2. Academic Validation
  3. Ultra-short lipopeptides containing d-amino acid exhibiting excellent stability and antibacterial activity against gram-positive bacteria

Ultra-short lipopeptides containing d-amino acid exhibiting excellent stability and antibacterial activity against gram-positive bacteria

  • Eur J Med Chem. 2025 Apr 5:287:117341. doi: 10.1016/j.ejmech.2025.117341.
Jing Zou 1,  Jiahui Wang 1,  Luyang Gao 1,  Wenjing Xue 1,  Jingyi Zhu 1,  Yun Zhang 2,  Sanhu Gou 2,  Hui Liu 2,  Chao Zhong 3,  Jingman Ni 4
Affiliations

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, PR China.
  • 2 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, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
  • 3 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, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address: zhongc@lzu.edu.cn.
  • 4 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, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address: nijm@lzu.edu.cn.
PMID: 39908797 DOI: 10.1016/j.ejmech.2025.117341
Abstract

As novel Antibacterial agents, antimicrobial Peptides (AMPs) possess broad-spectrum Antibacterial activity and low drug resistance, holding significant development potential. Nevertheless, the stability of AMPs significantly restricts their application. In light of this, we synthesized a series of ultra-short lipopeptides using d-amino acid substitution to enhance the stability of ultra-short Lipopeptide C12-RRW-NH2 that was selected from our previous research while maintaining its Antibacterial activity against gram-positive bacteria. Amongst, the ultra-short Lipopeptide Lip7 (C12-rrw-NH2) with full d-amino acid demonstrated outstanding stability in protease, serum, and salt ion environments. It exerted excellent Antibacterial activity against gram-positive bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). Meanwhile, Lip7 presented a low propensity to develop Bacterial resistance with potential for combination therapy with conventional Antibiotics. Studies on its Antibacterial mechanism revealed that Lip7 could rapidly depolarize the Bacterial cytoplasmic membrane, disrupt the integrity of the Bacterial membrane, lead to leakage of nucleic acid and protein, promote the generation of Reactive Oxygen Species, and ultimately result in Bacterial death. Additionally, Lip7 also exhibited therapeutic potential in both local and systemic MRSA-infected mice models with better safety in vivo. These findings highlighted that Lip7 is an ideal novel Antibacterial alternative to offer guiding schemes for developing high-stability antimicrobial Peptides to fight multidrug-resistant gram-bacteria.

Keywords

Antibacterial activity; Gram-positive bacteria; Stability; Ultra-short lipopeptides; d-amino acids.

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