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

近年来，我们观察到“超级细菌”的数量急剧增加，这种细菌对所有已知的抗生素都有抗药性。这在医院环境中是一个特别重要的担忧，在医院里，超级细菌会在接受常规医疗程序的患者中造成无法治愈的感染。每年有2万多人死于超级细菌感染。在许多细菌中，这种耐药性是由其表面后来的一层厚厚的脂类(外膜)引起的。这种膜起到物理屏障的作用，阻止许多药物进入细菌细胞。这个外膜的脂质成分受到非常特殊的调节，因为它对它的物理完整性至关重要。然而，细菌用来运输脂质进出外膜的机制仍然不太清楚。最近，一组被称为MLA系统(用于维持脂质不对称性)的蛋白质被证明对于维持完整的外膜是必不可少的。本项目的目的是通过该系统表征脂质运输的分子基础。具体地说，我们将研究鲍曼不动杆菌的MLA系统。鲍曼不动杆菌是一种已知的多重耐药细菌，导致全球高达20%的抗生素耐药感染。我们将研究不同的MLA蛋白如何相互作用，以及它们如何招募和运输脂质。特别是，我们将利用高分辨率电子显微镜的最新进展来在原子水平上表征这些蛋白质。这将使我们能够了解MLA系统中的蛋白质如何识别脂类并将它们运输到外膜和/或从外膜运输。最终，这可能被用于开发防止抗生素耐药性的治疗方法。

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.