NMR-Metabolomic Profiling and Genome Mining Drive the Discovery of Cyclic Decapeptides from a Marine Streptomyces .

The integration of NMR-metabolomic and genomic analyses can provide enhanced identification of structural properties as well as key biosynthetic information, thus achieving the targeted discovery of new natural products. For this purpose, NMR-based metabolomic profiling of the marine-derived sp. S063 (CGMCC 14582) was performed, by which -methylated peptides possessing unusual negative H NMR chemical shift values were tracked. Meanwhile, genome mining of this strain revealed the presence of an unknown NRPS gene cluster () with piperazic-acid-encoding genes ( and ). Under the guidance of the combined information, two cyclic decapeptides, lenziamides D1 () and B1 (), were isolated from sp. S063, which contains piperazic acids with negative H NMR values. The structures of and were determined by extensive spectroscopic analysis combined with Marfey's method and ECD calculations. Furthermore, we provided a detailed model of lenziamide ( and ) biosynthesis in sp. S063. In the cytotoxicity evaluation, and showed moderate growth inhibition against the human cancer cells HEL, H1975, H1299, and drug-resistant A549-taxol with IC values of 8-24 μM.