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.

中文翻译：

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含有脂肪酸残基的蓝藻天然产物的发现

天然产物在几种人类活动中具有重要作用，最显着的是作为新药的来源。近年来，细菌基因组的大规模测序和注释揭示了数量众多的次级代谢产物生物合成基因簇，其产物尚未发现。例如，蓝细菌基因组包含大量可能整合了脂肪酸衍生部分的基因簇，但是在大多数情况下，我们缺乏有效预测或检测编码天然产物的知识和工具。在这里，我们利用蓝细菌中明显缺乏功能性β氧化途径来实现其脂肪酸衍生脂质组的有效稳定同位素标记。我们表明，用氘代脂肪酸补充蓝细菌培养物可用于轻松检测单个菌株中的天然产物特征。该策略的实用性在两个培养的蓝细菌中得到了证明，方法是发现多药耐药性逆转hapalosin的类似物，以及新型，细胞毒性的乳酸酯-Nocuolin A杂种-乳酸菌酸酯。