Unnatural Amino-Acid-Based Star-Shaped Poly(l-Ornithine)s as Emerging Long-Term and Biofilm-Disrupting Antimicrobial Peptides to Treat Pseudomonas aeruginosa-Infected Burn Wounds.

Abstract

Peptide-based antimicrobial materials are recognized as promising alternatives to antibiotics to circumvent the emergence of antibiotic-resistant bacteria or to combat multiple resistant bacteria by targeting the bacterial cell membrane. The components and conformations of antimicrobial peptides are extensively explored to achieve broad-spectrum and effective antimicrobial activity. Here, star-shaped antimicrobial polypeptides are fabricated by employing homologs of poly(l-lysine)s (i.e., poly(l-ornithine)s, poly(l-lysine)s, and poly(l-α,ζ-diaminoheptylic acid)s) with the aim of modulating their charge/hydrophobicity balance and rationalizing their structure-antimicrobial property relationships. The in vitro antibacterial investigation reveals that unnatural amino-acid-based star-shaped poly(l-ornithine)s have remarkable proteolytic stability, excellent biofilm-disrupting capacity, and broad-spectrum antimicrobial activity, even against difficult-to-kill Gram-negative Pseudomonas aeruginosa. Furthermore, star-shaped poly(l-ornithine)s significantly reduce the microbial burden and improve the burn wound healing of mouse skin infected with P. aeruginosa. These results demonstrate that unnatural amino-acid-based star-shaped poly(l-ornithine)s can serve as emerging long-term and biofilm-disrupting antimicrobial agents to treat biofilm-related infections in burn, especially caused by notorious P. aeruginosa.