A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori

• Published in: Signal transduction and targeted therapy Vol. 9; no. 1; pp. 183 - 18
• Main Authors: Guo, Xixi, Zhao, Xiaosa, Lu, Xi, Zhao, Liping, Zeng, Qingxuan, Chen, Fenbei, Zhang, Zhimeng, Xu, Mengyi, Feng, Shijiao, Fan, Tianyun, Wei, Wei, Zhang, Xin, Pang, Jing, You, Xuefu, Song, Danqing, Wang, Yanxiang, Jiang, Jiandong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2024; Nature Publishing Group
• Subjects: 631/154/309/555; 631/154/309/556; Amoxicillin; Amoxicillin - pharmacology; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Berberine; Berberine - chemistry; Berberine - pharmacokinetics; Berberine - pharmacology; Cancer Research; Cell Biology; Clarithromycin; Clarithromycin - pharmacology; Deep Learning; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Eradication; Gastric cancer; Helicobacter Infections - drug therapy; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - drug effects; Humans; Internal Medicine; Intestinal microflora; Medicine; Medicine & Public Health; Membrane proteins; Microbial Sensitivity Tests; Multidrug resistance; Neural networks; Omeprazole; Omeprazole - pharmacology; Oncology; Oral administration; Outer membrane proteins; Pathology; Penicillin; Pharmacokinetics; Protein transport; Strains (organisms); Tumorigenesis
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-024-01895-0

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.