Total Synthesis and Structure Assignment of the Relacidine Lipopeptide Antibiotics and Preparation of Analogues with Enhanced Stability

Al Ayed, Karol; Zamarbide Losada, Denise; Machushynets, Nataliia V.; Terlouw, Barbara; Elsayed, Somayah S.; Schill, Julian; Trebosc, Vincent; Pieren, Michel; Medema, Marnix H.; van Wezel, Gilles P.; Martin, Nathaniel I.


The unabated rise of antibiotic resistance has raised the specter of a post-antibiotic era and underscored the importance of developing new classes of antibiotics. The relacidines are a recently discovered group of nonribosomal lipopeptide antibiotics that show promising activity against Gram-negative pathogens and share structural similarities with brevicidine and laterocidine. While the first reports of the relacidines indicated that they possess a C-terminal five-amino acid macrolactone, an N-terminal lipid tail, and an overall positive charge, no stereochemical configuration was assigned, thereby precluding a full structure determination. To address this issue, we here report a bioinformatics guided total synthesis of relacidine A and B and show that the authentic natural products match our predicted and synthesized structures. Following on this, we also synthesized an analogue of relacidine A wherein the ester linkage of the macrolactone was replaced by the corresponding amide. This analogue was found to possess enhanced hydrolytic stability while maintaining the antibacterial activity of the natural product in both in vitro and in vivo efficacy studies.