Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues **

Abstract In recent years, extensive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. For example, cyanobacterial genomes contain a variety of gene clusters that likely incorporate fatty acid derived moieties, but for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products. Here, we exploit the apparent absence of a functional β‐oxidation pathway in cyanobacteria to achieve efficient stable‐isotope‐labeling of their fatty acid derived lipidome. We show that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains. The utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug‐resistance reverting hapalosin, and novel, cytotoxic, lactylate‐nocuolin A hybrids—the nocuolactylates.