Zhang Jing, Luan Liang, Xu Youdong, Jiang Shuyuan, Zhang Wenpeng, Tian Long, Ye Weifeng, Han Jiaqi, Zhang Changhao, Wang Taoran, Meng Qingbing
State Key Laboratory of National Security Specially Needed Medicines, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; Key laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.
Department of Laboratory Medical Center, General Hospital of Northern Theater Command, No.83, Wenhua Road, Shenhe District, Shenyang 110016, China.
J Adv Res. 2025 Jan 18. doi: 10.1016/j.jare.2025.01.029.
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-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-biofilm activity, mechanism of action, synergistic effects, in vivo efficacy, and pharmacokinetics of the analogues were evaluated.
Among these analogues, P-α-02-B stood out for its broad-spectrum and potent antimicrobial activity, anti-biofilm activity, desirable bacterial selectivity, high plasma stability, and synergistic effect with antibiotic levofloxacin. P-α-02-B exhibited strong membrane disturbance effect, which could be explained by its rigid α-helical structure revealed by molecular dynamics simulations. More importantly, P-α-02-B showed favorable therapeutic efficacy in vivo, whether used alone or in combination with levofloxacin.
P-α-02-B is a promising antimicrobial agent for MDR bacterial infections, demonstrating the effectiveness of the combination strategy for AMP development.
近年来，阳离子两亲性抗菌肽（AMPs）因其独特的膜破坏机制在对抗抗生素耐药性方面显示出巨大潜力。然而，AMPs的临床应用受到其稳定性和安全性不尽人意的限制。尽管人们已尝试提高AMPs的稳定性和安全性，但其中许多尝试都伴随着抗菌活性和细菌选择性的下降。
采用联合策略开发具有优异且平衡的抗菌活性、稳定性和安全性的AMPs。
通过巧妙调整电荷、疏水性并以平衡的方式引入特定非天然氨基酸的联合策略，设计了一系列sC18衍生的肽类似物。评估了这些类似物的抗菌活性、细胞毒性、溶血活性、稳定性、抗生物膜活性、作用机制、协同效应、体内疗效和药代动力学。
在这些类似物中，P-α-02-B因其广谱强效的抗菌活性、抗生物膜活性、理想的细菌选择性、高血浆稳定性以及与抗生素左氧氟沙星的协同效应而脱颖而出。P-α-02-B表现出强烈的膜干扰效应，分子动力学模拟揭示的刚性α-螺旋结构可以解释这一现象。更重要的是，P-α-02-B无论单独使用还是与左氧氟沙星联合使用，在体内均显示出良好的治疗效果。
P-α-02-B是一种用于治疗多重耐药菌感染的有前景的抗菌剂，证明了联合策略在AMPs开发中的有效性。
