Tian Long, Wang Taoran, Luan Liang, Meng Zhao, Han Jiaqi, Zhao Chunhui, Xu Yijie, Zeng Chunlan, Ye Weifeng, Jiang Shuyuan, Zhang Li, Yin Jiye, Meng Qingbin, Li Song
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
J Med Chem. 2025 May 8;68(9):9341-9356. doi: 10.1021/acs.jmedchem.4c03057. Epub 2025 Apr 20.
Antimicrobial peptides (AMPs) are considered promising agents to solve the problem of antibiotic resistance due to their unique membrane-disruption mechanism. In this research, de novo terminally symmetric β-turn AMPs were designed by combining the β-turn sequences derived from Tritrpticin with alternately arranged cationic and hydrophobic amino acid sequences. The structure-activity relationship of the peptides was studied. Among the designed peptides, P-07 (KIKIKPWWWPKIKIK-NH) exhibited potent antimicrobial activity against all the tested bacterial strains, showing the highest bacterial selectivity, relatively low cytotoxicity, high bactericidal efficiency, and low potential to induce bacterial resistance. The antimicrobial mechanisms of P-07 involving membrane-disruption and lipopolysaccharide-binding were proven. Moreover, the in vivo studies confirmed the wound-healing ability of P-07 using a mice bacteria-infected full-thickness wound model. Taken together, P-07 showed great promise in the treatment of multidrug-resistant bacterial infections.
抗菌肽（AMPs）因其独特的膜破坏机制而被认为是解决抗生素耐药性问题的有前途的药物。在本研究中，通过将源自胰蛋白酶的β-转角序列与交替排列的阳离子和疏水氨基酸序列相结合，设计了从头合成的末端对称β-转角AMPs。研究了这些肽的构效关系。在设计的肽中，P-07（KIKIKPWWWPKIKIK-NH）对所有测试的细菌菌株均表现出强大的抗菌活性，具有最高的细菌选择性、相对较低的细胞毒性、高杀菌效率以及低诱导细菌耐药性的潜力。已证实P-07的抗菌机制涉及膜破坏和脂多糖结合。此外，体内研究使用小鼠细菌感染的全层伤口模型证实了P-07的伤口愈合能力。综上所述，P-07在治疗多重耐药细菌感染方面显示出巨大的前景。
