Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism

Cell. 2011 Apr 1;145(1):39-53. doi: 10.1016/j.cell.2011.02.022. Epub 2011 Mar 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism
  • Disease Models, Animal
  • Drug Tolerance*
  • Granuloma / physiopathology
  • Humans
  • Larva / microbiology
  • Macrophages / microbiology*
  • Membrane Transport Modulators / pharmacology
  • Membrane Transport Proteins / metabolism
  • Mycobacterium Infections, Nontuberculous / drug therapy
  • Mycobacterium Infections, Nontuberculous / pathology
  • Mycobacterium Infections, Nontuberculous / physiopathology
  • Mycobacterium marinum / drug effects
  • Mycobacterium marinum / physiology*
  • Mycobacterium tuberculosis / physiology*
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology*
  • Tuberculosis / pathology
  • Tuberculosis / physiopathology
  • Verapamil / pharmacology
  • Zebrafish / microbiology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Membrane Transport Modulators
  • Membrane Transport Proteins
  • Verapamil