Shared PKS modules in biosynthesis of synergistic laxaphycins

Bacteria produce a wide range of lipopeptides that exhibit membrane-disrupting activities. Laxaphycins are structurally distinct macrocyclic lipopeptides that act together to produce synergistic antifungal and antiproliferative activities. Laxaphycins are produced by range of cyanobacteria but their biosynthetic origins remain unclear. Here we identify the biosynthetic pathways responsible for the biosynthesis of the laxaphycins produced by Scytonema hofmannii PCC 7110. We show that these laxaphycins, called scytocyclamides, are produced by this cyanobacterium and are encoded in a single biosynthetic gene cluster with shared polyketide synthase enzymes initiating two distinct non-ribosomal peptide synthetase pathways. To our knowledge, laxaphycins are the first clearly distinct polyketide synthase and non-ribosomal peptide synthetase hybrid natural products with shared branched biosynthesis. The unusual mechanism of shared enzymes synthetizing two distinct types of products may help future research on identifying and expressing natural product biosynthetic pathways and expands the known biosynthetic logic of this important family of natural products.