Nitrite impacts the survival of Mycobacterium tuberculosis in response to isoniazid and hydrogen peroxide
Version of Record online: 8 SEP 2013
© 2013 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 2, Issue 6, pages 901–911, December 2013
How to Cite
MicrobiologyOpen 2013; 2(6): 901–911
- Issue online: 6 DEC 2013
- Version of Record online: 8 SEP 2013
- Manuscript Accepted: 1 AUG 2013
- Manuscript Received: 23 JUL 2013
- National Institute of General Medical Sciences of the National Institutes of Health. Grant Number: GM07739
- William Randolph Hearst Foundation
- Hydrogen peroxide;
- Mycobacterium tuberculosis ;
- nitrate reductase;
When access to molecular oxygen is restricted, Mycobacterium tuberculosis (Mtb) can respire an alternative electron acceptor, nitrate. We found that Mtb within infected primary human macrophages in vitro at physiologic tissue oxygen tensions respired nitrate, generating copious nitrite. A strain of Mtb lacking a functioning nitrate reductase was more susceptible than wild-type Mtb to treatment with isoniazid during infection of macrophages. Likewise, nitrate reductase-deficient Mtb was more susceptible to isoniazid than wild-type Mtb in axenic culture, and more resistant to hydrogen peroxide. These phenotypes were reversed by the addition of exogenous nitrite. Further investigation suggested that nitrite might inhibit the bacterial catalase. To the extent that Mtb itself is the most relevant source of nitrite acting within Mtb, these findings suggest that inhibitors of Mtb's nitrate transporter or nitrate reductase could enhance the efficacy of isoniazid.