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.
Depsipeptides are an important class of bioactive natural products, where a growing number of genome-mined structures that display anti-microbial activity are macrocyclic depsipeptides. Chemically, peptide ester (depsipeptide) bond formation often...
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