Engineering Antioxidant-Enhanced Antimicrobial Peptides via n-Octanoic Acid and Cysteine Conjugation: Therapeutic Applications in Burn Injury

Abstract

Chronic wounds represent a major global health challenge, characterized by impaired healing, localized necrosis, and, in advanced stages, potential limb loss. The delayed healing process is multifactorial, involving the accumulation of exudate, microbial colonization, and immune dysfunction. Building upon our previous work with the broad-spectrum antimicrobial peptide LKAHR, this study introduces structural modifications via site-specific cysteine conjugation and alkyl chain functionalization. The mechanical properties of gelatin hydrogels were optimized through PEG cross-linking to improve drug delivery capabilities. Three modified antimicrobial peptides (AMPs) were systematically assessed for hemocompatibility, antimicrobial efficacy, and radical scavenging activity, with Cys2-LKAHR-C8 emerging as the top candidate. This optimized peptide demonstrated a 50% enhancement in antimicrobial efficacy compared to native LKAHR, along with potent free radical neutralization capacity. Mechanistically, it exerts hepatoprotective effects through glutathione-mimetic redox regulation. In translational validation, the PEG-gelatin hydrogel-mediated delivery of Cys2-LKAHR-C8 achieved 78% wound closure efficiency in chronic wounds, demonstrating sustained antimicrobial activity and improved tissue regeneration in burn infection models.