Tuberculosis is a worldwide health problem. Transmission is very efficient, and social conditions in many countries do not make it easy to control the disease. While vaccination is routine in most of the world, the great majority of the population only develops partial protection or no protection at all. Thus, tuberculosis, as the majority of infectious diseases, is treated with antibiotics. The regimen currently in use was introduced more than 40-50 years ago, and Mycobacterium tuberculosis resistance to the compounds in the treatment has been increasing for many years and, in certain regions of the world, is now a severe problem. The bacterium takes several days to die following incubation with a bactericidal compound, which is a norm for M. tuberculosis exposed to bactericidal drugs. The observation has guided the work in the direction of understanding and identifying """"""""escape"""""""" pathways used by the pathogen to survive longer, even in presence of a bactericidal compound. Our proposal is to develop new targets (escape pathways targets) that, combined with existing targets (and future novel targets), will have the ability to kill the bacterium faster, and prevent the emergence of resistance, ultimately decreasing the time of therapy. We already have obtained preliminary evidence for this hypothesis. We propose: 1. to study the bacterial response to anti-tuberculosis compounds (new and old ones) as measured by the proteomic response;2. To identify and inactivate bacterial targets involved in the escape mechanism. For a couple selected compounds and targets, we plan to address preliminarily the viability of the approach in the macrophage model system. The proposal not only addresses the discovery of novel targets, but the rational discovery of targets for which currently active compounds will act in the synergistic manner, accelerating bacterial killing, decreasing the time of therapy, decreasing the chances for side effects and the development of specific resistance mechanisms.

Public Health Relevance

Tuberculosis is a major public health concern worldwide. Therapy for the disease is not optimal because of the long duration and the need to use several antibiotics. While working to discover the target of mefloquine in M. tuberculosis, it became clear the bacterium synthesizes many proteins at the same time the antibiotic is expected to be acting against the bacterium. We then hypothesize that if one inactivates the proteins, the bacterium will probably die sooner than the wildtype bacterium.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-S (02))
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Lacourciere, Karen A
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Oregon State University
Schools of Veterinary Medicine
United States
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Danelishvili, Lia; Shulzhenko, Natalia; Chinison, Jessica J J et al. (2017) Mycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic ""Escape"" Pathways That Prolong Bacterial Survival. Antimicrob Agents Chemother 61: