Understanding the Role of Macrocycle Size and Amide Linkage in Teixobactin Analogues

Teixobactin is a promising antibiotic that targets cell wall biosynthesis in Gram-positive bacteria and displays a low propensity for resistance; however, its structural complexity presents challenges for analogue development and optimisation. In this study, we investigated the effects of macrocycle size and replacement of the native depsipeptide linkage with an amide bond on antibacterial activity using a simplified Leu10-teixobactin scaffold. An amide-based macrocyclisation strategy was developed for efficient lactam formation using readily accessible amino acid building blocks, avoiding reliance on synthetically demanding modified diamino acids employed in other approaches. Two complementary synthetic routes provided access to a series of ten analogues, comprising linear and macrocyclised variants with systematic variation at position 8. Antibacterial activity was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant clinical isolates. While linear analogues exhibited weak or no measurable antibacterial activity, macrocyclised analogues retained measurable antibacterial activity, indicating that macrocyclisation is essential within this scaffold, whereas moderate expansion of the macrocycle was tolerated. The structure–activity relationships identified here demonstrate the suitability of a simplified Leu10-teixobactin framework and provide a platform for further optimisation of teixobactin-inspired antibiotics.