Abstract

The study of biologically active natural products has been a very effective gateway to the identification of compounds with unique cellular targets that have been useful both as therapeutics and, more recently in the emerging field of chemical genetics, as modulators of complex biological systems. One of the key revelations to come from molecular phylogenetic analyses of environmental samples is that only a small fraction of bacteria present in the environment is easily cultured. Traditional approaches used for the discovery of new natural products are therefore unlikely to provide access to the vast majority of natural products that exist in nature. Soil microbes that have not yet been cultured and as a result have not been examined for the production of useful natural products outnumber their cultured counterparts by at least two to three orders of magnitude. Using PCR with degenerate primers based on conserved regions in genes known to be involved in the biosynthesis of natural products and high throughput sequencing we are proposing to screen cosmid libraries of DNA extracted directly from soil for biosynthetic pathways that encode the production of new natural products. Heterologous expression will then be used to access the molecules encoded by these new gene clusters and the resulting molecules screened for biological activity in a variety of human disease related screens. Relevance: Natural products, naturally derived small organic compounds, have traditionally been one of the major sources of FDA approved therapeutics. Uncultured bacteria are one of the largest remaining pools of genetic diversity that have not yet been examined for the production of secondary metabolites. The development of methods to functionally access the previously inaccessible natural products produced by uncultured bacteria should significantly increase the number and diversity of natural products that are available to test as probes of biological processes and therapeutic agents. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM077516-01
Application #
7085064
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Jones, Warren
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$299,091
Indirect Cost

  Institution

Name
Rockefeller University
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Charlop-Powers, Zachary; Brady, Sean F (2015) phylogeo: an R package for geographic analysis and visualization of microbiome data. Bioinformatics 31:2909-11
Montiel, Daniel; Kang, Hahk-Soo; Chang, Fang-Yuan et al. (2015) Yeast homologous recombination-based promoter engineering for the activation of silent natural product biosynthetic gene clusters. Proc Natl Acad Sci U S A 112:8953-8
Chang, Fang-Yuan; Ternei, Melinda A; Calle, Paula Y et al. (2015) Targeted metagenomics: finding rare tryptophan dimer natural products in the environment. J Am Chem Soc 137:6044-52
Cohen, Louis J; Kang, Hahk-Soo; Chu, John et al. (2015) Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. Proc Natl Acad Sci U S A 112:E4825-34
Owen, Jeremy G; Charlop-Powers, Zachary; Smith, Alexandra G et al. (2015) Multiplexed metagenome mining using short DNA sequence tags facilitates targeted discovery of epoxyketone proteasome inhibitors. Proc Natl Acad Sci U S A 112:4221-6
Charlop-Powers, Zachary; Owen, Jeremy G; Reddy, Boojala Vijay B et al. (2015) Global biogeographic sampling of bacterial secondary metabolism. Elife 4:e05048
Chang, Fang-Yuan; Brady, Sean F (2014) Characterization of an environmental DNA-derived gene cluster that encodes the bisindolylmaleimide methylarcyriarubin. Chembiochem 15:815-21
Reddy, Boojala Vijay B; Milshteyn, Aleksandr; Charlop-Powers, Zachary et al. (2014) eSNaPD: a versatile, web-based bioinformatics platform for surveying and mining natural product biosynthetic diversity from metagenomes. Chem Biol 21:1023-33
Biggins, John B; Kang, Hahk-Soo; Ternei, Melinda A et al. (2014) The chemical arsenal of Burkholderia pseudomallei is essential for pathogenicity. J Am Chem Soc 136:9484-90
Charlop-Powers, Zachary; Owen, Jeremy G; Reddy, Boojala Vijay B et al. (2014) Chemical-biogeographic survey of secondary metabolism in soil. Proc Natl Acad Sci U S A 111:3757-62

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