The broad, long term objective of the proposed studies is to design and engineer phosphonic acidbiosynthesis with the ultimate aim of developing a new framework for economical production of a widevariety of natural and unnatural natural products in Escherichia coli. Secondary metabolites - naturalproducts - produced by plants and microorganisms are a prolific source for pharmaceutical drugs. Recentadvances in molecular biology and genomics have revolutionized our ability to discover the biosyntheticpathways that synthesize natural products. However, since plants and microorganisms that produceinteresting natural products are often poorly characterized or even uncultivable, the ability to manipulate theirbiosynthetic pathways is rather limited. In addition, natural products have evolved for the purpose other thantreatment of human diseases. Although many natural products exhibit a diverse array of potent biologicalactivities, their therapeutic efficacy often needs to be improved by further diversifying the core structures.More importantly, many of the natural product based drugs are produced in minute amounts in their nativehosts, making the drugs very expensive. To address these issues, this proposal will use two importantphosphonic acid (fosfomycin and FR-900098) biosynthetic pathways as model systemsto develop newmethods and tools for economical biosynthesis of phosphonic acid antibiotics in E. coli. Such tools andmethods should be generally applicable to the economical biosynthesis of a wide variety of natural productsfor biomedical applications. Moreover, microbial overproduction of FR900098, a promising antimalarial drug,may provide sufficient amounts at a low price for use in malaria-afflicted regions in the world. Finally, as asynergistic component of the program project, all relevant enzymes from these two pathways as well asother phosphonic acid (phosphinothricin, A53868, plumbemycin, rhizocticin, and SF2312) pathways will beoverexpressed and purified for X-ray structural analysis by the Nair group. Some of them will also bebiochemically and mechanistically characterized by the Metcalf, van der Donk and Kelleher groups.
Showing the most recent 10 out of 119 publications
