The swinholide biosynthetic gene cluster from a terrestrial cyanobacterium Nostoc sp. UHCC 0450.

Swinholides are 42-carbon ring polyketides with a twofold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long-suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of the symbiotic heterotrophic proteobacterium. Here we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. UHCC 0450. We located the 85-kb trans -AT PKS swinholide gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthetic gene clusters share an almost identical order of catalytic domains, 85% nucleotide sequence identity and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthetic cluster from Anabaena sp. UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthetic clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans -AT PKSs of cyanobacteria and proteobacteria. Importance Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here we show that terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a twofold axis of symmetry and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthetic gene clusters of swinholide from Nostoc , as well as the related cytotoxic and antifungal scytophycin from Anabaena, and study the evolution of their trans -AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products.