Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Antioxid Redox Signal. 2011 Jan 1;14(1):15-23. doi: 10.1089/ars.2010.3146. Epub 2010 Aug 26.
Metronidazole (Mtz) is a prodrug that is converted to its active form when its nitro group is reduced and superoxide radicals are generated. The superoxide radicals are directly toxic to the bacterium. On the other hand, the transcriptional regulator, ferric uptake regulator (Fur), of Helicobacter pylori is a direct suppressor of the iron-cofactored superoxide dismutase SodB, which is essential for protection against superoxide attack. Here, we demonstrate that in some Mtz-resistant strains, SodB activity is induced in a dose-dependent manner on exposure to Mtz. Further, under Mtz exposure, the generation of superoxide radicals in Mtz-resistant strains was significantly reduced as compared with that in the Mtz-susceptible strains. These Mtz-resistant strains were found to carry amino acids mutation of Fur (C78Y, P114S; mutant-type Fur). The binding affinity of the mutant-type Fur to an operator sequence on the sodB promoter (Fur-Box) was significantly reduced. Our approach demonstrated that SodB expression is derepressed by mutant-type Fur, which is associated with the development of Mtz resistance.
甲硝唑（Mtz）是一种前体药物，当其硝基基团被还原并生成超氧自由基时，就会转化为其活性形式。超氧自由基直接对细菌有毒。另一方面，幽门螺杆菌的转录调节因子铁摄取调节因子（Fur）是铁辅因子超氧化物歧化酶 SodB 的直接抑制剂，SodB 对于防止超氧攻击至关重要。在这里，我们证明在一些 Mtz 耐药菌株中，SodB 活性在暴露于 Mtz 时呈剂量依赖性诱导。此外，与 Mtz 敏感株相比，Mtz 耐药株中超氧自由基的产生在 Mtz 暴露下显著减少。这些 Mtz 耐药株被发现携带 Fur（C78Y、P114S；突变型 Fur）的氨基酸突变。突变型 Fur 与 sodB 启动子上的一个操作序列（Fur-Box）的结合亲和力显著降低。我们的方法表明，SodB 的表达被突变型 Fur 解除抑制，这与 Mtz 耐药性的发展有关。
