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.