Decoding Lusichelins A-E: An In-Depth Look at the Metallophores of Lusitaniella coriacea LEGE 07167 – Structure, Production, and Functionality

Essential trace metals are vital for cellular processes such as respiration, DNA replication, and photosynthesis. Cyanobacteria must tightly regulate metal homeostasis to prevent deficiency or toxicity, yet their metallophores remain overlooked. Here, we report lusichelins A-E (1-5), new metallophores isolated from the marine cyanobacterium Lusitaniella coriacea LEGE 07167. Their structures and configurational assignments were determined using NMR, mass spectrometry, TD-DFT calculations, and retrobiosynthetic insights. Lusichelins feature a unique structural arrangement with thiazoline/thiazole rings connected by a vinyl group, an aliphatic carbon chain, or directly, enabling potential for hexadentate metal coordination. Genomic analysis identified a hybrid PKS/NRPS biosynthetic gene cluster consistent with the structure of lusichelins and bearing traits characterisitic of metallophore biosynthesis. Notably, lusichelin production was influenced by salt composition in the culture medium rather than iron availability, suggesting an atypical regulatory mechanism. Functionally, lusichelins acted as copper detoxifiers, and lusichelin B (2) exhibited cytotoxicity against colon carcinoma cells while reversing multidrug resistance via ABCB1 efflux pump modulation. These findings expand the understanding of cyanobacterial metallophores in microbial metal homeostatis and highlight their potential in biological applications