A recent discovery at UCLA may finally provide a method for long-term containment of tuberculosis. An extracellular protein, glutamine synthetase (GS), is secreted by Mycobacterium tuberculosis and has been cloned and sequenced. The protein plays a significant enzymatic role necessary for the multiplication of the bacterium. Specifically, it is involved in the synthesis of a poly-L-glutatmate-glutamine cell wall component found exclusively in pathogenic mycobacteria.

Using a synthetic compound, L-methionine-S-sulfoximine (MSO), our scientists have been able to block the enzymatic activity of the protein and inhibit bacterial multiplication. Treatment of M. tuberculosis with MSO selectively blocks the growth in broth cultures of pathogenic mycobacteria, including M. tuberculosis, M. bovis, and M. avium, but has no effect on nonpathogenic mycobacteria or nonmycobacterial microorganisms. The inhibitor also blocks the growth of M. tuberculosis and M. avium within human mononuclear phagocytes, the primary host cells of these pathogens, and at concentrations that are completely nontoxic to the mammalian cells, likely reflecting the 100-fold greater sensitivity to MSO of bacterial GS than of mammalian GS. Most importantly, in the guinea pig model of tuberculosis, MSO has been demonstrated to protect animals from tuberculosis and to act synergistically with isoniazid (INH). At the highest dose of MSO tested, the agent by itself was almost as efficacious as INH by itself.

Analogs to MSO with a higher therapeutic ratio are under investigations including analogs that do not enter the brain and lack the mammalian toxicity of MSO. Such analogs have thus far been demonstrated to be as efficacious as MSO in inhibiting M. tuberculosis growth in broth culture and in human macrophages. For a non-confidential description of the technology, please refer to http://www.research.ucla.edu/tech/ucla02-185.htm.

Related Papers (Selected) J Exp Med 1999 May 3;189(9):1425-36. An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes: extracellular proteins as potential novel drug targets. more... Infect Immun. 2003 Jan;71(1):456-64. Inhibition of Mycobacterium tuberculosis Glutamine Synthetase as a Novel Antibiotic Strategy against Tuberculosis: Demonstration of Efficacy In Vivo.more...

Reference: UCLA Case No. 1996-604

US Patent Number: 6,013,660