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

革兰氏阴性菌通常比革兰氏阳性菌对抗生素、清洁剂和其他有毒化学物质的耐药性更强，因为革兰氏阴性菌外膜的脂质复杂不对称。在应激条件下，这种不对称性会被破坏，导致脂多糖脱落和磷脂向外小叶迁移，这些磷脂双分子层斑块导致屏障功能降低，对细胞有害。最近发现了一种6蛋白途径，即Mla途径，可以积极地阻止磷脂在细胞表面的积累。敲除该途径的任何组分都会导致OM屏障缺陷和对抗生素药物的敏感性增加，此外还会消除肠侵入性大肠杆菌和弗氏沙门氏菌的毒力，使Mla途径的所有组分成为重要的毒力因子。此外，最近来自Knowles实验室的证据表明，这一途径也可能将脂质运输到外膜，因此将是脂质运输到外膜机制的第一个证据。目前对这一途径知之甚少，通过使用核磁共振、x射线晶体学和中子反射法等技术探测其结构和功能，我们将对脂质转运的基本过程获得有价值的见解，并有可能导致可药物袋和新化合物的鉴定，这些化合物不仅可以消除毒性，还可以阻碍受损OM的恢复，从而提高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.