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

• 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
• 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

 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（由申请人提供）：革兰氏阴性菌的外膜是某些营养物质扩散到周质空间和随后转运到细胞内的屏障。 牢房为了获得大量的、稀缺的、重要的营养物质，如铁-铁载体和维生素B12，对它们的转运底物具有亚纳摩尔亲和力的活性转运蛋白位于外膜中。由于外膜缺乏常规的能量来源，用于铁-铁载体和维生素B12主动运输穿过外膜并进入周质空间的能量来自细胞质膜的质子动力。细胞质膜中的TonB-ExbB-ExbD系统似乎收获质子动力，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细胞质和外膜之间TonB依赖性能量转导的机制。tonB的突变使许多致病物种的适应性显著降低。由于铁的可利用性在感染性疾病中发挥的作用，人们广泛认为TonB系统有潜力成为开发新抗生素的新靶点。我们现在充分了解TonB和ExbD之间的相互作用，以确定中断这种相互作用的药物，并可能作为抗菌剂或指导抗菌剂的开发。