A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori
作者机构：Chinese Acad Med Sci & Peking Union Med Coll Inst Med Biotechnol Beijing 100050 Peoples R China Hefei Comprehens Natl Sci Ctr Inst Hlth & Med Hefei 230601 Anhui Peoples R China Northeast Normal Univ Sch Informat Sci & Technol Changchun 130117 Peoples R China Jining Med Univ Affiliated Hosp Dept Pharm Jining 272029 Shandong Peoples R China
出 版 物：《SIGNAL TRANSDUCTION AND TARGETED THERAPY》 (信号转导与靶向治疗（英文）)
年 卷 期：2024年第9卷第1期
页 面：1-18页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
基 金：National Natural Science Foundation of China [32141003, 82330110, 61976050, 61972384, 82003575] CAMS Initiative for Innovative Medicine [2021-1-I2M-030]
摘 要：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 mu g/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.
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