In the United States, the incidence of TB has been falling over the past half-century, but remains high in HIV-infected persons, the elderly, homeless and under-served populations, and immigrants from endemic areas. Moreover, the emergence of multidrug-resistant strains complicates TB control efforts and posts a health threat to the general public, especially immunocompromised individuals. In HIV patients, an infection strain that has developed resistance to available drugs results in a 50% death rate within 60 days.1

UCLA researchers have identified agents that are useful for treating or preventing TB by inhibiting the growth of pathogenic mycobacteria including M. tuberculosis, M. bovis, and M. avium. These compounds are inhibitors of glutamine synthetase, an exported enzyme involved in bacterial cell wall synthesis. In addition, the agents have much higher therapeutic to toxicity ratios than methionine sulfoximine (MSO), a compound demonstrated in their previous publications to successfully inhibit the multiplication of pathogenic mycobacteria in broth culture, in macrophages, the host cells of M. tuberculosis, and in vivo in the demanding guinea pig model of pulmonary tuberculosis. Recently, UCLA researchers have shown that the MSO analog alpha-ethyl-MSO also inhibits M. tuberculosis in vivo in the guinea pig model of pulmonary TB. It does so at doses that are very well-tolerated and at least 30-fold greater than the maximum tolerated dose (MTD) of MSO. In contrast to MSO, alpha-ethyl-MSO does not enter the brain, where the major toxicity of MSO is manifest, and alpha-ethyl-MSO does not interfere with glutathione production. Moreover, alpha-ethyl-MSO acts synergistically with INH against M. tuberculosis in vivo in the guinea pig model.

The proposed therapeutic compounds would be administered to patients with active mycobacterial infection (including M. tuberculosis, M. bovis, and M. avium) or people harboring M. tuberculosis in a latent state as evidenced by a positive diagnostic test. They can be administered via multiple routes, such as intravenous, intramuscular, intraperitoneal, subcutaneous, and oral routes.

Reference: UCLA Case No. 2002-185

Related US Patent Number: 6,013,660

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