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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081059-05
Application #
8385538
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Korpela, Jukka K
Project Start
2008-12-15
Project End
2014-01-31
Budget Start
2012-12-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$435,865
Indirect Cost
$168,589
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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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

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