The proposal aims to develop new approaches to natural products discovery. While much effort has been placed on designing drug-like synthetic screening libraries, limited efforts have been put forth to logically design natural product screening libraries in terms of improving novelty of hits and increasing drug-like or lead-like structures within the library. This project will evaluate logical natural product library design on the outcome of high-throughput screening, primarily in the areas of oncology and infectious disease. In particular, we will apply LCMS-based untargeted metabolomics to help guide library design. We will use metabolomics, genomics, transcriptomics, and proteomics to investigate interspecies interactions. Understanding the systems biology governing interspecies interactions and secondary metabolite production will uncover new mechanisms to activate cryptic clusters. The outcomes of this proposal will be: (i) a template for producing natural product libraries enriched in new/novel small molecules with drug-like properties;and (ii) a platform for rapidly determining organisms where interspecies interactions change secondary metabolite production.

Public Health Relevance

Historically, natural products have been the single best source of therapeutic leads, especially in the area of antibiotics. The marine environment is one of the most diverse habitats on Earth, and therefore should also harbor some the highest natural product diversity on the planet. Using innovative tools to access this diversity will directly impat human health by improving therapeutic discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM104192-02
Application #
8656138
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
Project Start
2013-05-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$254,536
Indirect Cost
$83,536
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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
Li, Qian; Xu, Yan-Shuang; Ellis, Gregory A et al. (2013) Total Syntheses of Proposed (±)-Trichodermatides B and C. Tetrahedron Lett 54: