More than 60% of all drug targets are membrane proteins. However, only one of the current antituberculous drugs, ethambutol, targets membrane proteins of M. tuberculosis indicating that this vast potential is largely untapped for M. tuberculosis. The recent discovery of a new diarylquinoline drug that targets the ATP synthase of M. tuberculosis and exceeds the activities of the two main TB drugs isoniazid and rifampin provides proof of principle that this assumption is correct. Therefore, we have selected 11 out of approximately 800 putative inner membrane proteins of M. tuberculosis, which are essential for growth of M. tuberculosis in vitro or in mice. These proteins were selected to cover a broad variety of functions, such as transport of essential nutrients, cell division, export of proteins and cell wall and lipid biosynthesis. Furthermore, they are sufficiently small to be amenable to current solid-state NMR methods. Outer membrane proteins offer the tremendous advantage as drug targets that inhibitors may not need to cross the outer membrane which is an extremely efficient permeability barrier in mycobacteria. In addition, they are likely to represent novel drug targets because they do not appear to show any similarity to other proteins. Therefore, we included seven putative outer membrane proteins in our list of initial targets, six of which have no known function. The goal of this project is to validate the potential of the 18 selected membrane proteins as drug targets, to elucidate the physiological function of the 6 proteins with no known homologs and to identify putative interaction partners for some of these proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI074805-05
Application #
8519277
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$400,533
Indirect Cost
$68,075
Name
Florida State University
Department
Type
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
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Das, Bibhuti B; Zhang, Hua; Opella, Stanley J (2014) Dipolar Assisted Assignment Protocol (DAAP) for MAS solid-state NMR of rotationally aligned membrane proteins in phospholipid bilayers. J Magn Reson 242:224-32

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