The majority of pharmaceuticals are derived from natural products either directly or indirectly. However, the pipeline to new natural products has been drying up over the last decades as the technologies became less amenable to high- throughput screening and as finding new natural products became increasingly difficult. Substantial progress has been made in these areas by numerous labs, but there are still gaps in technology and in basic understanding of natural product sources. In this project, we will provide new methods and data to help fill these remaining gaps. In addition, we will build natural product compound libraries for screening at NIH and at the University of Wisconsin. The new methods include more rapid, automated, and integrated techniques for extraction, purification, and dereplication of natural products. Basic studies of natural product sources using marine symbiotic bacteria are aimed at answering questions about the most fruitful places to find new natural product producers and about methods to obtain these promising bacteria. These biological and chemical studies are synergistic and will provide the first large, ordered set of data linking cultivated symbiotic bacteria to chemistry in whole animals. The resulting methods are designed to be widely useful in multiple labs and to help in the development of broadly shared platforms for dereplication. The resulting libraries of natural products will be used in a variety of screens at established, high-throughput centers at NIH and U. Wisconsin. We will pursue promising leads as potential new pharmaceuticals.

Public Health Relevance

We will develop new methods for the rapid discovery of bioactive natural products and provide new data about sources of natural products that enable drug discovery. We will also provide libraries of natural products for screening. These results will have a large impact on natural products sciences because of new methods and knowledge. The human health impact will result from these new methods and potentially from new therapeutic small molecules discovered in the course of the project.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092009-03
Application #
8269071
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (50))
Program Officer
Lees, Robert G
Project Start
2010-08-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$368,775
Indirect Cost
$61,256
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Tianero, Ma Diarey B; Kwan, Jason C; Wyche, Thomas P et al. (2015) Species specificity of symbiosis and secondary metabolism in ascidians. ISME J 9:615-28
Kwan, Jason C; Tianero, Ma Diarey B; Donia, Mohamed S et al. (2014) Host control of symbiont natural product chemistry in cryptic populations of the tunicate Lissoclinum patella. PLoS One 9:e95850
Ellis, Gregory A; Wyche, Thomas P; Fry, Charles G et al. (2014) Solwaric acids A and B, antibacterial aromatic acids from a marine Solwaraspora sp. Mar Drugs 12:1013-22
Wyche, Thomas P; Piotrowski, Jeff S; Hou, Yanpeng et al. (2014) Forazoline?A: marine-derived polyketide with antifungal in?vivo efficacy. Angew Chem Int Ed Engl 53:11583-6
Wyche, Thomas P; Standiford, Miranda; Hou, Yanpeng et al. (2013) Activation of the nuclear factor E2-related factor 2 pathway by novel natural products halomadurones A-D and a synthetic analogue. Mar Drugs 11:5089-99
McIntosh, John A; Lin, Zhenjian; Tianero, Ma Diarey B et al. (2013) Aestuaramides, a natural library of cyanobactin cyclic peptides resulting from isoprene-derived Claisen rearrangements. ACS Chem Biol 8:877-83
Hou, Yanpeng; Braun, Doug R; Michel, Cole R et al. (2012) Microbial strain prioritization using metabolomics tools for the discovery of natural products. Anal Chem 84:4277-83
Adnani, Navid; Michel, Cole R; Bugni, Tim S (2012) Universal quantification of structurally diverse natural products using an evaporative light scattering detector. J Nat Prod 75:802-6
Wyche, Thomas P; Hou, Yanpeng; Vazquez-Rivera, Emmanuel et al. (2012) Peptidolipins B-F, antibacterial lipopeptides from an ascidian-derived Nocardia sp. J Nat Prod 75:735-40
Wyche, Thomas P; Hou, Yanpeng; Braun, Doug et al. (2011) First natural analogs of the cytotoxic thiodepsipeptide thiocoraline A from a marine Verrucosispora sp. J Org Chem 76:6542-7