Analogues of gramicidin S: A promising direction for future antibacterial drug development?

Gramicidin S (GS) is a potent cyclic decapeptide antibiotic produced by Bacillus brevis, exhibiting strong activity against Gram-positive bacteria and remaining in clinical use for the topical treatment of skin and throat infections. Despite its efficacy, GS's clinical application is restricted due to significant hemolytic toxicity associated with its membranolytic mechanism of action. This review summarizes over 80 years of structure–activity relationship (SAR) studies on GS and its analogues, highlighting key strategies to enhance antibacterial activity while reducing cytotoxicity. Particular focus is given to the influence of amino acid substitutions, stereochemistry, sequence modifications, and the incorporation of peptidomimetic fragments. Additionally, we discuss GS-based oligo- and polymers, as well as analogues with expanded or contracted macrocycles, emphasizing their effects on biological activity and conformational stability. Collectively, these insights underscore the value of GS as a resilient scaffold for next-generation antimicrobial peptide design with improved therapeutic indices and potency towards resistant pathogens.