A. Nikolai von Krusenseirn
53 - Exploring aryl-aryl bond formation in bacterial biosynthesis of natural products
Bacteria use enzymes to catalyze the formation of various pharmacologically relevant yet synthetically challenging structural moieties in their secondary metabolites. Aryl-aryl bonds are essential to the bioactivity of many naturally occurring antibiotics, such as vancomycin, actinorhodin, and chloroeremomycin, but reproducing these linkages in the laboratory requires numerous difficult steps and expensive, environmentally-taxing organometallic reagents. We seek to: (1) identify enzymes that catalyze aryl-aryl bond formation through a comparative analysis of gene cluster sequence and secondary metabolite structure, (2) characterize identified enzymes through in vitro biochemical assays, and (3) develop biocatalysts to create structural analogs and novel antibiotic compounds. This project focuses on complestatin, a vancomycin-type antibiotic which has been shown to inhibit HIV interaction with CD4 receptors. We explore the enzyme-catalyzed oxidations that form the two key aryl linkages in complestatin’s structure in order to better understand the biosynthetic pathway, as well as evaluate the enzymes’ potential to produce complestatin derivatives or hybrid antibiotics.