幽门螺杆菌（H. pylori）是目前公认的与胃肿瘤发生相关的首要致癌病原体，其高患病率和耐药性使其难以应对。基于图神经网络的深度学习模型，采用 13,638 个分子的不同训练集进行预训练和微调，有助于预测和探索针对幽门螺杆菌的新分子。具有 3,13-二取代烯烃的阳性预测新型小檗碱衍生物 8 对所有测试的药物敏感和耐药幽门螺杆菌菌株均表现出效力，最低抑制浓度 (MIC) 为 0.25-0.5μg/mL。药代动力学研究表明，理想的胃滞留量为 8，给药后 24 小时胃内浓度显着高于 MIC。口服8和奥美拉唑（OPZ）显示出与三联疗法（即OPZ  阿莫西林（AMX）  克拉霉素（CLA）相当的胃细菌减少（2.2-log减少），且对肠道菌群没有明显干扰。 OPZ、AMX、CLA 和 8 的组合可以进一步降低细菌负荷（减少 2.8 个对数）。更重要的是，8 种单一疗法的根除率与三联疗法（OPZ  AMX  CLA）和四联疗法（OPZ  AMX  CLA 柠檬酸铋）组相当。 SecA和BamD在外膜蛋白（OMP）转运和组装中起主要作用，通过化学蛋白质组学技术被鉴定并验证为8的直接靶标。总之，通过针对相对保守的OMPs转运和组装系统，8有潜力被开发为新型抗H.幽门螺杆菌候选者，特别是用于根除耐药菌株。© 2024。作者。

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 μg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.© 2024. The Author(s).