Synthetic Studies towards the Calcium-Dependent Lipopeptide Antibiotic Cadaside B

In the current global crisis of antimicrobial resistance, antimicrobial peptides represent a promising source of alternative antibiotics. Recently discovered cadaside B, a novel calcium-dependent antibiotic, exhibits potent antimicrobial activity towards Gram-positive pathogens including multi-drug resistant strains. These properties, coupled with a novel structure, non-cytotoxicity, and low likelihood of developing resistance render cadaside B an important synthetic target. Herein, a synthetic strategy towards cadaside B is reported with the key steps involving on-resin depsipeptide bond formation and solution-phase macrolactamization. Good agreement of the synthetic cadaside B MS/MS fragmentation pattern was observed with the natural product, but a different ¹H NMR spectrum and absence of antimicrobial activity suggest an undetected epimerization event took place during the synthesis. Herein the findings of our synthetic journey and suggestions for future directions are presented.