Metallo-beta-lactamase α-helix fragment modified peptide N10 shows broad antimicrobial, antioxidant, and anti-inflammatory effects.

The global rise of antibiotic resistance, particularly due to Metallo-beta-lactamases (MBLs), severely limits the efficacy of β-lactam antibiotics and poses a critical health threat. Current treatments struggle against carbapenem-resistant bacteria, necessitating novel therapeutic strategies. Antimicrobial Peptides (AMPs) offer a promising alternative due to their broad-spectrum activity and unique mechanisms of action. This study explores modifying an MBL α-helix fragment, a key driver of carbapenem resistance, into a therapeutic peptide to overcome this critical gap in antimicrobial development.

Researchers developed peptide N10 by modifying an α-helix fragment of Metallo-beta-lactamase with D-amino acids. Its antibacterial efficacy was assessed in vitro using broth microdilution, time-kill curve, and growth curve assays. Membrane damage was visualized via fluorescence microscopy, hydrogen ion SEM, and TEM. An in vitro cell infection model evaluated N10's impact on reactive oxygen species (ROS) and inflammatory factors at 2× MIC. In vivo safety was determined by cytotoxicity and hemolytic activity tests. Finally, a carbapenem-resistant Escherichia coli-infected mouse model tested a "0-2-12 h" therapeutic strategy.

Peptide N10 demonstrated significant antibacterial activity, with effective minimum inhibitory concentrations (MICs) ranging from 2 to 16 μg/mL against various bacteria. Microscopic analyses (fluorescence microscopy, SEM, TEM) revealed that N10 induced extensive bacterial membrane damage and structural collapse, indicating a direct lytic mechanism. In a cell infection model, N10 at 2× MIC effectively decreased levels of reactive oxygen species (ROS) and inflammatory factors, bringing them to near-control levels, suggesting potent anti-inflammatory and antioxidant properties. Crucially, in vivo safety assessments showed no apparent cytotoxicity or hemolytic activity, even at a high concentration of 512 μg/mL. Furthermore, a "0-2-12 h" therapeutic strategy employing N10 in a carbapenem-resistant Escherichia coli-infected mouse model yielded noticeable therapeutic effects, highlighting its potential for in vivo application against resistant pathogens.