Decoding Lusichelins A-E: An In-Depth Look at the Metallophores of 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 (-), new metallophores isolated from the marine cyanobacterium LEGE 07167. Their structures and configurational assignments were determined by using NMR, mass spectrometry, TD-DFT calculations, and retrobiosynthetic insights. Lusichelins feature a unique structural arrangement with thiazoline/thiazole rings connected via a vinyl group, an aliphatic carbon chain, or directly enabling the potential for metal coordination. Genomic analysis identified a hybrid PKS/NRPS biosynthetic gene cluster consistent with the lusichelin structure, bearing traits characteristic of metallophore biosynthesis. Functionally, lusichelins act as metallophores capable of chelating both iron and copper. Lusichelin C () consistently bound iron under both metal-rich and metal-limited culture conditions, while copper complexation was only observed under elevated copper levels. At physiologically relevant pH values, no significant metal-binding preference was detected. Moreover, compound production was maximized under metal-rich conditions and in response to copper limitation. Lusichelin B () exhibited cytotoxicity against colon carcinoma cells while reversing multidrug resistance via ABCB1 efflux pump modulation. These findings expand our understanding of cyanobacterial metallophores in microbial metal homeostasis and highlight their biological potential.