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

Mandelie van der Walt; Carel Oosthhuizen; Chris Lorenz; Miruna Serian; James Mason; Megan Bester; Anabella Gaspar

doi:10.1021/acsmedchemlett.5c00038

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

Mandelie van der Walt, Carel Oosthhuizen, Chris Lorenz, Miruna Serian, James Mason, Megan Bester, Anabella Gaspar^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	998-1007
Number of pages	10
Journal	Acs Medicinal Chemistry Letters
Volume	16
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.5c00038
Publication status	Published - 1 May 2025

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

abstract = "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.",

author = "{van der Walt}, Mandelie and Carel Oosthhuizen and Chris Lorenz and Miruna Serian and James Mason and Megan Bester and Anabella Gaspar",

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AU - van der Walt, Mandelie

AU - Oosthhuizen, Carel

AU - Lorenz, Chris

AU - Serian, Miruna

AU - Mason, James

AU - Bester, Megan

AU - Gaspar, Anabella

PY - 2025/5/1

Y1 - 2025/5/1

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.

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

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