The Total Chemical Synthesis and Biological Evaluation of the Cationic Antimicrobial Peptides, Laterocidine and Brevicidine

Abstract

Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from Brevibacillus laterosporus through a global genome-mining approach. Both laterocidine and brevicidine exhibit potent antimicrobial activity toward Gram-negative bacteria, including difficult-to-treat Pseudonomas aeruginosa and colistin-resistant Escherichia coli, and a low risk of resistance development. Herein, we report the first total syntheses of laterocidine and brevicidine via an efficient and high-yielding combination of solid-phase synthesis and solution-phase macrolactamization. The crucial depsipeptide bond of the macrolactone rings of laterocidine and brevicidine was established on-resin between the side-chain hydroxy group of Thr⁹ with Alloc-Gly-OH or Alloc-Ser(tBu)-OH, respectively. A conserved glycine residue within the lactone macrocycle is exploited for the initial immobilization onto the hyper acid-labile 2-chlorotrityl chloride resin, subsequently enabling an efficient solution-phase macrocyclization to yield laterocidine and brevicidine in 36% and 10% overall yields, respectively (with respect to resin loading). A biological evaluation against both Gram-positive and Gram-negative bacteria demonstrated that synthetic laterocidine and brevicidine possessed a potent and selective antimicrobial activity toward Gram-negative bacteria, in accordance with the isolated compounds.