[1S05m] 13. Microbial Engineering for Natural Products Synthesis - Part 1

10:00 AM - 10:45 AM JST(1:00 AM - 1:45 AM UTC)

[1MENP-01-KL] Discovery and engineering of natural product molecules for drug development

○David Howard Sherman¹ (1. University of Michigan (USA))

Keywords:

Natural Products,Polyketide Synthases,Indole Alkaloids,C-H Functionalization,Drug Development

My talk will focus on various highlights from select research programs initiated and on-going over the past three decades. One project that has spanned this period relates to modular polyketide synthases, and our development of chemoenzymatic synthesis/cascade biocatalysis to generate new macrolide antibiotic molecules. Our work has probed the mechanisms, and engineering of key catalytic domains, and we have linked our ability to generate new molecules with antibiotic activity and ribosome inhibition. A second area of long-standing interest has focused on fungal derived indole alkaloids and assembly of complex multi-ring systems through two classes of enzymes that catalyze intramolecular Diels-Alder reactions. Late-stage C-H oxidation and halogenation has also featured as an important aspect of macrolides and indole alkaloids as the precise modification of their core molecules ultimately enables potent biological activity. More recently, we have developed new semi-synthetic natural product molecules to advance an anti-HIV Nef series of lead compounds that provide a potential path to eradicate the virus. Pathway engineering has been essential for strain optimization to assure a sustainable supply of the two plecomacrolide source materials. I will also highlight studies to identify the endosymbiont producer of ET-743, and current programs to characterize cyanobacterial bloom-derived metabolites in the Great Lakes. Finally, our field collection programs have resulted in a growing marine/terrestrial-derived microbial strain collection and pure natural products/extract library. Centered at the Life Sciences Institute Natural Product Discovery Core, we have benefitted from an institutional Biosciences Initiative that has grown our capabilities significantly, and highlights will be described.