Molecular Basis for Substrate Recognition of Outer Membrane Proteins of the Human Pathogen Pseudomonas Aeruginosa

细菌膜是出了名的不透气--这是它们很难用现有的抗生素击败的原因之一。这导致了所谓的“超级细菌”的广泛发展，即对多种不同抗生素产生抗药性的细菌。这种现象给现代医疗带来了一个严重的问题。铜绿假单胞菌是一种人、动物和植物的病原体，对多种不同的抗生素具有耐药性。在人类中，它往往针对那些免疫系统已经受损的人，并对很大一部分医院获得性感染负责。在我们开始合理的药物设计来对抗铜绿假单胞菌之前，我们必须了解细菌细胞的渗透途径。考虑到自然界已经受益于多年的进化，通过首先试图了解细菌生存所需的分子如何进入它来利用这一点是有意义的。在这个项目中，我们将使用一系列的计算方法，并由我们的合作者进行电生理学实验，以阐明二肽通过OprD蛋白进入细胞的分子路径。该蛋白是位于铜绿假单胞菌外膜的底物特异性通道蛋白家族中最大的成员之一。最近报道的研究表明，联合使用抗生素(联合疗法)可能比只使用一种类型的抗生素更有效。然而，联合治疗在分子水平上的后果目前还完全未知。因此，除了在“正常”条件下研究OprD外，我们还将探索当其局部环境被抗生素多粘菌素B1改变时蛋白质的行为。

Bacterial membranes are notoriously impermeable - this is one of the reasons they are so difficult to beat with currently available antibiotics. This is leading to the widespread development of so-called 'superbugs'; bacteria that are resistant to many different antibiotics. This phenomenon provides modern healthcare with a serious problem. Pseudomonas aeruginosa is a human, animal and plant pathogen that is resistant to many different antibiotics. In humans, it tends to target those with already compromised immune systems, and is responsible for a large proportion of hospital acquired infections. Before we can embark on rational drug design to combat Pseudomonas aeruginosa, we must understand the routes via which the bacterial cell can be penetrated. Given that nature has had the benefit of years of evolution, it makes sense to exploit this by first trying to understand how molecules necessary for the survival of the bacterium, enter it. In this project we will use a range of computational methods supported by electrophysiology experiments by our collaborators, to elucidate the molecular pathways taken by dipeptides to enter the cell through the OprD protein. This protein is one member of the largest family of substrate-specific channel proteins located within the outer membrane of Pseudomonas aeruginosa. Recently reported studies reveal that using a combination of antibiotics (combination therapy) can be more effective than administering just one type. However the molecular-level consequences of combination therapy are currently completely unknown. Thus, in addition to studying OprD under 'normal' conditions, we will also explore how the protein behaves when its local environment is altered by polymyxin B1- an antibiotic.