H. pyloriのSodB活性はメトロニダゾール耐性に関与し, その活性化には菌体膜鉄トランスポーターFecA1による鉄イオン供給が必須である。in silico検索よりFecA1結合性化合物として同定したnordihidroguaiaretic acid(NDGA)は, H. pyloriのSodB活性を抑制し, 酸化ストレス感受性を, fecA1遺伝子欠損株と同レベルまで高めた。また, H. pylori感染マウスへのNDGA投与は感染菌量を低下させ, H. pyloriの感染能破綻を招来すると考えられた。さらに, NDGAは, サルモネラ及び病原性大腸菌に対しても酸化ストレス感受性を高めた。
Superoxide dismutase (SodB) of H. pylori plays an indispensable role in the development of drug resistance against metronidazole. The activation of SodB requires Fe2+ supply through FecA1, suggesting that FecA1 is a possible target for a novel eradication therapy. By in silico screening, we explored FecA1-binding compounds and identified nordihydroguaiaretic acid (NDGA), that reduced intrabacterial Fe2+ levels and SodB activity and then increased the H2O2 sensitivity to the same levels observed in fecA1-deletion mutants. NDGA decreased the colonization density of H. pylori in the mouse stomach, indicating the repression of gastric mucosal-colonization of H. pylori via inhibition of intracellular Fe2+ uptake by FecA1. In addition, NDGA also increased the in vitro H2O2 sensitivity of Salmonella typhimurium and enteropathogenic E. coli. These results suggest that NDGA might be effective for the development of a novel therapy selectively against inflammogenic enteropathogenic bacteria.

研究種目 : 挑戦的萌芽研究
研究期間 : 2014～2015
課題番号 : 26670065
研究分野 : 消化器内科学