A significant limitation in natural product drug discovery is the inability to effectively convert sequence information to new compounds in a rapid and high throughput fashion. The long-term objective of this project is to systematically address this issue with the goal of re-establishing the once vibrant pipeline of environmentally-derived natural compounds, with a special emphasis on discovering new antibiotics. The final vision is the development of a microfluidics biosynthetic platform capable of generality, speed, throughput, and economy in natural product pathway reconstitution and compound discovery. The goal of the current R21 application is captured in the following specific aim: To generate the complex natural product antibiotic erythromycin A using cell-free biosynthesis. By doing so, precedent will be set for the ability to produce such compounds using a purely in vitro approach. This and additional preliminary data collected through the proposed work will then be the basis for continual research towards a cell-free biosynthetic platform capable of precise engineering and ultra-high throughput. As a result, the platform will allow unprecedented access to the broadest range of new chemical entities, including novel antibiotic compounds, while being unencumbered by the constraints of a cellular host.

Public Health Relevance

The proposal is designed to establish the initial steps (cell-free complex natural product biosynthesis) to expand access to new environmentally-encoded compounds at an unprecedented rate and throughput. Long- term success will provide new antibiotics in a more efficient, economical, rapid, and effective manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI126367-01A1
Application #
9317105
Study Section
Special Emphasis Panel (ZRG1-IDM-T (82)S)
Program Officer
Xu, Zuoyu
Project Start
2017-01-15
Project End
2018-12-31
Budget Start
2017-01-15
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$249,305
Indirect Cost
$58,192
Name
State University of New York at Buffalo
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Fang, Lei; Guell, Marc; Church, George M et al. (2018) Heterologous erythromycin production across strain and plasmid construction. Biotechnol Prog 34:271-276
Fang, Lei; Zhang, Guojian; El-Halfawy, Omar et al. (2018) Broadened glycosylation patterning of heterologously produced erythromycin. Biotechnol Bioeng 115:2771-2777