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