title: Nitrite impacts the survival of Mycobacterium tuberculosis in response to isoniazid and hydrogen peroxide.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York; Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York.
authors.forename: Amy
authors.initials: A
authors.lastname: Cunningham-Bussel
authors.forename: Franz C
authors.initials: FC
authors.lastname: Bange
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D050296:Microbial Viability / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D050901:Nitrate Reductase / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D009573:Nitrites; D006861:Hydrogen Peroxide; D050901:Nitrate Reductase; D007538:Isoniazid
keywords: Hydrogen peroxide; Mycobacterium tuberculosis; isoniazid; nitrate reductase; nitrite
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