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

人类病原体铜绿假单胞菌外膜蛋白底物识别的分子基础

• 批准号: BB/M029573/1
• 负责人: Syma Khalid
• 金额: $ 33.43万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM029573%2F1
• 关键词: Molecular; Basis; Substrate; Recognition; Outer

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.

众所周知，细菌的膜是不可渗透的——这也是目前可用的抗生素很难击败它们的原因之一。这导致了所谓的“超级细菌”的广泛发展；对许多不同的抗生素都有抗药性的细菌。这种现象给现代医疗保健带来了一个严重的问题。铜绿假单胞菌是一种人类、动物和植物病原体，对许多不同的抗生素具有耐药性。在人类中，它倾向于针对那些免疫系统已经受损的人，并且是医院获得性感染的主要原因。在我们能够着手设计合理的药物来对抗铜绿假单胞菌之前，我们必须了解细菌细胞可以穿透的途径。考虑到自然界已经受益于多年的进化，利用这一点是有意义的，首先要努力了解细菌生存所必需的分子是如何进入的。在这个项目中，我们将使用一系列由我们的合作者的电生理学实验支持的计算方法，来阐明二肽通过OprD蛋白进入细胞的分子途径。该蛋白是位于铜绿假单胞菌外膜内的底物特异性通道蛋白最大家族的成员之一。最近报告的研究表明，使用联合抗生素（联合治疗）比只使用一种抗生素更有效。然而，联合治疗的分子水平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多粘菌素B1（一种抗生素）改变时该蛋白的行为。

项目成果

Correction to "Directional Porin Binding of Intrinsically Disordered Protein Sequences Promotes Colicin Epitope Display in the Bacterial Periplasm".

• DOI: 10.1021/acs.biochem.8b00864
• 发表时间: 2018-09-04
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Housden NG;Rassam P;Lee S;Samsudin F;Kaminska R;Sharp C;Goult JD;Francis ML;Khalid S;Bayley H;Kleanthous C
• 通讯作者: Kleanthous C

Directional Porin Binding of Intrinsically Disordered Protein Sequences Promotes Colicin Epitope Display in the Bacterial Periplasm.

固有无序蛋白序列的定向孔蛋白结合可促进细菌周期中的结肠表位。

• DOI: 10.1021/acs.biochem.8b00621
• 发表时间: 2018-07-24
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Housden NG;Rassam P;Lee S;Samsudin F;Kaminska R;Sharp C;Goult JD;Francis ML;Khalid S;Bayley H;Kleanthous C
• 通讯作者: Kleanthous C

Binding From both sides: TolR and full-length OmpA bind and maintain the local structure of the E. coli cell wall

• DOI: 10.1101/409466
• 发表时间: 2018-09
• 期刊: bioRxiv
• 作者: Alister Boags;Firdaus Samsudin;S. Khalid