Monotherapy with a novel intervenolin derivative, AS‐1934, is an effective treatment for <italic>Helicobacter pylori</italic> infection.

Abstract: Background: <italic>Helicobacter pylori</italic> (<italic>H. pylori</italic>) 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 <italic>H. pylori</italic> is termed “triple therapy” and consists of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole. However, the antibiotics used to treat <italic>H. pylori</italic> 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 <italic>H. pylori</italic>. Objective: 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 <italic>H. pylori</italic> infection. Results: We demonstrate that intervenolin, and its derivatives showed selective anti‐<italic>H. pylori</italic> activity, including antibiotic‐resistant strains, without any effect on intestinal bacteria. We showed that dihydroorotate dehydrogenase, a key enzyme for <italic>de novo</italic> pyrimidine biosynthesis, is a target and treatment with intervenolin or its derivatives decreased the protein and mRNA levels of <italic>H. pylori</italic> urease, which protects <italic>H. pylori</italic> against acidic conditions in the stomach. Using a mouse model of <italic>H. pylori</italic> infection, oral monotherapy with the intervenolin derivative AS‐1934 had a stronger anti‐<italic>H. pylori</italic> effect than the triple therapy commonly used worldwide to eradicate <italic>H. pylori</italic>. Conclusion: AS‐1934 has potential advantages over current treatment options for <italic>H. pylori</italic> infection. [ABSTRACT FROM AUTHOR]