Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan.
Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, Microbial Chemistry Research Foundation, Shinagawa-ku, Tokyo, Japan.
Helicobacter. 2018 Apr;23(2):e12470. doi: 10.1111/hel.12470. Epub 2018 Feb 28.
Helicobacter pylori (H. pylori) infection causes various gastrointestinal diseases including gastric cancer. Hence, eradication of this infection could prevent these diseases. The most popular first-line treatment protocol to eradicate H. pylori is termed "triple therapy" and consists of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole. However, the antibiotics used to treat H. pylori infection are hindered by the antibiotics-resistant bacteria and by their antimicrobial activity against intestinal bacteria, leading to side effects. Therefore, an alternative treatment with fewer adverse side effects is urgently required to improve the overall eradication rate of H. pylori.
The aim of this study was to assess the effectiveness and mechanism of action of an antitumor agent, intervenolin, and its derivatives as an agent for the treatment of H. pylori infection.
We demonstrate that intervenolin, and its derivatives showed selective anti-H. pylori activity, including antibiotic-resistant strains, without any effect on intestinal bacteria. We showed that dihydroorotate dehydrogenase, a key enzyme for de novo pyrimidine biosynthesis, is a target and treatment with intervenolin or its derivatives decreased the protein and mRNA levels of H. pylori urease, which protects H. pylori against acidic conditions in the stomach. Using a mouse model of H. pylori infection, oral monotherapy with the intervenolin derivative AS-1934 had a stronger anti-H. pylori effect than the triple therapy commonly used worldwide to eradicate H. pylori.
AS-1934 has potential advantages over current treatment options for H. pylori infection.
幽门螺杆菌（H. pylori）感染可导致多种胃肠道疾病，包括胃癌。因此，根除这种感染可以预防这些疾病。根除 H. pylori 的最流行的一线治疗方案被称为“三联疗法”，包括质子泵抑制剂（PPI）、克拉霉素和阿莫西林或甲硝唑。然而，用于治疗 H. pylori 感染的抗生素受到抗生素耐药菌和其对肠道细菌的抗菌活性的阻碍，导致副作用。因此，迫切需要一种具有较少不良反应的替代治疗方法，以提高 H. pylori 的总体根除率。
本研究旨在评估抗肿瘤药物 intervenolin 及其衍生物作为治疗 H. pylori 感染的药物的有效性和作用机制。
我们证明 intervenolin 及其衍生物对 H. pylori 具有选择性的抗活性，包括抗生素耐药菌株，而对肠道细菌没有任何影响。我们表明，二氢乳清酸脱氢酶是从头嘧啶生物合成的关键酶，是一个靶点，干预啉或其衍生物的治疗降低了 H. pylori 脲酶的蛋白和 mRNA 水平，脲酶保护 H. pylori 免受胃酸的影响。在 H. pylori 感染的小鼠模型中，干预啉衍生物 AS-1934 的口服单一疗法比全球常用的根除 H. pylori 的三联疗法具有更强的抗 H. pylori 作用。
AS-1934 比目前治疗 H. pylori 感染的选择方案具有潜在优势。
