M. tuberculosis is the world's leading cause of death from a single infectious agent and the leading cause of death in AIDS patients. The emergence of multidrug resistant tuberculosis poses a major threat to the public health, giving new urgency to research aimed at combating this ancient scourge. Moreover, multidrug resistant strains of M. tuberculosis (MDRTB) are a potential weapon of bioterrorism, and such strains have been classified as NIAID/CDC Category C Bioterrorism Agents. Studies proposed in this grant application build upon advances made in collaborative efforts between the Horwitz laboratory at UCLA and the Griffith laboratory at the U. of Wisconsin over the past two years to develop novel antimicrobials against M. tuberculosis for treatment of drug resistant organisms. During the past several years, the Horwitz and Griffith laboratories have laid the groundwork for the development of a new antimicrobial strategy against M. tuberculosis - targeting M. tuberculosis glutamine synthetase (GS). Thus, Horwitz et al. demonstrated that M. tuberculosis GS is a promising antimicrobial target, and that the high production of this enzyme is correlated with pathogenicity in mycobacteria and with the presence of a poly-L-glutamate/glutamine structure in the cell wall of pathogenic mycobacteria. Horwitz et al. showed further that inhibition of GS with L-methionine-SR-sulfoximine (MSO) inhibits M. tuberculosis growth in cell-free culture, in human macrophages, and in vivo in guinea pigs challenged by aerosol with M. tuberculosis. In combination with ascorbate, MSO is almost as potent as isoniazid, the leading antituberculous drug. Importantly, working in a collaboration during the past year, the Horwitz and Griffith laboratories have identified analogs of MSO that are highly potent against M. tuberculosis in vitro but lack certain drawbacks of MSO. This application has two major goals: 1) Develop novel MSO analogs that are better drug candidates than MSO because they are a) more selective for glutamine synthetase (GS) vs gamma-glutamylcysteine synthetase (gamma -GCS); and/or b) less well taken up into the brain where MSO exerts its major toxicity in sensitive species; and/or c) even more selective for M. tuberculosis GS vs. mammalian GS, and test the toxicity of the analogs in mice. 2) Test the novel MSO analogs for their capacity to inhibit M. tuberculosis growth in broth culture, in human macrophages, and in guinea pigs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Laughon, Barbara E
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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