Multi-Lasso Peptide-Based Synergistic Nanocomposite: A High-Stability, Broad-Spectrum Antimicrobial Agent with Potential for Combined Antibacterial Therapy

Lasso peptides, natural biological microcins composed of small molecules, have demonstrated efficient bactericidal activity. However, a single lasso peptide is characterized by a narrow and targeted bactericidal spectrum. In this study, a chitosan (CN) derivative-based polymer nanomaterial incorporating three lasso peptides (MccY, MccJ25, and Klebsidin) was designed and synthesized to broaden its antimicrobial spectrum. To enhance resistance to acid and alkali conditions, arginine was appended to the terminus of conjugates, resulting in Chitosan-Lasso-Peptides-Arg (CN-LPs-Arg), and the nanomaterial biocompatibility and bactericidal activity were characterized. Chemical stability test results demonstrate that CN-LPs-Arg effectively buffered the acid-base effect of the compound. Notably, CN-LPs-Arg extended the antimicrobial spectrum of Gram-negative and Gram-positive strains including