title: Nitrate enhances the survival of Mycobacterium tuberculosis during inhibition of respiration.
abstract: 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.
authors.affiliation: Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA. chuck@sohaskey.com
authors.forename: Charles D
authors.initials: CD
authors.lastname: Sohaskey
mesh_terms: D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*; D050901:Nitrate Reductase / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D013234:Stem Cells; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D009566:Nitrates; D009573:Nitrites; D000431:Ethanol; D050901:Nitrate Reductase; D013881:Thioridazine; D010100:Oxygen