Cell
Volume 145, Issue 1, 1 April 2011, Pages 39-53
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Article
Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism

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Summary

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.

Highlights

► In zebrafish, replicating intracellular Mycobacterium marinum become drug tolerant ► A tolerant bacterial population also develops in M. tuberculosis-infected macrophages ► Bacterial efflux pumps mediate intracellular growth and tolerance within macrophages ► Tolerance is subject to pharmacological inhibition by available efflux pump blockers

Cited by (0)

5

These authors contributed equally to this work

6

These authors contributed equally to this work

7

Present address: Department of Medicine, Division of Infectious Diseases and Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94143, USA

8

Present address: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA