，稀缺，重要的营养素，例如铁螺体和维生素B12，其运输底物具有亚纳摩尔亲和力的活性转运蛋白位于外膜。由于外膜缺乏常规的能源，因此铁 - 辅助载体和维生素B12在整个外膜和周围空间中的主动运输能量源自细胞质膜的质子力力。细胞质膜中的TONB-EXBB-EXBD系统似乎会收集质子敏化力，并以未知形式将其转移到外膜活性转运蛋白。我们的长期目标是了解大肠杆菌的细胞质和外膜之间的TONB依赖性能量转移的机制。 TONB中的突变使许多致病物种的拟合度明显降低。由于铁的可用性在传染病中发挥了作用，因此广泛认为TONB系统具有潜力是开发新抗生素的新目标。现在，我们正确理解TONB和EXBD之间的相互作用，以识别中断这种相互作用的药物，并有可能用作抗菌物或引导抗菌发育。