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The Hitchhiker's Guide to the Periplasm: Unexpected Molecular Interactions of Antibiotics Revealed by Considering Crowding Effects in E. coli
bioRxiv - Biochemistry Pub Date : 2020-06-03 , DOI: 10.1101/2020.06.03.132118
Conrado Pedebos , Iain P. S. Smith , Alister Boags , Syma Khalid

The periplasm of Gram-negative bacteria is a highly crowded environment comprised of many different molecular species. Antibacterial agents that causes lysis of Gram-negative bacteria by their action against the inner membrane must cross the periplasm to arrive at their target membrane. Very little is currently known about their route through the periplasm, and the interactions they experience. To this end, here atomistic molecular dynamics simulations are used to study the path taken by the antibiotic polymyxin B1 through a number of models of the periplasm which are crowded with proteins and osmolytes to different extents. The simulations reveal that PMB1 forms transient and long-lived interactions with proteins and osmolytes that are free in solution as well as lipoproteins anchored to the outer membrane and bound to the cell wall. We show that PMB1 may be able to hitchhike within the periplasm by binding to lipoprotein carriers. Overall our results show that PMB1 is rarely uncomplexed within the periplasm; an important consideration for interpretations of its therapeutic mechanism of action. It is likely that this observation can be extended to other antibiotics that rely on diffusion to cross the periplasm.

中文翻译:

Hitchhiker的周质指南:考虑到大肠杆菌中的拥挤效应,揭示了抗生素的意外分子相互作用

革兰氏阴性细菌的周质是一个高度拥挤的环境,由许多不同的分子种类组成。通过对内膜的作用而引起革兰氏阴性细菌裂解的抗菌剂必须穿过周质到达其靶膜。目前,关于它们穿过周质的途径及其所经历的相互作用的了解还很少。为此,这里使用原子分子动力学模拟来研究抗生素多粘菌素B1通过许多周质模型的途径,这些模型在不同程度上拥挤有蛋白质和渗透液。模拟显示,PMB1与溶液中游离的蛋白质和渗透液以及锚定在外膜上并结合在细胞壁上的脂蛋白形成瞬时和长期相互作用。我们显示,PMB1可能能够通过结合脂蛋白载体而在周质内搭便车。总的来说,我们的结果表明PMB1在周质中很少被复合。解释其治疗作用机理的重要考虑因素。该观察结果很可能可以扩展到其他依靠扩散穿过周质的抗生素。
更新日期:2020-06-03
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