Zhou Yang, Wu Juhong, Lin Haili, Song Meiru, Deng Lina, Mai Yuhan, Wang Zhiyou, Zeng Nannan, Zhang Wei, Liu Yichang, Jiang Longguang, Yuan Cai, Huang Mingdong, Li Jinyu, Xu Peng
College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350116, P.R. China.
College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, P.R. China.
J Med Chem. 2025 Jun 26;68(12):12658-12674. doi: 10.1021/acs.jmedchem.5c00407. Epub 2025 Jun 16.
Antimicrobial peptides (AMPs) are powerful tools in combating drug-resistant bacteria. However, their clinical application is hindered by poor pharmacokinetics and suboptimal antimicrobial activity. This study proposes a strategy to enhance the antimicrobial activity and biosafety of AMPs by modification with albumin-binding molecules (ABMs). This strategy was validated by employing two model peptides with moderate antimicrobial efficacy. First, ABM modification stabilizes the secondary structures, facilitating bacterial membrane disruption. Additionally, modified AMPs target albumin in blood vessels, reducing renal clearance in vivo. Moreover, this binding minimizes contact with blood and endothelial cells, consequently diminishing vascular toxicity without compromising antimicrobial activity. Molecular dynamic simulations followed by experimental validation revealed new molecular insights into the mechanism underlying AMP-mediated membrane disruption, confirming our design strategy. This dual mechanism, structural stabilization and albumin-mediated pharmacokinetic enhancement, addresses the key limitation of AMPs, offering a versatile approach to develop potent, systemically safe antimicrobial therapies.
抗菌肽（AMPs）是对抗耐药细菌的有力工具。然而，其临床应用受到不良药代动力学和次优抗菌活性的阻碍。本研究提出了一种通过用白蛋白结合分子（ABMs）修饰来增强抗菌肽的抗菌活性和生物安全性的策略。该策略通过使用两种具有中等抗菌效力的模型肽进行了验证。首先，ABM修饰稳定了二级结构，促进细菌膜破坏。此外，修饰后的抗菌肽靶向血管中的白蛋白，减少体内肾清除率。而且，这种结合使与血液和内皮细胞的接触最小化，从而在不影响抗菌活性的情况下降低血管毒性。分子动力学模拟随后进行实验验证，揭示了抗菌肽介导的膜破坏机制的新分子见解，证实了我们的设计策略。这种双重机制，即结构稳定和白蛋白介导的药代动力学增强，解决了抗菌肽的关键局限性，为开发有效的、全身安全的抗菌疗法提供了一种通用方法。
