Marine invertebrates, such as sponges, tunicates, and gorgonians, produce a stunning diversity of secondary metabolites, many of which show promise as pharmaceutical agents. However, supplying marine natural products for clinical development has been a major hurdle, since the organisms are often rare or difficult to collect. Recombinant DNA technology offers a possible strategy to circumvent the supply problem by expression of biosynthetic genes in bacterial culture, but there are many problems that have prevented the widespread use of this approach. The large bacterial diversity found within marine invertebrates and the difficulty of whole pathway expression greatly hinder the usefulness of the approach. In addition, it is often difficult to engineer pathways to produce new natural products. We recently reported the first example of rational whole-pathway identification and heterologous expression for a marine natural product from an animal-bacterium symbiosis. A pathway encoding formation of patellamides A and C was identified in Prochloron, the obligate symbiont of an ascidian, and expressed in Escherichia coli. In this project, we will capitalize on this early success by cloning and engineering biomedically important natural product pathways from a variety of symbiotic associations in the marine environment. By further exploring this model symbiotic system, we will establish and validate methodology for the general cloning of symbiotic products, develop a supply of drugs that are currently in clinical or preclinical trials, and discover new drugs via rational pathway engineering. This study will thus provide practical solutions to problems in drug discovery and development with marine natural products.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Jones, Warren
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University of Utah
Schools of Pharmacy
Salt Lake City
United States
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Ruffner, Duane E; Schmidt, Eric W; Heemstra, John R (2015) Assessing the combinatorial potential of the RiPP cyanobactin tru pathway. ACS Synth Biol 4:482-92
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
Agarwal, Vinayak; Pierce, Elizabeth; McIntosh, John et al. (2012) Structures of cyanobactin maturation enzymes define a family of transamidating proteases. Chem Biol 19:1411-22
Schmidt, Eric W; Donia, Mohamed S; McIntosh, John A et al. (2012) Origin and variation of tunicate secondary metabolites. J Nat Prod 75:295-304
Tianero, Ma Diarey B; Donia, Mohamed S; Young, Travis S et al. (2012) Ribosomal route to small-molecule diversity. J Am Chem Soc 134:418-25
Donia, Mohamed S; Fricke, W Florian; Partensky, Frederic et al. (2011) Complex microbiome underlying secondary and primary metabolism in the tunicate-Prochloron symbiosis. Proc Natl Acad Sci U S A 108:E1423-32
Donia, Mohamed S; Schmidt, Eric W (2011) Linking chemistry and genetics in the growing cyanobactin natural products family. Chem Biol 18:508-19
Donia, Mohamed S; Fricke, W Florian; Ravel, Jacques et al. (2011) Variation in tropical reef symbiont metagenomes defined by secondary metabolism. PLoS One 6:e17897
Donia, Mohamed S; Ruffner, Duane E; Cao, Sheng et al. (2011) Accessing the hidden majority of marine natural products through metagenomics. Chembiochem 12:1230-6
McIntosh, John A; Donia, Mohamed S; Nair, Satish K et al. (2011) Enzymatic basis of ribosomal peptide prenylation in cyanobacteria. J Am Chem Soc 133:13698-705

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