One-Step Synthesis of Antimicrobial Polypeptide-Selenium Nanoparticles Exhibiting Broad-Spectrum Efficacy against Bacteria and Fungi with Superior Resistance Prevention

The growing threat of antimicrobial resistance (AMR) necessitates innovative strategies beyond conventional antibiotics. In response, we developed a rapid one-step method to sythesize antimicrobial peptide (AMP) ε-poly-L-lysine stabilized selenium nanoparticles (ε-PL-Se NPs). These polycrystalline NPs with highly positive net surface charges, exhibited superior antimicrobial activity against a broad panel of pathogens, including the Gram-positive and -negative bacteria Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa and their drug-resistant counterparts, as well as the yeast Candida albicans. Notably, 10PL-Se NPs exhibited 6-log reduction of methicillin-resistant S. aureus (MRSA) at a concentration of 5 μg/mL within 90 min, with minimum bactericidal concentrations (MBCs) below 50 μg/mL for all tested bacterial strains. The minimum fungicidal concentration (MFC) of 10PL-Se NPs against C. albicans was 26 ± 10 μg/mL. Crucially, bacteria exposed to ε-PL-Se NPs exhibited significantly delayed resistance development compared to the conventional antibiotic kanamycin. S. aureus developed resistance to kanamycin after ∼72 generations, whereas resistance to 10PL-Se NPs emerged after ∼216 generations. Remarkably, E. coli showed resistance to kanamycin after ∼39 generations but failed to develop resistance to 10PL-Se NPs even after 300 generations. This work highlights the synergistic interactions between ε-PL and Se NPs, offering a robust and scalable strategy to combat AMR.