Development of novel broad-spectrum amphipathic antimicrobial peptides against multidrug-resistant bacteria through a rational combination strategy

作者：Jing Zhang, Liang Luan, Youdong Xu, Shuyuan Jiang, Wenpeng Zhang, Long Tian, Weifeng Ye, Jiaqi Han, Changhao Zhang, Taoran Wang, Qingbin Meng · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.01.029 · 被引用次数：13 · 研究领域：Antimicrobial Peptides and Activities、Antimicrobial agents and applications、Peptidase Inhibition and Analysis

• A series of sC18 4b -derived cationic amphipathic antimicrobial peptides were designed by a combination strategy. • P-α-02-B, a screened analogue, displayed broad-spectrum and potent antimicrobial activity with high bacterial selectivity • P-α-02-B exhibited superior plasma stability, overcoming a major limitation of traditional AMPs. • When combined with levofloxacin, P-α-02-B showed a synergistic antimicrobial effect • In vivo studies confirmed the favorable therapeutic efficacy of P-α-02-B, both as a standalone agent and in combination therapy, against multidrug-resistant bacterial infections. In recent years, cationic amphipathic antimicrobial peptides (AMPs) have shown great promise in combating antibiotic resistance on account of their distinctive membrane-disruptive mechanism. However, the clinical application of AMPs is restricted by their unsatisfactory stability and safety. Although attempts have been made to improve the stability and safety of AMPs, many of them are accompanied by a decline in their antimicrobial activity and bacterial selectivity. To develop AMPs with excellent and balanced antimicrobial activity, stability, and safety using a combination strategy. A series of sC18 4b -derived peptide analogues were designed by a combination strategy of subtly adjusting the charges, hydrophobic properties, and introducing specific unnatural amino acids in a well-balanced manner. The antimicrobial activity, cytotoxicity, hemolytic activity, stability, anti-biofil...