How do bacteria localize macromolecular complexes at their cell pole?

细菌是单细胞生物体，也是传染病的病原体，可引起多种疾病。自20世纪50年代S以来，由于抗生素的发展，细菌感染的威胁已基本消退。然而，近年来细菌对这些药物表现出越来越多的抗药性。事实上，我们正在迅速接近抗生素后世界：据估计，全球每年有120万人死于抗生素耐药细菌感染，预测表明，到2050年，这一数字将增加到每年约1000万人。因此，我们迫切需要确定抗击细菌感染的新方法。细菌以前被低估的一个方面是，它们拥有一个非常严格监管的内部组织，以确保其各种成分和细胞器的适当定位，特别是在细胞分裂期间。特别是，细菌中普遍存在一个蛋白质家族(命名为PARA/FlhG/Mind)，并已被证明调节分子和细胞器在细胞极点的位置。然而，目前在分子水平上还不清楚该家族的作用机制。在这里，我们建议使用一系列生物物理技术来确定该蛋白家族的一般作用机制。具体地说，我们认为这些蛋白质形成细丝的倾向，推动它们的货物穿过细胞，是它们功能的核心。我们将特别利用冷冻电子显微镜和人工智能驱动的建模方面的最新进展，以了解这些蛋白质如何在原子水平上组装，以及它如何使它们能够在细胞极点招募各自的货物。这一建议将从根本上改变我们对细菌细胞生物学的理解，并可能导致新型抗菌疗法的发展。

Bacteria are unicellular organisms, as well as infectious agents, causative of multiple diseases. Since the 1950's, the threat of bacterial infections had largely subsided, due to the development of antibiotics. However, bacteria have showed an increasing amount of resistance to these in recent years. Indeed, we are fast-approaching a post-antibiotic world: an estimated 1.2 M people die annually from antibiotic-resistant bacterial infections world-wide, and projections indicate that this number will increase to ~ 10 M/year by 2050. We therefore urgently need to identify new approaches to combat bacterial infections. A previously-underappreciated aspect of bacteria is that they possess a very tightly-regulated internal organization, to ensure the proper localization of its various components and organelles, notably during cell division. In particular, a family of proteins (permed ParA/FlhG/MinD) is ubiquitous in bacteria, and has been shown to regulate the positioning of molecules and organelles at the pole of the cell. However, the mechanism of action of this family is currently not understood at the molecular level.Here, we propose to use a range of biophysical techniques to determine the general mechanism of action of this family of proteins. Specifically, we propose that the propensity of these proteins to form filaments, driving their cargo across the cell, is central to their function. We will notably exploit recent advances in cryo-electron microscopy, and in Artificial Intelligence-driven modelling, to understand how these proteins assemble at the atomic level, and how it allows them to recruit their respective cargo at the cell pole. This proposal will provide a fundamental shift in our understanding of bacterial cell biology, and could lead to the development of novel antibacterial therapeutics.