S108: Manipulating natural product expression in laboratory-cultured cyanobacteria

During their long evolutionary history, cyanobacteria have acquired complex traits such as filamentous growth, sheaths, nitrogen fixation, thermophily, and motility, permitting their colonization of diverse habitats.  Nitrogenous cyanobacterial metabolites frequently possess potent anti-proliferative properties and these molecules exhibit distinct metabolic themes including the integration of polyketide and nonribosomal peptide biosynthetic units, the incorporation of D and b amino acids, and a high degree of N- and O-methylation. Laboratory culture experiments using cyanobacteria from the Red Sea and Panama have provided insights into the composition, phylogeny, growth and natural product production in these microbial assemblages. Using phylogenetic and chemical characterization, we have determined that cyanobacteria from the Red Sea are closely related to various cyanobacteria collected pan-tropically. We have characterized the structures and relative cytotoxicities of new thiazoline-containing depsipeptides, including grassypeptolides, apratoxins and an unprecedented metal-binding cyclic depsipeptide, isolated from three laboratory-cultured Red Sea cyanobacteria. In addition, we have recently reported studies on the mechanism of cancer cell death induced by coibamide A, an N-methyl-stabilized lariat depsipeptide that displays an unprecedented selectivity profile in the National Cancer Institute cancer cell line panel. This cyanobacterial metabolite, isolated as part of the Panama ICBG program, induces morphologically distinct forms of cell death according to cell type and represents a natural product scaffold with potential for the study of mTOR-independent signaling and cell death mechanisms in apoptotic-resistant cancer cells. Its re-supply from laboratory-cultured cyanobacteria for in vivo anticancer studies is the subject of ongoing investigation.