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A New Gramicidin S Analogue with Potent Antibacterial Activity and Negligible Hemolytic Toxicity.

Antibiotic resistance is an urgent threat to global health, with the decreasing efficacy of conventional drugs underscoring the urgency for innovative therapeutic strategies. Antimicrobial peptides present as promising alternatives to conventional antibiotics. Gramicidin S is one such naturally occurring antimicrobial peptide that is effective against Staphylococcus aureus , with a minimum inhibitory concentration (MIC) of 4 μg/mL (3.6 μM). Despite this potent activity, its significant hemolytic toxicity restricts its clinical use to topical applications. Herein, we present rational modifications to the key β-strand and β-turn regions of gramicidin S to concurrently mitigate hemolytic effects, while maintaining potency. Critically, peptide 9 displayed negligible hemolytic toxicity, while possessing significant antibacterial potency against a panel of methicillin-sensitive and methicillin-resistant S. aureus clinical isolates (MIC of 8 μg/mL, 7.2 μM). Given the substantial antibacterial activity and near absence of cytotoxicity, 9 presents as a potential candidate for systemic administration in the treatment of S. aureus bacteremia/sepsis.

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