Genome Mining Leads to the Discovery of Kasichelins A–D, Unusual β-Alanine- and β-Aminoisobutyric Acid-Containing Siderophores from Streptomyces

Genome mining of a Streptomyces strain collected in Tanzania revealed its potential to produce a novel siderophore. Heterologous expression of the corresponding biosynthetic gene cluster (BGC) in S. coelicolor M512 resulted in the production of kasichelin A, a new metal-chelating molecule featuring a phenolate oxazoline and a hydroxamate moiety as iron-binding ligands connected via a β-aminoisobutyric acid (BAIBA) linker. Further analysis of the heterologous producer and subsequent optimization of the culture conditions for the wild-type strain led to the isolation of three additional congeners, kasichelins B, C, and D. Marfey’s analysis of kasichelin C, the most abundant congener, established its absolute configuration as 2R,7R,10S,11R. Notably, kasichelin C was found to be identical to L-654,040, a partially characterized compound previously described in the patent literature. The iron-binding properties of the kasichelins were evaluated using the chrome azurol S (CAS) assay, UV/vis spectroscopy, and electrospray ionization-mass spectrometry (ESI-MS). All four kasichelins exhibit comparable iron(III)-binding affinities and surpass deferoxamine in their ability to sequester the metal, despite natural variations in their ligands and linker structures. The biosynthetic origin of the unusual BAIBA moiety presents an intriguing direction for future research.