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submitted on 16.10.2020 and posted on 16.10.2020by Sandra A. C. Figueiredo, Marco Preto, Gabriela Moreira, Teresa P. Martins, Kathleen Abt, André Melo, Vitor M. Vasconcelos, Pedro Leao
Natural products have an important role in several human activities, most notably as sources of new drugs. In recent years, massive 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 large number 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 lack of a functional beta-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.