Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from the natural source and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds, contributing to the raising costs and reduced number of new drug molecules. The development of scalable manufacturing platforms for natural product synthesis will address many challenges faced between natural product drug discovery and therapeutic application. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. However, current approaches in metabolic pathway engineering require a significant investment in time and resources and do not scale with the complexity and breadth represented in natural product biosynthesis pathways. As such, for many natural products of interest, microbial biosynthesis strategies are currently viewed as impossible. The goal of the proposed project is to develop synthetic biology platforms that will dramatically advance the application of cellular biosynthesis strategies to natural product drug discovery, development, and production. The scale and efficiency of manufacturing processes that can be engineered into microbial systems will be transformed through the development of new approaches that will enable the implementation of key biosynthesis process optimization strategies. In particular, the project will pioneer and apply the following approaches: (i) noninvasive and real-time detection of metabolite levels, (ii) closed loop embedded control of biosynthesis system behavior, (iii) active organelle routing supporting biosynthesis specialization and compartmentalization;and (iv) high- throughput screening methods for discovery of new biosynthetic activities within a microbial chassis. The power of these new approaches will be demonst

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1AT007886-02
Application #
8543644
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Hopp, Craig
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$761,450
Indirect Cost
$276,450
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Thodey, Kate; Galanie, Stephanie; Smolke, Christina D (2014) A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat Chem Biol 10:837-44
Siddiqui, Michael S; Choksi, Atri; Smolke, Christina D (2014) A system for multilocus chromosomal integration and transformation-free selection marker rescue. FEMS Yeast Res 14:1171-85
Galanie, Stephanie; Siddiqui, Michael S; Smolke, Christina D (2013) Molecular tools for chemical biotechnology. Curr Opin Biotechnol 24:1000-9
Wang, Yen-Hsiang; Wei, Kathy Y; Smolke, Christina D (2013) Synthetic biology: advancing the design of diverse genetic systems. Annu Rev Chem Biomol Eng 4:69-102