Abstract

This subprogram's overall goal is discovering novel natural products that are active in oncology screens. The subprogram will maximize the likelihood of discovering novel natural products by focusing on endophytic fungi from unexplored ecological niches and uncultured soil microbes. The subprogram will also utilize DNA-based techniques for identifying productive sources. Active compounds will be isolated using bioassay-guided fractionation and structurally characterized by spectroscopic, crystallographic, and/or chemical techniques.
The specific aims are: 1. Provide prefractionated fungal extracts for screening in oncology assays. Endophytic fungi, 500 to 750 isolates/year, will be collected in Costa Rica, prioritized by growth characteristics, fermented using productive media and conditions, and extracted. The crude extracts will be prefractionated to provide fractions for screening at Wyeth and the Institute of Chemistry and Cell Biology in cancer relevant assays. Select endophytic fungal strains will be genotyped by 18S ribosomal-DNA sequencing to provide molecular taxonomy for these difficult to classify fungi. 2. Provide extracts from heterologous expression of environmental DNA for screening in oncology assays. Environmental DNA (eDNA) will be collected from a variety of microbial environments, cleaned up and size selected to prepare cosmid libraries. The libraries will initially be selected in E. coli, and probed with a variety of DNA probes based on known natural products synthetic modules by colony hybridization. Positive clones will be retransformed into appropriate hosts and fermented. Crude extracts?the DNA selection serves as a stringent prefractionation?will be supplied to oncology relevant assays. 3. Carry out refermentation, bioassay-guided fractionation, and structure determination of screening positives. Selected cultures, either fungal of microbial, will be refermented (if necessary), extracted and subjected to bioassay-guided fractionation. Compounds that continue to elicit interest in oncology screens will be structurally characterized by spectroscopic, crystallographic, and/or chemical techniques.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067786-13
Application #
7629962
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
13
Fiscal Year
2007
Total Cost
$614,470
Indirect Cost

  Institution

Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Dalisay, Doralyn S; Williams, David E; Wang, Xiao Ling et al. (2013) Marine sediment-derived Streptomyces bacteria from British Columbia, Canada are a promising microbiota resource for the discovery of antimicrobial natural products. PLoS One 8:e77078
Prasad, Pritesh; Aalbersberg, William; Feussner, Klaus-D et al. (2011) Papuamides E and F, Cytotoxic Depsipeptides from the Marine Sponge Melophlus sp. Tetrahedron 67:8529-8531
Williams, David E; Loganzo, Frank; Whitney, Lauren et al. (2011) Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity. Pharm Biol 49:296-301
Janso, Jeffrey E; Carter, Guy T (2010) Biosynthetic potential of phylogenetically unique endophytic actinomycetes from tropical plants. Appl Environ Microbiol 76:4377-86
Williams, David E; Yu, Ker; Behrisch, Hans W et al. (2009) Rolloamides A and B, cytotoxic cyclic heptapeptides isolated from the Caribbean marine sponge Eurypon laughlini. J Nat Prod 72:1253-7
Williams, David E; Hollander, Irwin; Feldberg, Larry et al. (2009) Scalarane-based sesterterpenoid RCE-protease inhibitors isolated from the Indonesian marine sponge Carteriospongia foliascens. J Nat Prod 72:1106-9
Whitson, Emily L; Bugni, Tim S; Chockalingam, Priya S et al. (2009) Fibrosterol sulfates from the Philippine sponge Lissodendoryx (Acanthodoryx) fibrosa: sterol dimers that inhibit PKCzeta. J Org Chem 74:5902-8
Roll, Deborah M; Barbieri, Laurel R; Bigelis, Ramunas et al. (2009) The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144. J Nat Prod 72:1944-8
Whitson, Emily L; Ratnayake, Anokha S; Bugni, Tim S et al. (2009) Isolation, structure elucidation, and synthesis of eudistomides A and B, lipopeptides from a Fijian ascidian Eudistoma sp. J Org Chem 74:1156-62
Bugni, Tim S; Harper, Mary Kay; McCulloch, Malcolm W B et al. (2008) Fractionated marine invertebrate extract libraries for drug discovery. Molecules 13:1372-83

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