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Journal of Bacteriology, April 2008, p. 2981-2986, Vol. 190, No. 8
0021-9193/08/$08.00+0     doi:10.1128/JB.01857-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Nitrate Enhances the Survival of Mycobacterium tuberculosis during Inhibition of Respiration

Department of Veterans Affairs Medical Center, Long Beach, California 90822,¹ Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92717²

Received 26 November 2007/ Accepted 8 February 2008

When oxygen is slowly depleted from growing cultures of Mycobacterium tuberculosis, they enter a state of nonreplicating persistence that resembles the dormant state seen with latent tuberculosis. In this hypoxic state, nitrate reductase activity is strongly induced. Nitrate in the medium had no effect on long-term persistence during gradual oxygen depletion (Wayne model) for up to 46 days, but significantly enhanced survival during sudden anaerobiosis. This enhancement required a functional nitrate reductase. Thioridazine is a member of the class of phenothiazines that act, in part, by inhibiting respiration. Thioridazine was toxic to both actively growing and nonreplicating cultures of M. tuberculosis. At a sublethal concentration of thioridazine, nitrate in the medium improved the growth. At lethal concentrations of thioridazine, nitrate increased survival during aerobic incubation as well as in microaerobic cultures that had just entered nonreplicating persistence (NRP-1). In contrast, the survival of anaerobic persistent (NRP-2) cultures exposed to thioridazine was not increased by the addition of nitrate. Nitrate reduction is proposed to play a role during the sudden interruption of aerobic respiration due to causes such as hypoxia, thioridazine, or nitric oxide.

Published ahead of print on 22 February 2008.