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Elucidation of the physiology of non-replicating, drug tolerant Mycobacterium tuberculosis with the aid of the small molecule probe ML338.


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2012 Dec 17 [updated 2013 Sep 16].


The problem of tuberculosis continues to take a tremendous toll on global health, accounting for almost 2 million deaths per year, despite the discovery of antitubercular chemotherapy more than half a century ago. In fact, the crisis is growing due to the alarming increase in multi-drug resistant, and even totally-drug resistant strains, coupled with the extremely little progress made in discovering new TB drugs. One of the major barriers to discovering new, potentially more effective agents has been the lack of a fundamental understanding of the physiology of the M. tuberculosis bacilli as they exist within the infected human host. This physiology contributes to their ability to survive for decades within an infected individual despite host immunity, and to persist even in the face of what should otherwise be effective chemotherapy thus dictating the extremely long treatment courses that are required for cure. Toward the goal of developing chemical tools to help understand the M. tuberculosis bacterial state during infection and to identify essential functions that represent vulnerabilities in this state that could be targeted by chemotherapy, this report describes the discovery and development of the probe ML338. ML338 is the first small molecule which selectively targets dormant non-replicating M. tuberculosis bacilli in which a completely drug tolerant state has been adopted in the presence of nutrient deprivation. This feature distinguishes it from all current TB drugs and other molecules that have been previously described to target the M. tuberculosis bacillus. As studies have suggested the relevance of the bacterial physiologic state adopted under nutrient deprivation during TB infection, ML338 represents an invaluable tool both for identifying essential functions and vulnerabilities of the M. tuberculosis bacilli in this state and for studying the relevance of this state in vivo during infection. Thus, studies with ML338 will have the potential to provide insight into new targets but also new models for identifying more effective TB chemotherapy.

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