article · Journal of the American Chemical Society
Marine cyanobacteria produce specialised molecules called metallophores to capture trace metals and shield cells from metal toxicity. Researchers identified three structurally novel metallophores, named leptochelins A to C, from geographically dispersed strains of the marine cyanobacterial genus Leptothoe. These halogenated hybrid natural products coordinate with metal ions through multiple heterocyclic rings. Genomic sequencing of the producing strains revealed a shared, highly homologous biosynthetic gene cluster corresponding to the compounds. Chemical analyses demonstrated that leptochelins bind several metals, including iron, copper, cobalt, and zinc, exhibiting the strongest preference for copper. Laboratory tests indicate these molecules assist in iron uptake and mitigate copper toxicity in ecological settings. In addition to their environmental functions, the leptochelins demonstrated significant cytotoxicity when evaluated against multiple cancer cell lines.
Metals are essential nutrients for living cells, but excessive concentrations can prove lethal. Uncovering the chemical structures organisms use to manage metal intake deepens knowledge of microbial survival in marine habitats. The discovery that these same metal-binding molecules can kill cancer cells in laboratory models also provides basic researchers with new chemical frameworks that bridge environmental biology and drug discovery.
The cytotoxic effects of leptochelins against cancer cell lines point to potential early-stage leads for oncology drug discovery programmes. Additionally, their metal-binding capabilities could interest developers working on chemical chelators. Because the research remains at the stage of laboratory discovery, structural elucidation, and preliminary in vitro screening, any commercial application is at an early stage and requires extensive further biological evaluation.
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Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus <i>Leptothoe</i>. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three <i>Leptothoe</i> strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.
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DOI: 10.1021/jacs.4c05399
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