Toxicity of nitrogen oxides and related oxidants on mycobacteria: M. tuberculosis is resistant to peroxynitrite anion

Abstract

Objective: To test the toxicity of reactive nitrogen intermediates (RNI), including authentic nitric oxide (NO), nitrogen dioxide (NO2), and peroxynitrite anion (ONOO−), a potent oxidant derived from NO and superoxide anion, on various mycobacterial strains including M. tuberculosis.Design: Relatively avirulent mycobacteria including M. smegmatis and BCG, as well as the pathogenic M. Bovis Ravenel andM. tuberculosis Erdman and the clinical isolate M160 (also known as the C strain) were tested for their susceptibility to the toxic effects of NO, NO2, and ONOO−. Deaerated, NO–saturated solutions as well as an anaerobic in vitro system in which mycobacteria can be exposed to desired concentrations of authentic NO or NO2, were employed in these studies. An in vitro ONOO−killing assay was used to examine the adverse effects of this NO–derived oxidant on the various strains of mycobacteria.Results: Both NO and NO2exhibit antimycobacterial activity, with the former being more potent. Results obtained using ONOO−killing assay revealed that while avirulent mycobacteria including BCG and M. smegmatis are susceptible to this NO–derived oxidant, the virulent Erdman strain of M. tuberculosis and M. bovis, as well as the clinical tuberculous isolate M160, are remarkably resistant.Conclusion: These results suggest that the interactions between RNI and various species of mycobactiera could be highly specific. And since activated macrophages produce peroxynitrite, the significance of the ONOO−resistance of M. tuberculosis strains in relation to intracellular survival deserves further investigation.