Enhanced Gram-Negative Membrane Disruption and In Vivo Efficacy via Lysine-Arginine Enrichment of Opis16a

TY - JOUR

T1 - Enhanced Gram-Negative Membrane Disruption and In Vivo Efficacy via Lysine-Arginine Enrichment of Opis16a

AU - van der Walt, Mandelie

AU - Oosthhuizen, Carel

AU - Lorenz, Chris

AU - Serian, Miruna

AU - Mason, James

AU - Bester, Megan

AU - Gaspar, Anabella

N1 - Publisher Copyright: © 2025 The Authors. Published by American Chemical Society.

PY - 2025/6/12

Y1 - 2025/6/12

N2 - Infections complicate burn wound care, especially with the rise of antimicrobial resistance. Antimicrobial peptides (AMPs) offer the potential for advancing wound care by combating persistent infections. Opis16a, a scorpion venom-derived AMP, exhibits potent antibacterial activity by targeting Gram-negative membranes, causing rapid membrane disruption and bacterial cell death. Here, four novel Opis16a analogues were developed with improved membrane targeting and antibacterial efficacy. One analogue shows particular promise for topical application in Gram-negative burn wound infections. Enhanced peptide–lipid hydrogen bonding increases conformational stability, membrane insertion, and permeabilization rates. Substituting lysine residues in the C-terminal with arginine leads to the most consistent improvement in activity, selectivity for pathogen over HaCat cells, and stability in serum. In an in vivo Galleria mellonella burn wound model, a 5 mg/kg topical dose provides better protection than Opis16a against Enterobacter cloacae NICD 16103. These findings highlight the potential of optimized bactericidal AMPs to improve burn wound care.

AB - Infections complicate burn wound care, especially with the rise of antimicrobial resistance. Antimicrobial peptides (AMPs) offer the potential for advancing wound care by combating persistent infections. Opis16a, a scorpion venom-derived AMP, exhibits potent antibacterial activity by targeting Gram-negative membranes, causing rapid membrane disruption and bacterial cell death. Here, four novel Opis16a analogues were developed with improved membrane targeting and antibacterial efficacy. One analogue shows particular promise for topical application in Gram-negative burn wound infections. Enhanced peptide–lipid hydrogen bonding increases conformational stability, membrane insertion, and permeabilization rates. Substituting lysine residues in the C-terminal with arginine leads to the most consistent improvement in activity, selectivity for pathogen over HaCat cells, and stability in serum. In an in vivo Galleria mellonella burn wound model, a 5 mg/kg topical dose provides better protection than Opis16a against Enterobacter cloacae NICD 16103. These findings highlight the potential of optimized bactericidal AMPs to improve burn wound care.

UR - https://www.scopus.com/pages/publications/105004042143

U2 - 10.1021/acsmedchemlett.5c00038

DO - 10.1021/acsmedchemlett.5c00038

M3 - Article

SN - 1948-5875

VL - 16

SP - 998

EP - 1007

JO - Acs Medicinal Chemistry Letters

JF - Acs Medicinal Chemistry Letters

IS - 6

ER -