Institute of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstraße 2, 37077, Göttingen, Germany.
Computational Biology, School of Life Sciences, University of Dundee, Nethergate, Dundee, DD1 5EH, UK.
Sci Rep. 2019 Feb 4;9(1):1264. doi: 10.1038/s41598-018-37066-9.
The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.
大多数抗生素通过革兰氏阴性菌外膜的渗透是通过孔蛋白通道进行的。为了在抗生素耐药危机的情况下设计对革兰氏阴性菌活性更高的药物，必须更好地理解这些通道对渗透物物理化学性质的严格限制。在这里，我们展示了高分辨率电生理学、新的噪声过滤分析方案和原子生物分子模拟的结合，揭示了β-内酰胺抗生素氨苄西林与致病性细菌脑膜炎奈瑟菌的孔蛋白 PorB 之间的弱结合事件。特别是，基于通道中电渗透流的原理，利用电生理学特征中经常出现的不对称性来详细描述结合位点和分子相互作用。我们的结果为决定两性离子抗生素在孔蛋白通道中结合和渗透的因素提供了依据。
