Broad Institute Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis: Probe for both Non-Replicating & Replicating organisms Inhibitor Probe Project
Over one third of the world's population is infected with tuberculosis. In 1993, the World Health Organization declared a global health emergency with the resurgence of tuberculosis in the setting of HIV infection and with the emergence of multi-drug resistant TB. In 2004, 14.6 million people had active TB, 8.9 million new cases were documented, and 1.7 million deaths were attributed to TB. more ..
Over one third of the world's population is infected with tuberculosis. In 1993, the World Health Organization declared a global health emergency with the resurgence of tuberculosis in the setting of HIV infection and with the emergence of multi-drug resistant TB. In 2004, 14.6 million people had active TB, 8.9 million new cases were documented, and 1.7 million deaths were attributed to TB. Future projections are even more alarming, due to the catastrophic synergy between TB and HIV. In this setting however, we have been forced to rely on suboptimal drugs that were developed in the 1950-60's, with TB drug development vanishing after the 1970's. At present, chemotherapy for TB requires at least six months of a complex multi-drug regimen. Treatment length greatly hinders effective TB control due to the challenges of compliance, which contribute to the development of multi-drug resistance. Despite the alarming implications for public health, research funding has lagged far behind the problem, and the pharmaceutical industry has all but ignored TB. New agents that achieve more rapid cures would transform the current pandemic; however, major barriers exist to developing such novel therapeutics including the lack of understanding of the in vivo physiologic states of TB bacilli as they adapt to the host microenvironment in order to survive for extended periods of time.
While anti-tuberculosis drugs can kill the culprit Mycobacterium tuberculosis (TB) bacilli in in vitro, axenic culture in a few days, treatment of an infected human host takes on the order of 6 months. Treating clinically latent forms of TB requires even longer periods of time, ~ 9 months. The difference between the in vitro and in vivo requirement is thought to be due to TB bacilli existing in a different physiologic state in vivo that is potentially "drug tolerant" due to the assumption of a metabolically dormant, non-replicating state. Understanding what functions are essential in these dormant bacilli and the mechanisms by which they switch between non-replicating and replicating states would be invaluable to the development of more effective, potentially shorter course TB therapy. Because of the current limitations in TB genetics resulting in the inadequate ability to study essential gene functions, the identification and use of small molecule probes that modulate survival of non-replicating and replicating TB bacilli, with good selectivity for TB over host cell types will help the elucidation of TB biology and the development of new therapeutics against TB.
1. IC90 in Luc starvation assay < 10 uM
2. Active against replicating TB at IC90 < 10 uM
Biological Mode of Action: Cellular
Cellular Toxicity: Non-toxic to mammalian cells at 3X effective IC50 or at 30 uM
Functional Groups to be avoided:
1. Chemically reactive groups
2. Metabolically labile groups
3. pH sensitive or hydrolytically unstable
Chemical Solubility Criteria: Soluble in aqueous solution
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