Work

Design and evaluation of octopromycin-derived peptides as multifunctional antimicrobial agents against multidrug-resistant pathogens

Year: 2025

Type: article

Abstract: Octopromycin (OPM), an antimicrobial peptide from Octopus minor, shows potent activity against multidrug-resistant (MDR) Acinetobacter baumannii. Guided by the structure-activity relationship of the N-terminal domain OPM23, we designed short α-helical peptides with enhanced antimicrobial, anti-inflammatory, and antibiofilm properties while maintaining low toxicity. Antimicrobial activity was assessed by broth microdilution; protease and serum stability by HPLC. Mechanism of action was examined using membrane depolarization, NPN uptake, β-galactosidase (ONPG) hydrolysis, flow cytometry, and scanning electron microscopy. Anti-inflammatory effects were evaluated by ELISA, RT-PCR, and lipopolysaccharide (LPS) interaction assays, and biofilm inhibition/eradication was tested against MDR Pseudomonas aeruginosa (MDRPA). Four peptides-OPM23-a7, OPM23-a8, and their D-enantiomers OPM23-a7-d and OPM23-a8-d-exhibited strong antimicrobial, anti-inflammatory, and antibiofilm activities with minimal hemolytic and cytotoxic effects. The D-enantiomers showed pronounced stability under physiologically challenging conditions, including high salt, proteolytic environments, and human serum. Mechanistic studies indicated disruption of bacterial membrane integrity with leakage of intracellular contents. In LPS-stimulated RAW264.7 macrophages, the peptides suppressed pro-inflammatory cytokine release via dual actions-direct LPS binding and inhibition of LPS-receptor interactions. Beyond preventing MDRPA biofilm formation, the peptides substantially reduced biomass and viability within mature biofilms. Collectively, the OPM-derived peptides showed multifunctional activity in vitro with favorable stability and low toxicity. These findings support their potential as promising peptide candidates, while in vivo efficacy and pharmacokinetic studies will be required to assess translational feasibility.

Source: Scientific Reports

DOI: 10.1038/s41598-025-25213-y