Azetidine-Bearing Non-Ribosomal Peptides, Bonnevillamides D and E, Isolated from a Carrion Beetle-Associated Actinomycete

Abstract

Two new nonribosomal peptides, bonnevillamides D and E (<b>1</b> and <b>2</b>), have been discovered in <i>Streptomyces</i> sp. UTZ13 isolated from the carrion beetle, <i>Nicrophorus concolor</i>. Combinational analysis of the UV, MS, and NMR spectroscopic data revealed that their planar structures were comprised of dichlorinated linear peptides containing nonproteinogenic amino acid residues, such as 4-methylazetidinecarboxylic acid and 4-<i>O</i>-acetyl-5-methylproline. The configurations of bonnevillamides D and E (<b>1</b> and <b>2</b>) were determined based on ROESY correlations, the advanced Marfey's method, phenylglycine methyl ester derivatization, molecular modeling, and circular dichroism spectroscopy. The nonribosomal peptide synthetase biosynthetic pathway of bonnevillamides D and E has been proposed using bioinformatic analysis of the whole-genome sequence data of <i>Streptomyces</i> sp. UTZ13. Their biological activity toward the aggregation of amyloid-β, which is one of the key pathogenic proteins in Alzheimer's disease, was evaluated using a thioflavin T assay and gel electrophoresis. Bonnevillamides D and E reversed the fibril formation by inducing the monomerization of amyloid-β aggregates.