Marine natural products offer an astounding source of biomolecules that can be potentially utilized for the treatment of various diseases. For instance, ET-743 (Yondelis), a tetrahydroisoquinoline recently approved by FDA for chemotherapy of advanced or metastatic soft tissue sarcoma due to its potent anti-cancer activity, has been isolated from tunicate Ecteinascidia turbinate. Recent metagenomic studies suggest that a bacterial endosymbiont of the tunicate Candidatus Endoecteinascidia frumentensis is the original producer of this molecule. ET-743 is currently synthesized through a lengthy and costly semi-synthetic process starting from a fermentation-derived intermediate and requiring 17 steps of chemical reactions.
Towards creating a sustainable and economical source for ET-743, we will employ a multifaceted approach to study the biosynthesis pathway in its native host through microfluidic cultivation and to engineer refactored pathways in recombinant producing bacterium.