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A structurally novel metabolite, fatuamide A ( 1 ), was discovered from a laboratory cultured strain of the marine cyanobacterium Leptolyngbya sp., collected from Faga'itua Bay, American Samoa. A bioassay-guided approach using NCI-H460 human lung cancer cells directed the isolation of fatuamide A, which was obtained from the most cytotoxic fraction. The planar structure of fatuamide A was elucidated by integrated NMR and MS/MS analysis, and a combination of bioinformatic and computational approaches was used to deduce the absolute configuration at its eight stereocenters. A putative hybrid PKS/NRPS biosynthetic gene cluster responsible for fatuamide A production was identified from the sequenced genomic DNA of the cultured cyanobacterium. The biosynthetic gene cluster possessed elements that suggested fatuamide A binds metals, and this metallophore property was demonstrated by native metabolomics and indicated a preference for binding copper. The producing strain was found to be highly resistant to toxicity from elevated copper concentrations in culture media.

Genome mining of Paraneptunicella aestuarii NBU2194 resulted in the identification of a family of 17-membered macrolides, neptunizhulides A-F. Their structures were elucidated by comprehensive spectroscopic data analysis. Stereochemical assignments of the neptunizhulides were determined by J -based configuration analysis, ROESY NMR, Mosher's ester derivatization, and bioinformatic predictions. Bioinformatic analysis and a 15 N-serine labeling experiment resulted in the identification of a putative trans -acyltransferase polyketide synthase ( trans -AT PKS) biosynthetic gene cluster, and a biosynthetic pathway is proposed.