Novel Hybrid Peptide ML-2 with Antibacterial and Antibiofilm Activity Against Pseudomonas aeruginosa.

Antimicrobial resistance significantly contributes to treatment failures in bacterial infections and poses a major global public health challenge, urgently necessitating the development of new antimicrobial agents, such as antimicrobial peptides (AMPs), which represent a promising drug class. This study aimed to develop a novel, highly effective, low-toxicity antimicrobial agent employing a hybridization strategy to fuse the broad-spectrum AMP LL-37 with the low-toxicity Musca domestica antifungal peptide-1 A. The resulting hybrid peptides (ML-1, ML-2, and ML-3) exhibited markedly reduced cytotoxicity and hemolytic activity relative to LL-37. Notably, ML-2 demonstrated broad-spectrum antimicrobial activity, with particularly exerted effective antibacterial and antibiofilm effects against Pseudomonas aeruginosa in vitro. Moreover, with excellent stability, ML-2 retained activity against P. aeruginosa following pepsin treatment and thermal stress. Importantly, P. aeruginosa developed resistance to ML-2 more slowly than to the potent antibiotic ciprofloxacin. Mechanistically, ML-2 killed bacteria by increasing cell membrane permeability and disrupting cell integrity. Altogether, these findings suggest that the hybrid peptide ML-2 has potential as a novel antimicrobial agent against P. aeruginosa.