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

被引：5

作者：

Ouyang, Xu ^{[1
,2
]}

Li, Beibei ^{[1
,2
]}

Yang, Tingting ^{[1
,2
]}

Yang, Yinyin ^{[1
,2
]}

Ba, Zufang ^{[1
,2
]}

Zhang, Jingying ^{[1
,2
]}

Yang, Ping ^{[1
,2
]}

Liu, Yao ^{[1
,2
]}

Wang, Yu ^{[1
,2
]}

Zhao, Yuhuan ^{[1
,2
]}

Mao, Wenbo ^{[1
,2
]}

Wu, Xiaoyan ^{[1
,2
]}

Zeng, Xiaoxuan ^{[1
,2
]}

Zhong, Chao ^{[1
,2
,3
]}

Liu, Hui ^{[1
,2
,3
]}

Zhang, Yun ^{[1
,2
,3
]}

Gou, Sanhu ^{[1
,2
,3
]}

Ni, Jingman ^{[1
,2
,3
]}

机构：

[1] Lanzhou Univ, Chinese Acad Med Sci, Inst Pharmaceut, Sch Pharm,Key Lab Preclin Study New Drugs Gansu Pr, 2019RU066, Lanzhou 730000, Peoples R China

[2] Lanzhou Univ, Chinese Acad Med Sci, Res Unit Peptide Sci, 2019RU066, Lanzhou 730000, Peoples R China

[3] Chinese Acad Med Sci, Peking Union Med Coll, Inst Mat Med, Beijing 100050, Peoples R China

来源：

ACS INFECTIOUS DISEASES | 2024年 / 10卷 / 09期

基金：

中国国家自然科学基金;

关键词：

antimicrobial peptides; drug resistance; templatedesign method; WK2; CATIONIC ANTIMICROBIAL PEPTIDES; RESISTANCE; MEMBRANE; MECHANISM;

D O I：

10.1021/acsinfecdis.3c00706

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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)(n)I, 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 alpha-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.

引用

页码：3138 / 3157

页数：20