Sun Hongfei, An Guifeng, Bao Sarula, Du Wenbo, Su Ya, Sun Dezhi, Zhang Xiaohui
Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, China.
Biomater Sci. 2025 Aug 5;13(16):4555-4564. doi: 10.1039/d5bm00785b.
Developing novel antimicrobial peptide (AMP) mimetics is a crucial approach to addressing the growing problem of bacterial resistance by inheriting the antibacterial advantages of AMPs while overcoming their inherent limitations. However, improperly controlled positive charges and hydrophobic structures in AMP mimetics can lead to strong cytotoxicity. Therefore, achieving high antibacterial efficacy while maintaining favorable biocompatibility is a crucial challenge for AMP mimetics. Herein, based on poly-α-L-lysine (PLL), which possesses potential for biological applications, we introduced varying numbers of aryl side chains to prepare a series of poly (α-amino acids)-based AMP mimetics. Through structure-activity relationship (SAR) studies modulating the balance between positive charge and hydrophobic units, we identified PAA-1, which exhibits a favorable balance between antimicrobial activity and biocompatibility. antibacterial studies demonstrated that PAA-1 exhibits potent activity against drug-resistant bacteria and biofilm compared to vancomycin, with negligible toxicity. Mechanistic studies suggested that PAA-1 inherits the membrane-damaging mechanism of AMP and shows no drug resistance after 14 consecutive passages. studies indicated that PAA-1 exhibits superior therapeutic efficacy against (MRSA)-induced peritonitis, providing greater survival protection compared to vancomycin, with a 7-day survival rate of 80% and demonstrating favorable biosafety. This study constructed AMP mimetics with a balanced antibacterial-biocompatibility profile by optimizing SAR. This provides a referable methodology for discovering more effective AMP mimetics and offers a preclinical research protocol for peritonitis treatment.
开发新型抗菌肽（AMP）模拟物是解决日益严重的细菌耐药性问题的关键途径，通过继承AMP的抗菌优势同时克服其固有局限性。然而，AMP模拟物中不当控制的正电荷和疏水结构可能导致强烈的细胞毒性。因此，在保持良好生物相容性的同时实现高抗菌效果是AMP模拟物面临的关键挑战。在此，基于具有生物应用潜力的聚-α-L-赖氨酸（PLL），我们引入不同数量的芳基侧链来制备一系列基于聚（α-氨基酸）的AMP模拟物。通过结构-活性关系（SAR）研究来调节正电荷和疏水单元之间的平衡，我们确定了PAA-1，它在抗菌活性和生物相容性之间表现出良好的平衡。抗菌研究表明，与万古霉素相比，PAA-1对耐药菌和生物膜具有强大的活性，且毒性可忽略不计。机制研究表明，PAA-1继承了AMP的膜损伤机制，并且在连续传代14次后未表现出耐药性。研究表明，PAA-1对耐甲氧西林金黄色葡萄球菌（MRSA）诱导的腹膜炎具有卓越的治疗效果，与万古霉素相比提供了更大的生存保护，7天生存率为80%，并显示出良好的生物安全性。本研究通过优化SAR构建了具有平衡抗菌-生物相容性的AMP模拟物。这为发现更有效的AMP模拟物提供了一种可参考的方法，并为腹膜炎治疗提供了一个临床前研究方案。
