Structure and mechanism of the Mla lipid transport system in the multidrug-resistant bacterium A. baumannii

多重耐药鲍曼不动杆菌Mla脂质转运系统的结构与机制

基本信息

批准号：
BB/R019061/2
负责人：
Julien Bergeron
金额：
$ 33万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR019061%2F2
关键词：
Structure mechanism Mla lipid transport

项目摘要

In recent years, we have observed a dramatic increase in "superbugs", bacteria that are resistant to all known antibiotics. This is a particularly important worry in hospital settings, where superbugs cause untreatable infections in patients undergoing routine medical procedures. More than 20,000 people die from superbug infections every year.In many bacteria, this drug resistance is caused by a thick lipid later (the outer membrane) on their surface. This membrane acts as a physical barrier, preventing many drugs from entering the bacterial cell. The lipid composition of this outer membrane is very specifically regulated, as it is critical for its physical integrity. However, the mechanisms used by bacteria to transport lipids to and from the outer membrane are still poorly understood.Recently, a set of proteins termed the Mla system (for Maintenance of Lipid Asymmetry) was shown to be essential to maintain an intact outer membrane. The aim of this project is to characterize the molecular basis for lipid transport by this system. Specifically, we will study the Mla system from the bacterium Acinetobacter baumannii, a known multi-drug resistant bacterium responsible for up to 20% of antibiotic-resistant infections world-wide.We will study how the different Mla proteins interact with each other, and how they recruit and transport lipids. In particular, we will exploit the latest advances in high-resolution electron microscopy to characterize these proteins at the atomic level.This will allow us to understand how the proteins from the Mla system recognize lipids and transport them to and/or from the outer membrane. Ultimately, this could be exploited for the development of therapeutics that prevent antibiotics resistance.

近年来，我们观察到“超级细菌”的急剧增加，这些细菌对所有已知的抗生素具有抗性。这是医院环境中特别重要的担心，在该医院环境中，超级细菌会引起接受常规医疗程序的患者不可治疗的感染。每年有超过20,000人死于超级细菌感染。在许多细菌中，这种耐药性是由于其表面上的较厚的脂质（外膜）引起的。该膜充当物理障碍，防止许多药物进入细菌细胞。该外膜的脂质组成非常具体调节，因为它对于其物理完整性至关重要。然而，细菌用于将脂质传输到外膜的机制仍然很少了解。实际上，一组称为MLA系统的蛋白质（用于维持脂质不对称性）对于维持完整的外膜至关重要。该项目的目的是表征该系统脂质转运的分子基础。具体而言，我们将从细菌鲍曼尼（Baumannii）中研究MLA系统，Baumannii是一种已知的多药抗性细菌，负责全球多达20％的抗生素耐药性感染。我们将研究不同的MLA蛋白如何相互相互作用，以及如何募集和运输Lipids。特别是，我们将利用高分辨率电子显微镜的最新进展来表征原子水平的这些蛋白质。这将使我们能够了解MLA系统中的蛋白质如何识别脂质并将其传输到和/或从外膜传输。最终，这可以利用用于预防抗生素耐药性的治疗剂的发展。