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 three 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, the assembly of LPS and OMPs will be reconstituted in vitro. 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.
|Maloj?i?, Goran; Andres, Dorothee; Grabowicz, Marcin et al. (2014) LptE binds to and alters the physical state of LPS to catalyze its assembly at the cell surface. Proc Natl Acad Sci U S A 111:9467-72|
|Sherman, David J; Lazarus, Michael B; Murphy, Lea et al. (2014) Decoupling catalytic activity from biological function of the ATPase that powers lipopolysaccharide transport. Proc Natl Acad Sci U S A 111:4982-7|
|Villa, Riccardo; Martorana, Alessandra M; Okuda, Suguru et al. (2013) The Escherichia coli Lpt transenvelope protein complex for lipopolysaccharide export is assembled via conserved structurally homologous domains. J Bacteriol 195:1100-8|
|Zhang, Ge; Meredith, Timothy C; Kahne, Daniel (2013) On the essentiality of lipopolysaccharide to Gram-negative bacteria. Curr Opin Microbiol 16:779-85|
|Sherman, David J; Okuda, Suguru; Denny, William A et al. (2013) Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli. Bioorg Med Chem 21:4846-51|
|Hagan, Christine L; Westwood, David B; Kahne, Daniel (2013) bam Lipoproteins Assemble BamA in vitro. Biochemistry 52:6108-13|
|Ricci, Dante P; Hagan, Christine L; Kahne, Daniel et al. (2012) Activation of the Escherichia coli ?-barrel assembly machine (Bam) is required for essential components to interact properly with substrate. Proc Natl Acad Sci U S A 109:3487-91|
|Freinkman, Elizaveta; Chng, Shu-Sin; Kahne, Daniel (2011) The complex that inserts lipopolysaccharide into the bacterial outer membrane forms a two-protein plug-and-barrel. Proc Natl Acad Sci U S A 108:2486-91|
|Hagan, Christine L; Kahne, Daniel (2011) The reconstituted Escherichia coli Bam complex catalyzes multiple rounds of ýý-barrel assembly. Biochemistry 50:7444-6|
|Chimalakonda, Gitanjali; Ruiz, Natividad; Chng, Shu-Sin et al. (2011) Lipoprotein LptE is required for the assembly of LptD by the beta-barrel assembly machine in the outer membrane of Escherichia coli. Proc Natl Acad Sci U S A 108:2492-7|
Showing the most recent 10 out of 16 publications