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

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.