How do bacteria localize macromolecular complexes at their cell pole?

细菌如何将大分子复合物定位在其细胞极？

• 批准号: BB/Y001095/1
• 负责人: Julien Bergeron
• 金额: $ 115.36万
• 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: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY001095%2F1
• 关键词: How; do; bacteria; localize; macromolecular

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.

细菌是单细胞生物以及感染剂，是多种疾病的原因。自1950年代以来，由于抗生素的发展，细菌感染的威胁在很大程度上消失了。但是，近年来，细菌对这些细菌的抗药性增加了。的确，我们正在快速接触抗生素的世界：估计每年在全球抗生素耐药细菌感染中死亡的1.2 m人死亡，预测表明，到2050年，这个数字将增加到〜10 m/年。因此，我们毫不犹豫地需要识别出新的方法来打击细菌感染。以前不受欢迎的细菌方面是它们具有非常严格调节的内部组织，以确保其各种成分和细胞器的适当定位，尤其是在细胞分裂期间。特别是，蛋白质（Permed Para/flhg/Mind）家族在细菌中无处不在，并且已证明可以调节分子和细胞器在细胞极点的位置。但是，目前在分子水平上尚不清楚该家族的作用机理。在这里，我们建议使用一系列生物物理技术来确定该蛋白质家族的一般作用机理。具体而言，我们建议这些蛋白质形成细丝的倾向，将其货物驱动在细胞上是其功能的核心。我们将明显利用冷冻电子显微镜以及人工智能驱动的建模的最新进展，以了解这些蛋白质如何在原子水平上组装，以及它如何允许它们在细胞极点招募各自的货物。该提案将为我们对细菌细胞生物学的理解提供根本的转变，并可能导致新型抗菌治疗剂的发展。