Infectious Diseases Division, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, 02903, USA.
Sci Rep. 2018 Feb 27;8(1):3701. doi: 10.1038/s41598-018-22037-x.
There is an urgent need to discover novel antimicrobial therapies. Drug repurposing can reduce the time and cost risk associated with drug development. We report the inhibitory effects of anthelmintic drugs (niclosamide, oxyclozanide, closantel, rafoxanide) against Helicobacter pylori strain 60190 and pursued further characterization of niclosamide against H. pylori. The MIC of niclosamide against H. pylori was 0.25 μg/mL. Niclosamide was stable in acidic pH and demonstrated partial synergy with metronidazole and proton pump inhibitors, such as omeprazole and pantoprazole. Niclosamide administration at 1 × MIC concentration, eliminated 3-log CFU of H. pylori adhesion/invasion to AGS cells. Interestingly, no resistance developed even after exposure of H. pylori bacteria to niclosamide for 30 days. The cytotoxic assay demonstrated that niclosamide is not hemolytic and has an IC of 4 μg/mL in hepatic and gastric cell lines. Niclosamide administration decreased transmembrane pH as determined by DiSC(5) assay indicating that the mechanism of action of the anti-H. pylori activity of niclosamide was the disruption of H. pylori proton motive force. Niclosamide was effective in the Galleria mellonella-H. pylori infection model (p = 0.0001) and it can be develop further to combat H. pylori infection. However, results need to be confirmed with other H. pylori and clinical strains.
迫切需要发现新的抗菌治疗方法。药物再利用可以降低药物开发相关的时间和成本风险。我们报告了驱虫药（尼氯硝唑、氯硝柳胺、氯羟吡啶、三氯苯达唑）对幽门螺杆菌菌株 60190 的抑制作用，并进一步研究了尼氯硝唑对幽门螺杆菌的作用。尼氯硝唑对幽门螺杆菌的 MIC 为 0.25 μg/mL。尼氯硝唑在酸性 pH 值下稳定，并与甲硝唑和质子泵抑制剂（如奥美拉唑和泮托拉唑）表现出部分协同作用。尼氯硝唑以 1×MIC 浓度给药，可消除 3 对数 CFU 的幽门螺杆菌黏附/侵袭 AGS 细胞。有趣的是，即使在幽门螺杆菌暴露于尼氯硝唑 30 天后，也没有产生耐药性。细胞毒性测定表明，尼氯硝唑不溶血，在肝和胃细胞系中的 IC 为 4 μg/mL。尼氯硝唑给药降低了 DiSC(5)测定法测定的跨膜 pH 值，表明尼氯硝唑抗幽门螺杆菌活性的作用机制是破坏幽门螺杆菌质子动力。尼氯硝唑在大蜡螟-幽门螺杆菌感染模型中有效（p=0.0001），可以进一步开发用于对抗幽门螺杆菌感染。然而，结果需要用其他幽门螺杆菌和临床菌株进行确认。
