Understanding the Biogenesis of Outer Membranes (The initial project to work on the BAM complex has been relegated to a side project in light of resea

了解外膜的生物发生（根据研究，BAM 复合体的最初项目已降级为一个副项目）

• 批准号: 1900521
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1900521
• 关键词: Understanding; Biogenesis; Outer; Membranes; initial

Gram-negative bacteria are generally more resistant than Gram-positive bacteria to antibiotics, detergents, and other toxic chemicals because of the sophisticated asymmetry of lipids in their outer membranes. Under stress conditions this asymmetry can be disrupted leading to shedding of LPS and phospholipid migration to the outer leaflet, these phospholipid bilayer patches lead to reduced barrier function and are detrimental to the cell. Recently a 6 protein pathway, the Mla pathway, has been identified that actively prevents phospholipid accumulation at the cell surface. Knocking out any component of this pathway leads to OM barrier defects and increased susceptibility to antibiotic agents in addition to also abolishing virulence in enteroinvasive E. coli and S. flexneri, making all components of the Mla pathway important virulence factors. Furthermore recent evidence from the Knowles lab suggests that this pathway may also be able to transport lipid to the outer membrane, and therefore would be the first evidence of a mechanism for how lipids are transported to the outer membrane. At present almost little is known about this pathway, by probing its structures and function using techniques such as NMR, X-ray crystallography and neutron reflectometry, we will gain valuable insight in to the fundamental process of lipid transport and potentially lead to the identification of druggable pockets and novel compounds that will not only abolish virulence but also impede restoration of a damaged OM and therefore increase the effectiveness of already available antibiotics.

由于外膜中脂质的复杂不对称性，革兰氏阴性细菌通常比革兰氏阳性细菌对抗生素、清洁剂和其他有毒化学物质具有更强的抵抗力。在应激条件下，这种不对称性可能会被破坏，导致 LPS 脱落和磷脂迁移到外叶，这些磷脂双层斑块会导致屏障功能降低，对细胞有害。最近，已鉴定出 6 种蛋白途径（Mla 途径）可主动防止细胞表面的磷脂积累。敲除该途径的任何成分都会导致 OM 屏障缺陷并增加对抗生素药物的敏感性，此外还会消除肠侵袭性大肠杆菌和弗氏链球菌的毒力，从而使 Mla 途径的所有成分都成为重要的毒力因子。此外，诺尔斯实验室的最新证据表明，该途径也可能能够将脂质转运至外膜，因此将是脂质如何转运至外膜机制的第一个证据。目前，人们对这条途径几乎知之甚少，通过使用核磁共振、X射线晶体学和中子反射测量等技术探测其结构和功能，我们将获得对脂质转运基本过程的宝贵见解，并有可能识别出可成药的口袋和新化合物，这些化合物不仅可以消除毒力，还可以阻碍受损OM的恢复，从而提高现有抗生素的有效性。