The antitumor compound psymberin as a model to develop heterologous expression systems for polyketides from uncultivated sponge symbionts

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There is increasing evidence that many bioactive natural products isolated from marine sponges are synthesized by as-yet unculturable bacterial symbionts. However, the elusive lifestyle of these microbes has so far precluded the systematic exploration of their chemical and pharmacological potential. Our group has recently developed a suite of metagenomic techniques that demonstrated for the first time a bacterial origin for sponge-derived polyketides by providing access to the biosynthetic genes. Goal of the proposed work is to develop bacterial expression systems for symbiont genes that can be used to generate sustainable production sources of rare marine natural products. The model compound for these studies will be psymberin, a potent inhibitor of solid tumors isolated from the sponge Psammocinia aff. bulbosa. Using various preselected host strains, gene transfer systems and promoters, expression will be assessed at the transcriptional, translational and metabolic level to produce psymberin intermediates and ultimately the authentic natural product. This work is expected to provide fundamental insights into how renewable sources for complex metabolites can be created that are assembled by poorly studied biosynthetic enzymes of unusual organisms.