Metallo-beta-lactamase α-helix fragment modified peptide N10 is a multifunctional antimicrobial peptide

ABSTRACT Metallo-beta-lactamases (MBLs) increase the spread of drug resistance among bacteria worldwide and have severely limited the efficacy of β-lactam antibiotics. To develop alternative therapeutics, we used the MBL α-helix fragment as the original peptide, which is the main reason for carbapenem resistance, and modified it into D-amino acid to replace cyclic peptide N10. The antibacterial effect of N10 was detected through the broth microdilution method and time–kill curve and growth curve detection, and the effective minimum inhibitory concentrations (MICs) of N10 to bacteria ranged from 2 to 16 μg/mL. Based on the fluorescence microscopy, hydrogen ion SEM and TEM results, N10 showed extensive membrane damage and structural collapse. In the cell infection model, N10 decreased the levels of ROS and inflammatory factors to near-control levels at 2× MIC. In vivo , there was no apparent cytotoxicity or hemolytic activity even at 512 μg/mL. The “0–2–12 h” therapeutic strategy also resulted in noticeable therapeutic effects in a carbapenem-resistant Escherichia coli -infected mouse model. Our research revealed a new antimicrobial peptide source and modification strategy, which broadens the antibacterial mode and therapeutic procedure. IMPORTANCE In this study, we modified an metallo-beta-lactamase family protein into the novel, safe, environmentally friendly antimicrobial peptide N10, which has antimicrobial, antioxidant, and anti-inflammatory properties both in vivo and in vitro . We also investigated the preliminary antimicrobial mechanism of the biopeptide. This study broadens the use of drug resistance genes and provides direction for in vivo therapeutic strategies.