2. Academic Validation
  3. Association of idealized amphiphiles and protease inhibitors: Conferring antimicrobial peptides with stable antibacterial activity under physiological conditions to combat multidrug-resistant bacteria

Association of idealized amphiphiles and protease inhibitors: Conferring antimicrobial peptides with stable antibacterial activity under physiological conditions to combat multidrug-resistant bacteria

  • Drug Resist Updat. 2024 Dec 9:79:101183. doi: 10.1016/j.drup.2024.101183.
Yongjie Zhu 1,  Bowen Li 1,  Wanying Xu 1,  Yuanmengxue Wang 1,  Guoyu Li 1,  Chongpeng Bi 1,  Changxuan Shao 2,  Anshan Shan 3
Affiliations

Affiliations

  • 1 College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
  • 2 College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China. Electronic address: cxshao@neau.edu.cn.
  • 3 College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China. Electronic address: asshan@neau.edu.cn.
PMID: 39667175 DOI: 10.1016/j.drup.2024.101183
Abstract

Aims: The unstable antimicrobial activity of antimicrobial Peptides (AMPs) under physiological conditions (especially the degradation instigated proteases) seems to be a persistent impediment for their successful implementation in clinical trials. Consequently, our objective was to devise AMP engineering frameworks that could sustain robust Antibacterial efficacy within physiological environments.

Methods: In this work, we harvested AMPs with stable antimicrobial activity under the physiological barriers through the combination of idealized amphiphiles and trypsin inhibitors.

Results: We screened and identified the lead Peptides IK3-A and IK3-S, which showed potent activity against Gram-negative bacteria, including multidrug-resistant (MDR) bacteria, and exhibited promising biocompatibility with mammalian cells. Remarkably, IK3-A and IK3-S maintained sustained Antibacterial potency under physiological salts, serum, and protease conditions. Furthermore, both IK3-A and IK3-S kill Gram-negative bacteria by attacking the Bacterial cell membrane and inducing oxidative damage (at high concentrations). Crucially, IK3-A and IK3-S have optimal safety and efficacy in mice.

Conclusions: This is the first work to compare the effects of different trypsin inhibitors on the resistance of AMPs to protease hydrolysis on the same sequence platform. In conclusion, these findings provide guidance for the molecular design of AMPs with stable Antibacterial activity under physiological conditions and facilitates the process of clinical translation of AMPs as antimicrobial biomaterials against MDR bacteria. Moreover, this may stimulate a more general interest in Protease Inhibitors as molecular scaffolds in the creation of highly stable peptide-based biomaterials.

Keywords

Antibacterial mechanism; Antimicrobial peptides; In vivo efficacy; Stable antibacterial activity; Trypsin inhibitors.

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