Chemical Synthesis and Biological Activity of Analogues of the Lantibiotic Epilancin 15X

[Image: see text] Lantibiotics are a large family of antibacterial peptide natural products containing multiple post-translational modifications, including the thioether structures lanthionine and methyllanthionine. Efforts to probe structure–activity relationships and engineer improved pharmacological properties have driven the development of new methods to produce non-natural analogues of these compounds. In this study, solid-supported chemical synthesis was used to produce analogues of the potent lantibiotic epilancin 15X, in order to assess the importance of several N-terminal post-translational modifications for biological activity. Surprisingly, substitution of these moieties, including the unusual N-terminal d-lactyl moiety, resulted in relatively small changes in the antimicrobial activity and pore-forming ability of the peptides.