Discovery of the Lipopeptides Albubactins A–H from Streptomyces albidoflavus RKJM0023 via Chemical Elicitation with Rhamnolipids and Synthesis of Albubactin A

Abstract

The marine tunicate-derived Streptomyces albidoflavus RKJM0023 was cultured in the presence of a rhamnolipid mixture in an effort to elicit the production of silent natural products. MS/MS-based molecular networking analysis enhanced with nonparametric statistics highlighted the upregulation of a molecular cluster (Kruskal−Wallis p = 1.6 e −6 for 1) in which no MS/MS features had library matches. Targeted isolation of these features resulted in the discovery of nine new N-acylated lipopeptides, albubactins A−H (1−8) each containing a unique glutamine tripeptide and a C-terminal ethyl ester moiety. Three related albubactin acids A−C (9−11) lacking the ethyl ester were also identified. NMR spectroscopy and UPLC-HR-ESI-MS/MS demonstrated that the albubactins were obtained as mixtures that shared a common m/z and differed only in their acylated terminal groups. Due to the complex spectroscopic elucidation with many overlapping shifts, a total synthesis of albubactin A (1) was completed and used to determine the absolute configuration of the new albubactins.