Antibiotic resistant Gram-negative infections pose a serious threat to human health. The outer membrane of Gram-negative bacteria is a unique structure essential for survival; it also functions as a physical barrier to block entry of many classes of antibiotics and thereby render them ineffective. This research is directed towards understanding the structure and function of two multi-protein machines responsible for the biogenesis of two major components of the outer membrane, lipopolysaccharide (LPS) and outer membrane proteins (OMPs). To understand the protein-protein interactions within each machine and their molecular structures, biochemical and structural studies will be undertaken. To dissect the functions of the individual components of these machines, intermediates in transport and assembly of LPS and OMPs will be characterized structurally, biochemically, and in cells. A better understanding of the protein machinery and the processes in which they are involved may lead to the discovery of inhibitors that could ultimately be developed to treat Gram-negative infections.
The research proposed here is directed towards understanding the protein machinery responsible for the biogenesis of the outer membrane of Gram-negative bacteria, a structure that is essential for their survival. A better understanding of the protein components of this machinery and the processes in which they are involved may lead to the discovery of inhibitors that could ultimately be developed for therapeutic uses to treat Gram- negative infections.
|Bertani, Blake R; Taylor, Rebecca J; Nagy, Emma et al. (2018) A cluster of residues in the lipopolysaccharide exporter that selects substrate variants for transport to the outer membrane. Mol Microbiol 109:541-554|
|Mandler, Michael D; Baidin, Vadim; Lee, James et al. (2018) Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport. J Am Chem Soc 140:6749-6753|
|Sherman, David J; Xie, Ran; Taylor, Rebecca J et al. (2018) Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge. Science 359:798-801|
|Zhang, Ge; Baidin, Vadim; Pahil, Karanbir S et al. (2018) Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors. Proc Natl Acad Sci U S A 115:6834-6839|
|Lee, James; Sutterlin, Holly A; Wzorek, Joseph S et al. (2018) Substrate binding to BamD triggers a conformational change in BamA to control membrane insertion. Proc Natl Acad Sci U S A 115:2359-2364|
|Xie, Ran; Taylor, Rebecca J; Kahne, Daniel (2018) Outer Membrane Translocon Communicates with Inner Membrane ATPase To Stop Lipopolysaccharide Transport. J Am Chem Soc 140:12691-12694|
|May, Janine M; Owens, Tristan W; Mandler, Michael D et al. (2017) The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport. J Am Chem Soc 139:17221-17224|
|Moison, Eileen; Xie, Ran; Zhang, Ge et al. (2017) A Fluorescent Probe Distinguishes between Inhibition of Early and Late Steps of Lipopolysaccharide Biogenesis in Whole Cells. ACS Chem Biol 12:928-932|
|Wzorek, Joseph S; Lee, James; Tomasek, David et al. (2017) Membrane integration of an essential ?-barrel protein prerequires burial of an extracellular loop. Proc Natl Acad Sci U S A 114:2598-2603|
|Okuda, Suguru; Sherman, David J; Silhavy, Thomas J et al. (2016) Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat Rev Microbiol 14:337-45|
Showing the most recent 10 out of 38 publications