Gramicidin S analogues as a pathway to overcome antimicrobial resistance

The growing occurrence of antimicrobial resistance represents a major challenge to global healthcare and necessitates the development of novel therapeutic agents capable of overcoming multidrug-resistant (MDR) pathogens. Gramicidin S (GS), a cyclic decapeptide antibiotic has attracted renewed interest as a promising template for next-generation antimicrobial therapeutics. Its primary mechanism of action involves disruption of bacterial membranes, resulting in rapid bactericidal activity and a low propensity for resistance development. This review summarizes current knowledge on the activity of GS and its analogues against clinically relevant MDR bacteria. Despite antibiotic's long history of clinical use, resistance to GS remains limited. However, its broader therapeutic application is constrained by cytotoxicity, which has driven extensive efforts toward structural optimization. We discuss recent advances in the design of GS analogues, highlighting key structure-activity relationships involving cationic charge, hydrophobicity, amphipathicity and conformational flexibility. Strategies such as β-turn modification, incorporation of non-proteinogenic amino acids and machine learning-guided design have yielded derivatives with improved selectivity and reduced toxicity. These findings underscore the potential of GS as a versatile platform for developing novel peptide antibiotics to combat antimicrobial resistance.