Therapeutic Potential of Novel Antimicrobial Peptide Pap12-6-10: Mechanisms of Antibacterial and Anti-inflammatory Action Against Gram-Negative Sepsis
- Type
- Article
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.68, no.19, pp.20283 - 20303
- Issued Date
- 2025-10
- 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.
- Publisher
- AMER CHEMICAL SOC
- ISSN
- 0022-2623
- Appears in Collections:
- Department of Chemistry > 1. Journal Articles
- 파일 목록
-
-
관련 파일이 존재하지 않습니다.
-
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.