数字农科院2.0

Discovery of antibacterial and synergistic acylhydrazone functionalized α-mangostin derivatives against drug-resistant pathogens

文献类型： 外文期刊

作者： Tang, Qun;Zhang, Haiyang;Jiao, Zirui;Bai, Han;Han, Xiangan;Wang, Xiaoyang;Zhang, Keyu;Wang, Chunmei;Zhou, Wen

作者机构：

关键词： alpha-Mangostin;acylhydrazone;MRSA;antibacterial;synergistic effect

期刊名称： BIOORGANIC CHEMISTRY

ISSN： 0045-2068

年卷期： 2025 年 166 卷

页码：

收录情况： SCIE（2025版）

摘要： By strategically combining the acylhydrazone scaffold with alpha-mangostin (alpha-MG)'s membrane-targeting properties, we designed 48 novel conjugates to enhance antibacterial potential and biofilm penetration while reducing toxicity. The candidate compound 7-8 demonstrated exceptional anti-Methicillin-Resistant Staphylococcus aureus (MRSA) activity (MIC = 1 mu g/mL) with in vivo efficacy (5 mg/kg, s.c.) comparable to vancomycin. 7-8 exhibited superior safety profiles versus alpha-MG, including minimal cytotoxicity (IC50 > 100 mu g/mL in A549/LO-2 cells), negligible hemolysis (HC50 > 400 mu g/mL), excellent in vivo tolerance, and no genotoxicity. Mechanistic studies revealed a dual antibacterial action: i) membrane disruption causing cellular content leakage, and ii) ROS-mediated oxidative stress. 7-8 also showed remarkable biofilm inhibition/eradication capacity through downregulation of key biofilm genes (ica, agr). Pharmacokinetic evaluation revealed favorable metabolic stability, moderate plasma protein binding, and optimal lipophilicity. These results established 7-8 as a promising multi-target therapeutic candidate against drug-resistant infections, combining enhanced biofilm penetration with improved safety.

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