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

IF 11.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Journal of Advanced Research Pub Date : 2025-01-18 DOI:10.1016/j.jare.2025.01.029
Jing Zhang, Liang Luan, Youdong Xu, Shuyuan Jiang, Wenpeng Zhang, Long Tian, Weifeng Ye, Jiaqi Han, Changhao Zhang, Taoran Wang, Qingbing Meng
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Abstract

Introduction

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.

Objectives

To develop AMPs with excellent and balanced antimicrobial activity, stability, and safety using a combination strategy.

Methods

A series of sC184b-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.

Results

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.

Conclusion

P-α-02-B is a promising antimicrobial agent for MDR bacterial infections, demonstrating the effectiveness of the combination strategy for AMP development.

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通过合理组合策略开发抗多药耐药细菌的新型广谱两性抗菌肽
近年来,阳离子两性抗菌肽(AMPs)由于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的前景。然而,由于其稳定性和安全性不理想,抗菌肽的临床应用受到限制。尽管人们已经尝试提高抗菌肽的稳定性和安全性,但它们中的许多都伴随着抗菌活性和细菌选择性的下降。目的采用联合用药策略开发抗菌活性、稳定性和安全性均良好的抗菌肽。方法采用巧妙调整电荷、疏水性和平衡引入特定非天然氨基酸的组合策略,设计了一系列源自sc184b的肽类似物。对其抑菌活性、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、体内药效和药代动力学进行了评价。结果P-α-02-B具有广谱有效的抗菌活性、抗生物膜活性、良好的细菌选择性、较高的血浆稳定性和与抗生素左氧氟沙星的协同作用。P-α-02-B表现出较强的膜扰动效应,分子动力学模拟表明其具有刚性的α-螺旋结构。更重要的是,无论是单独使用还是与左氧氟沙星联合使用,P-α-02-B在体内均显示出良好的治疗效果。结论p -α-02-B是一种很有前景的耐多药细菌感染抗菌药物,表明联合策略开发AMP是有效的。
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索莱宝
6-diamidino-2-phenylindole (DAPI)
索莱宝
Propidium iodide (PI)
索莱宝
Triton X-100
索莱宝
6-diamidino-2-phenylindole (DAPI)
索莱宝
Propidium iodide (PI)
索莱宝
Triton X-100
索莱宝
6-diamidino-2-phenylindole (DAPI)
索莱宝
Propidium iodide (PI)
索莱宝
Triton X-100
麦克林
meropenem trihydrate
麦克林
Levofloxacin
麦克林
meropenem trihydrate
麦克林
Levofloxacin
麦克林
meropenem trihydrate
麦克林
Levofloxacin
麦克林
meropenem trihydrate
麦克林
Levofloxacin
阿拉丁
2-Nitrophenyl β-D-galactopyranoside (ONPG)
阿拉丁
1-N-phenylnaphthylamine (NPN)
阿拉丁
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)
阿拉丁
Crystal violet
阿拉丁
2-Nitrophenyl β-D-galactopyranoside (ONPG)
阿拉丁
1-N-phenylnaphthylamine (NPN)
阿拉丁
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)
阿拉丁
Crystal violet
阿拉丁
2-Nitrophenyl β-D-galactopyranoside (ONPG)
阿拉丁
1-N-phenylnaphthylamine (NPN)
阿拉丁
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)
阿拉丁
Crystal violet
阿拉丁
2-Nitrophenyl β-D-galactopyranoside (ONPG)
阿拉丁
1-N-phenylnaphthylamine (NPN)
阿拉丁
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)
阿拉丁
Crystal violet
来源期刊
Journal of Advanced Research
Journal of Advanced Research Multidisciplinary-Multidisciplinary
CiteScore
21.60
自引率
0.90%
发文量
280
审稿时长
12 weeks
期刊介绍: Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.
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