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
Wright, Anna K; Batsomboon, Paratchata; Dai, Jian et al. (2016) Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel. J Am Chem Soc 138:1506-9
Martinot, Amanda J; Farrow, Mary; Bai, Lu et al. (2016) Mycobacterial Metabolic Syndrome: LprG and Rv1410 Regulate Triacylglyceride Levels, Growth Rate and Virulence in Mycobacterium tuberculosis. PLoS Pathog 12:e1005351
Sun, Jim; Siroy, Axel; Lokareddy, Ravi K et al. (2015) The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD. Nat Struct Mol Biol 22:672-8
Neyrolles, Olivier; Wolschendorf, Frank; Mitra, Avishek et al. (2015) Mycobacteria, metals, and the macrophage. Immunol Rev 264:249-63
Opella, Stanley J (2015) Solid-state NMR and membrane proteins. J Magn Reson 253:129-37
Danilchanka, Olga; Pires, David; Anes, Elsa et al. (2015) The Mycobacterium tuberculosis outer membrane channel protein CpnT confers susceptibility to toxic molecules. Antimicrob Agents Chemother 59:2328-36
Opella, Stanley J (2015) Relating structure and function of viral membrane-spanning miniproteins. Curr Opin Virol 12:121-5
Das, Nabanita; Dai, Jian; Hung, Ivan et al. (2015) Structure of CrgA, a cell division structural and regulatory protein from Mycobacterium tuberculosis, in lipid bilayers. Proc Natl Acad Sci U S A 112:E119-26
Gong, Xiao-Min; Ding, Yi; Yu, Jinghua et al. (2015) Structure of the Na,K-ATPase regulatory protein FXYD2b in micelles: implications for membrane-water interfacial arginines. Biochim Biophys Acta 1848:299-306
Landeta, Cristina; Blazyk, Jessica L; Hatahet, Feras et al. (2015) Compounds targeting disulfide bond forming enzyme DsbB of Gram-negative bacteria. Nat Chem Biol 11:292-8

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