Oh Jinyoung, Choi Su-Mi, Yun Yeojin, Choi Jieun, Barron Annelise E, Park Kyung-Hwa, Seo Jiwon
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
Eur J Med Chem. 2025 Nov 5;297:117920. doi: 10.1016/j.ejmech.2025.117920. Epub 2025 Jun 29.
Antimicrobial resistance poses a critical threat to global health, necessitating the development of new therapeutics. Peptoids are synthetic analogs of peptides with an N-substituted glycine backbone and have been investigated for antimicrobial therapeutic applications due to their resistance to proteolysis and tunable structures. This study explores antimicrobial peptoids functionalized with polyamine side chains, leveraging the cationic nature of polyamines to enhance interactions with bacterial membranes. A structure-activity relationship (SAR) analysis was conducted to elucidate the influence of polyamine chain length and density on antimicrobial potency and selectivity. The optimized peptoids demonstrated potent activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, while maintaining low cytotoxicity toward mammalian cells. Mechanistic studies demonstrated that these peptoids employ multiple killing mechanisms, including membrane disruption, oxidative damage, and intracellular aggregation of proteins and nucleic acids. This work highlights the potential of polyamine-functionalized peptoids for developing next-generation antimicrobial agents and provides insights into the design principles for enhancing their efficacy and safety.
抗菌耐药性对全球健康构成了严重威胁，因此需要开发新的治疗方法。类肽是具有N-取代甘氨酸主链的肽的合成类似物，由于其对蛋白水解的抗性和可调节的结构，已被研究用于抗菌治疗应用。本研究探索了用多胺侧链功能化的抗菌类肽，利用多胺的阳离子性质增强与细菌膜的相互作用。进行了构效关系（SAR）分析，以阐明多胺链长度和密度对抗菌效力和选择性的影响。优化后的类肽对革兰氏阳性菌和革兰氏阴性菌，包括多重耐药菌株，表现出强大的活性，同时对哺乳动物细胞保持低细胞毒性。机理研究表明，这些类肽采用多种杀伤机制，包括膜破坏、氧化损伤以及蛋白质和核酸的细胞内聚集。这项工作突出了多胺功能化类肽在开发下一代抗菌剂方面的潜力，并为提高其疗效和安全性的设计原则提供了见解。
