Emerimicins V-X, 15-Residue Peptaibols Discovered from anAcremoniumsp. Through Integrated Genomic and Chemical Approaches

Abstract

Fermentation ofAcremonium tubakiiW. Gams isolated from a soil sample collected from the University of Utah led to the isolation and characterization of six new linear pentadecapeptides, emerimicins V-X (1-6). Peptaibols containing 15-residues are quite rare, with only 22 reported. Genome mining and bioinformatic analysis were used to identify the emerimicin 60 kbpemebiosynthetic cluster harboring a single 16-module hybrid polyketide-nonribosomal peptide synthetase. A detailed bioinformatic investigation of the corresponding 15 adenylation domains, combined with 1D and 2D NMR experiments, LC-MS/MS data, and advanced Marfey’s method, allowed for the elucidation and absolute configuration of all proteinogenic and nonproteinogenic amino acid residues in1-6. As some peptaibols possess cytotoxic activity, a zebrafish embryotoxicity assay was used to evaluate the toxicity of the six emerimicins and showed that emerimicin V (1) and VI (2) exhibit the most potent activity. Additionally, out of the six emerimicins,1displayed modest activity againstEnterococcus faecalis, methicillin-resistant Staphylococcus aureus, and vancomycin-resistantEnterococcus faecium with MIC values of 64, 32, and 64 μg/mL, respectively.