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 (1 and 2), have been discovered in Streptomyces sp. UTZ13 isolated from the carrion beetle, Nicrophorus concolor. 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 4methylazetidinecarboxylic acid and 4-O-acetyl-5-methylproline. The configurations of bonnevillamides D and E (1 and 2) 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 Streptomyces 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.

Streptocinnamides A and B, Depsipeptides from Streptomyces sp. KMM 9044

“…A rare amino acid, N -hydroxy-valine (N-OHVal 5 ), was previously found in some marine antibiotics. , We also identified it in 1 and 2 by NMR and MS/MS (ESI), and this conclusion was confirmed by the reductive treatment of 1 with TiCl 3 to convert an N -OH group to an N -H group . This conversion was supported by the (−)­HRMS (ESI) spectrum, which showed the ion peak at [M – H] − calcd for [C 52 H 73 N 7 O 17 Cl 3 ] − m / z 1172.4134, found m / z 1172.4123.…”

Antibiotics from Insect-Associated Actinobacteria

“…Using the above-mentioned criteria and methodology, we identified 71 research papers from 2016 [ 26 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , ...…”

Biosyntheses of azetidine-containing natural products

“…Bonnevillamides A–C show a marked effect on heart development and cardiac function for zebrafish embryonic development, while bonnevillamides D and E inhibit fibril formation as well as pathogenic aggregation of amyloid-β peptides, representing a potential candidate for Alzheimer's disease. 29,30…”

“…Notably, the bnv cluster also encodes a putative class I SAM-dependent methyltransferase (BnvI) and a cobalamin-dependent radical SAM enzyme (BnvC), which are presumed for the biosynthesis of cis -MAZ from SAM, akin to the VioH and VioG involved in the biogenesis of trans -MAZ in vioprolides. 30 It is noteworthy that the biosynthesis of bonnevillamides is still ill-understood at the moment, and more work needs to be done to clarify this proposed biosynthetic pathway.…”