Tsugawa Hitoshi, Mori Hideki, Matsuzaki Juntaro, Masaoka Tatsuhiro, Hirayama Tasuku, Nagasawa Hideko, Sakakibara Yasubumi, Suematsu Makoto, Suzuki Hidekazu
Department of Biochemistry & Integrative Medical Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Biomed Res Int. 2015;2015:734548. doi: 10.1155/2015/734548. Epub 2015 Apr 6.
Iron-cofactored superoxide dismutase (SodB) of Helicobacter pylori plays an indispensable role in the bacterium's colonization of the stomach. Previously, we demonstrated that FecA1, a Fe(3+)-dicitrate transporter homolog, contributes to SodB activation by supplying ferrous iron (Fe(2+)) to SodB, and fecA1-deletion mutant strains have reduced gastric mucosal-colonization ability in Mongolian gerbils, suggesting that FecA1 is a possible target for the development of a novel eradication therapy. This study aimed to identify novel FecA1-binding compounds in silico and then examined the effect of a predicted FecA1-binding compound on H. pylori SodB activity in vitro. Specifically, we demonstrated that nordihydroguaiaretic acid (NDGA) is a predicted FecA1-binding compound. NDGA reduced intracellular Fe(2+) levels in H. pylori and reduced SodB activity. Additionally, NDGA increased H2O2 sensitivity of H. pylori and increased the metronidazole (Mtz) sensitivity. The present study demonstrated that NDGA repressed SodB activity associated with the gastric mucosal-colonization via inhibition of intracellular Fe(2+) uptake by FecA1, suggesting that NDGA might be effective for the development of a novel eradication therapy.
幽门螺杆菌的铁辅助超氧化物歧化酶（SodB）在该细菌的胃部定殖过程中发挥着不可或缺的作用。此前，我们证明了FecA1（一种柠檬酸铁（Ⅲ）转运蛋白同源物）通过向SodB供应亚铁（Fe（Ⅱ））来促进SodB的激活，并且fecA1缺失突变株在蒙古沙鼠中的胃黏膜定殖能力降低，这表明FecA1可能是开发新型根除疗法的一个潜在靶点。本研究旨在通过计算机模拟鉴定新型FecA1结合化合物，然后检测一种预测的FecA1结合化合物对幽门螺杆菌SodB体外活性的影响。具体而言，我们证明了去甲二氢愈创木酸（NDGA）是一种预测的FecA1结合化合物。NDGA降低了幽门螺杆菌细胞内的Fe（Ⅱ）水平，并降低了SodB活性。此外，NDGA增加了幽门螺杆菌对H2O2的敏感性，并增加了对甲硝唑（Mtz）的敏感性。本研究表明，NDGA通过抑制FecA1对细胞内Fe（Ⅱ）的摄取来抑制与胃黏膜定殖相关的SodB活性，这表明NDGA可能对开发新型根除疗法有效。
