Inhibition of the Essential TonB-ExbD Interaction in Escherichia coli

 描述(申请人提供)：革兰氏阴性细菌的外膜是某些营养物质扩散到周质空间并随后运输到 牢房。为了获得大量、稀缺的重要营养物质，如铁载体和维生素B12，其运输底物具有亚纳米分子亲和力的活性转运蛋白位于外膜。由于外膜缺乏常规能源，铁铁载体和维生素B12通过外膜主动运输到周质空间的能量来自于细胞质膜的质子动力。细胞膜中的TonB-ExbB-ExbD系统似乎可以获得质子动力，并以未知的形式将其传递给外膜活性转运蛋白。我们的长期目标是了解大肠杆菌细胞质和外膜之间依赖TonB的能量转导的机制。TonB基因的突变使许多致病物种的适合性大大降低。由于铁的可利用性在传染病中的作用，人们普遍认为TonB系统具有开发新抗生素的新靶点的潜力。我们现在对TonB和ExbD之间的相互作用有了足够的了解，可以确定哪些药物可以中断这种相互作用，并有可能作为抗菌剂或指导抗菌药物的开发。

 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.