Chen Li, Song Kunping, Cheng Mengwei, Wong Aloysius, Tian Xuechen, Yang Yixin, Ang Mia Yang, Tan Geok Yuan Annie, Choo Siew Woh
Department of Biology, College of Science and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou 325060, China.
Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
Biology (Basel). 2025 Jul 28;14(8):949. doi: 10.3390/biology14080949.
The global antimicrobial resistance crisis demands innovative strategies to combat bacterial infections, including those caused by drug-sensitive pathogens that evade treatment through biofilm formation or metabolic adaptations. Here, we demonstrate that Squama Manitis extract (SME)-a traditional Chinese medicine component-exhibits broad-spectrum bactericidal activity against clinically significant pathogens, including both Gram-positive () and Gram-negative () species (MIC = 31.25 mg/mL), achieving significant reduction in bacterial viability within 24 h. Through integrated multi-omics analysis combining scanning electron microscopy and RNA sequencing, we reveal SME's unprecedented tripartite mechanism of action: (1) direct membrane disruption causing cell envelope collapse, (2) metabolic paralysis through coordinated suppression of TCA cycle and fatty acid degradation pathways, and (3) inhibition of DNA repair systems (SOS response and recombination downregulation). Despite its potent activity, SME shows low cytotoxicity toward mammalian cells (>90% viability) and can penetrate Gram-negative outer membranes. These features highlight SME's potential to address drug-resistant infections through synthetic lethality across stress response, energy metabolism, and DNA integrity pathways. While advocating for synthetic alternatives to endangered animal products, this study establishes SME as a polypharmacological template for resistance-resilient antimicrobial design, demonstrating how traditional knowledge and modern systems biology can converge to guide sustainable anti-infective development.
全球抗菌药物耐药性危机需要创新策略来对抗细菌感染，包括那些由对药物敏感的病原体引起的感染，这些病原体通过生物膜形成或代谢适应来逃避治疗。在此，我们证明了穿山甲提取物（SME）——一种中药成分——对临床上重要的病原体具有广谱杀菌活性，包括革兰氏阳性菌（）和革兰氏阴性菌（）（最低抑菌浓度 = 31.25 mg/mL），在24小时内可显著降低细菌活力。通过结合扫描电子显微镜和RNA测序的综合多组学分析，我们揭示了SME前所未有的三方作用机制：（1）直接破坏细胞膜导致细胞包膜崩溃，（2）通过协同抑制三羧酸循环和脂肪酸降解途径导致代谢麻痹，（3）抑制DNA修复系统（SOS反应和重组下调）。尽管SME具有强大的活性，但对哺乳动物细胞显示出低细胞毒性（>90%活力），并且可以穿透革兰氏阴性菌的外膜。这些特性突出了SME通过在应激反应、能量代谢和DNA完整性途径中的合成致死作用来解决耐药性感染的潜力。在倡导使用濒危动物产品的合成替代品的同时，本研究将SME确立为抗耐药抗菌设计的多药理学模板，展示了传统知识和现代系统生物学如何结合起来指导可持续抗感染药物的开发。
