High Therapeutic Index α-Helical AMPs and Their Therapeutic Potential on Bacterial Lung and Skin Wound Infections.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL ACS Infectious Diseases Pub Date : 2024-09-13 Epub Date: 2024-08-14 DOI:10.1021/acsinfecdis.3c00706

Xu Ouyang, Beibei Li, Tingting Yang, Yinyin Yang, Zufang Ba, Jingying Zhang, Ping Yang, Yao Liu, Yu Wang, Yuhuan Zhao, Wenbo Mao, Xiaoyan Wu, Xiaoxuan Zeng, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou, Jingman Ni

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Abstract

Antimicrobial peptides (AMPs) possess strong antibacterial activity and low drug resistance, making them ideal candidates for bactericidal drugs for addressing the issue of traditional antibiotic resistance. In this study, a template (G(XXKK)_nI, G = Gly; X = Leu, Ile, Phe, or Trp; n = 2, 3, or 4; K = Lys; I = Ile.) was employed for the devised of a variety of novel α-helical AMPs with a high therapeutic index. The AMP with the highest therapeutic index, WK₂, was ultimately chosen following a thorough screening process. It demonstrates broad-spectrum and potent activity against both standard and multidrug-resistant bacteria, while also showing low hemolysis and rapid and efficient time-kill kinetics. Additionally, WK₂ exhibits excellent efficacy in treating mouse models of Klebsiella pneumonia-induced lung infections and methicillin-resistant Staphylococcus aureus (MRSA)-induced skin wound infections while demonstrating good safety profiles in vivo. In conclusion, the template-based design methodology for novel AMPs with high therapeutic indices offers new insights into addressing antibiotic resistance problems. WK₂ represents a promising antimicrobial agent.

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高治疗指数 α-Helical AMPs 及其对肺部和皮肤细菌感染的治疗潜力

抗菌肽（AMPs）具有较强的抗菌活性和较低的耐药性，是解决传统抗生素耐药性问题的理想杀菌药物候选物。本研究采用一种模板（G(XXKK)nI，G = Gly；X = Leu、Ile、Phe 或 Trp；n = 2、3 或 4；K = Lys；I = Ile。经过全面筛选，最终选出了治疗指数最高的 AMP WK2。它对标准细菌和耐多药细菌都具有广谱、强效的活性，同时还具有低溶血和快速高效的时间杀伤动力学特性。此外，WK2 在治疗小鼠克雷伯氏肺炎诱导的肺部感染和耐甲氧西林金黄色葡萄球菌（MRSA）诱导的皮肤伤口感染模型中表现出卓越的疗效，同时在体内表现出良好的安全性。总之，基于模板的高治疗指数新型 AMPs 设计方法为解决抗生素耐药性问题提供了新的思路。WK2 是一种很有前景的抗菌剂。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.