Virtually every animal on Earth interacts with bacteria. In many cases, over the course of ancient symbioses bacteria have evolved specific small molecule natural products to interact with their host organisms and with other competing microbes. These compounds can be exceptionally bioactive, and some are even FDA-approved agents for treating diseases such as cancers. The molecules presumably co-evolved with their molecular targets in many different animals, meaning that they are selected by evolution to have functional effects on animals. In turn, these effects can be exploited for the creation of new pharmaceuticals. These interactions are just beginning to be understood and represent a virtually untapped reservoir for discovering agents with potential to treat human diseases. Here, we will perform fundamental experiments on marine symbiotic systems, cultivate bacteria, and discover and develop bioactive small molecules. Our focus will be on molecules that affect competing bacteria (antibiotics) and the host organism (molecules that affect eukaryotic cells and might have use in neurology or oncology). We will take a rational, hypothesis-driven approach to understanding and exploiting symbiotic interactions. In this proposal, we will focus on associations between animals and bacteria in US coastal waters. There, we have found specific symbiotic bacteria that synthesize unexpectedly diverse new, bioactive compounds. We seek to understand these interactions while obtaining new compounds for further development as therapeutic agents.
Our aims are to: 1) Understand how natural products shape symbiotic interactions. We will focus on specific interactions between different phyla of marine invertebrates and their associated, cultivable bacteria. 2) Discover new natural products from cultivated bacteria. We will use a metabolomics approach to rapidly hone in on previously unknown natural products. These compounds have been proven so far to be exceptionally active and include new compounds with new carbon skeletons. We will focus on innovative antibiotic and neuroactivity assays available at University of Wisconsin and University of Utah. We will also develop libraries that can be more widely screened. 3) Develop natural products for application in treating human diseases. We will combine chemical and biotechnological approaches to assess the promise of newly discovered agents and to move them toward application. We will begin with a few lead compounds already discovered in our labs, then use the established pipeline for other agents discovered in this project.

Public Health Relevance

This project proposes innovations in the discovery of therapeutic agents from natural sources. The focus will be on targets that affect cell action potential, which include agents that might find use in cancers or neurological disorders, as well as on antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM107557-02S1
Application #
8906200
Study Section
Program Officer
Gerratana, Barbara
Project Start
2014-06-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$52,264
Indirect Cost
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
Lin, Zhenjian; Koch, Michael; Abdel Aziz, May Hamdy et al. (2014) Oxazinin A, a pseudodimeric natural product of mixed biosynthetic origin from a filamentous fungus. Org Lett 16:4774-7