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.
Microbiologyopen. 2013 Dec;2(6):901-11. doi: 10.1002/mbo3.126. Epub 2013 Sep 8.
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.
当分子氧的获取受到限制时，结核分枝杆菌（Mtb）可以呼吸替代电子受体，硝酸盐。我们发现，在体外生理组织氧张力下感染的原代人巨噬细胞内，Mtb 呼吸硝酸盐，产生大量亚硝酸盐。与野生型 Mtb 相比，一种缺乏功能正常的硝酸盐还原酶的 Mtb 菌株在感染巨噬细胞时更容易受到异烟肼的治疗。同样，在无细胞培养中，缺乏硝酸盐还原酶的 Mtb 比野生型 Mtb 对异烟肼更敏感，对过氧化氢更有抵抗力。这些表型在外源性亚硝酸盐的加入下得到逆转。进一步的研究表明，亚硝酸盐可能抑制细菌过氧化氢酶。在 Mtb 本身是在 Mtb 内发挥作用的最相关亚硝酸盐来源的程度上，这些发现表明，Mtb 的硝酸盐转运蛋白或硝酸盐还原酶的抑制剂可能增强异烟肼的疗效。
