Therapeutic Potential of Novel Antimicrobial Peptide Pap12-6-10: Mechanisms of Antibacterial and Anti-inflammatory Action Against Gram-Negative Sepsis

  • J Med Chem. 2025 Oct 9;68(19):20283-20303. doi: 10.1021/acs.jmedchem.5c01360.
Byeongkwon Kim  1 ,  Jin Kyeong Lee  1 ,  Minwon Son  1 ,  Hyeju Lee  1 ,  Chae Yeong Lee  1 ,  Junho Jeong  1 ,  Dasom Song  2 ,  Heewoong Yoon  2 ,  Eunha Hwang  3 ,  Myeong Seon Jeong  4 ,  Jiwon Seo  2 ,  Yangmee Kim  1
Affiliations
  • 1. Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
  • 2. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 3. Biopharmaceutical Research Center, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
  • 4. Center for Bio-imaging and Translational Research, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
PMID: 40970912 DOI: 10.1021/acs.jmedchem.5c01360
Abstract

To develop novel Antibiotics, we engineered 12-mer peptides derived from the N-terminus of papiliocin. Pap12-6-10 emerged as a potent Antibacterial agent against multidrug-resistant Gram-negative bacteria, demonstrating a low propensity for resistance development. Pap12-6-10 exerts its Antibacterial activity by permeabilizing Bacterial membranes through binding to lipopolysaccharide (LPS), inducing oxidative stress that leads to cell death. Pap12-6-10 modulates LPS-induced inflammatory responses by selectively targeting the TLR4 signaling pathways. Structural analysis using NMR, surface plasmon resonance, docking, and molecular dynamics simulations suggested that Pap12-6-10 binds to the hydrophobic pocket of MD-2, thereby preventing the LPS-induced dimerization of the TLR4/MD-2 complex, which is essential for inflammatory signaling during sepsis. In the Escherichia coli K1 and carbapenem-resistant Acinetobacter baumannii-induced sepsis mouse model Pap12-6-10 protected organ damage from septic shock and displayed significant therapeutic effects while maintaining low cytotoxicity. This study highlights its potential as a valuable candidate for treating Gram-negative infections.

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