Journal
CELL
Volume 145, Issue 1, Pages 39-53Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.02.022
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Funding
- Gates Foundation
- University of Washington
- Burroughs Wellcome Foundation
- NIH [RO1 AI036396, RO1 AI54503, U54AI057141, T32 AI55396, K08 AI076620, 5R21 AI073328-02, 5R21 AI078189-02]
- Levinson Emerging Scholars Program
- Mary Gates Endowment Grant
- Washington NASA
- Pfizer
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Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug or more specific efflux pump inhibitors to standard antitubercular therapy should shorten the duration of curative treatment.
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