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

  • ACS Infect Dis. 2024 Sep 13;10(9):3138-3157. doi: 10.1021/acsinfecdis.3c00706.
Xu Ouyang  1 ,  Beibei Li  1 ,  Tingting Yang  1 ,  Yinyin Yang  1 ,  Zufang Ba  1 ,  Jingying Zhang  1 ,  Ping Yang  1 ,  Yao Liu  1 ,  Yu Wang  1 ,  Yuhuan Zhao  1 ,  Wenbo Mao  1 ,  Xiaoyan Wu  1 ,  Xiaoxuan Zeng  1 ,  Chao Zhong  2  1 ,  Hui Liu  2  1 ,  Yun Zhang  2  1 ,  Sanhu Gou  2  1 ,  Jingman Ni  2  1
Affiliations
  • 1. Institute of Pharmaceutics, School of Pharmacy, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, P. R. China.
  • 2. Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
PMID: 39141008 DOI: 10.1021/acsinfecdis.3c00706
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.

Keywords
WK2; antimicrobial peptides; drug resistance; template design method.
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