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 .