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

革兰氏阴性细菌通常比革兰氏阳性细菌对抗生素、洗涤剂和其他有毒化学品更具抵抗力，因为它们的外膜中脂质的复杂不对称。在应激条件下，这种不对称性可能被破坏，导致内毒素脱落和磷脂迁移到外叶，这些磷脂双层贴片导致屏障功能降低，对细胞有害。最近发现了一种6蛋白途径，即MLA途径，它能有效地阻止磷脂在细胞表面的聚集。敲除该途径的任何组成部分都会导致OM屏障缺陷，增加对抗生素的敏感性，此外还会消除肠道侵袭性大肠杆菌和福氏志贺氏菌的毒力，使MLA途径的所有组成部分成为重要的毒力因子。此外，诺尔斯实验室最近的证据表明，这一途径也可能能够将脂类运输到外膜，因此将是脂类如何运输到外膜的机制的第一个证据。目前对这一途径知之甚少，通过利用核磁共振、X射线结晶学和中子反射术等技术探索其结构和功能，我们将对脂类运输的基本过程获得有价值的见解，并可能导致识别可用药袋和新化合物，这些化合物不仅可以消除毒力，还可以阻碍受损OM的修复，从而增加现有抗生素的有效性。

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.