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.

细菌是单细胞生物体，也是感染因子，可引起多种疾病。自20世纪50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退了。然而，近年来细菌对这些药物的耐药性越来越强。事实上，我们正在快速接近一个后抗生素世界：估计全世界每年有120万人死于耐药性细菌感染，预测表明，到2050年，这一数字将增加到约1000万/年。因此，我们迫切需要确定新的方法来对抗细菌感染。细菌的一个以前被低估的方面是，它们拥有一个非常严格的内部组织，以确保其各种成分和细胞器的正确定位，特别是在细胞分裂期间。特别地，蛋白质家族（permed帕拉/FlhG/MinD）在细菌中普遍存在，并且已经显示调节分子和细胞器在细胞极的定位。然而，该家族的作用机制目前尚不清楚在分子水平上，在这里，我们建议使用一系列的生物物理技术，以确定该家族的蛋白质的一般作用机制。具体来说，我们认为这些蛋白质形成细丝的倾向，驱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，以及如何使它们在细胞极招募各自的货物。这一提议将为我们对细菌细胞生物学的理解带来根本性的转变，并可能导致新型抗菌治疗方法的发展。