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Challenges and triumphs to genomics-based natural product discovery

  • Paul R. Jensen
  • Krystle L. Chavarria
  • William Fenical
  • Bradley S. Moore
  • Nadine Ziemert
Perspective

Abstract

Genome sequencing is rapidly changing the field of natural products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the products of silent or cryptic pathways. While genome mining has fast become a useful approach to natural product discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated products. This has led to bottlenecks in the discovery process that must be overcome for the potential of genomics-based natural product discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora, which is proving to be a useful model with which to apply genome mining as an approach to natural product discovery.

Keywords

Genomics Natural product biosynthesis Genome mining Salinispora 

Notes

Acknowledgments

PJ and WF acknowledge financial support from the National Institutes of Health (NIH R37 CA 044848 and RO1-GM086261) and the Fogerty Center International Cooperative Biodiversity Groups program (grant U01-TW007401-01). PJ, WF, and BSM acknowledge support from the NIH (grant R01-GM085770).

References

  1. 1.
    Ahmed L, Jensen P, Freel K, Brown R, Jones A, Kim B-Y, Goodfellow M (2013) Salinispora pacifica sp. nov., an actinomycete from marine sediments. Antonie Van Leeuwenhoek 103:1069–1078PubMedCrossRefGoogle Scholar
  2. 2.
    Anand S, Prasad MVR, Yadav G, Kumar N, Shehara J, Ansari MZ, Mohanty D (2010) SBSPKS: structure-based sequence analysis of polyketide synthases. Nucleic Acids Res 38:487–496CrossRefGoogle Scholar
  3. 3.
    Bachmann BO, Ravel J (2009) Methods for in silico prediction of microbial polyketide and nonribosomal peptide biosynthetic pathways from DNA sequence data. Methods Enzymol 458:181–217PubMedGoogle Scholar
  4. 4.
    Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147PubMedCrossRefGoogle Scholar
  5. 5.
    Eustáquio AS, O’Hagan D, Moore BS (2010) Engineering fluorometabolite production: fluorinase expression in Salinispora tropica yields fluorosalinosporamide A. J Nat Prod 73:378–382PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Eustáquio AS, Pojer F, Noe JP, Moore BS (2008) Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat Chem Biol 4:69–74PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Eustáquio AS, Nam S-J, Penn K, Lechner A, Wilson MC, Fenical W et al (2011) The discovery of salinosporamide K from the marine bacterium “Salinispora pacifica” by genome mining gives insight into pathway evolution. ChemBioChem 12:61–64PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Eustáquio AS, McGlinchey RP, Liu Y, Hazzard C, Beer LL, Florova G et al (2009) Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-l-methionine. Proc Nat Acad Sci 106:12295–12300PubMedCrossRefGoogle Scholar
  9. 9.
    Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora. Angew Chem 115:369–371CrossRefGoogle Scholar
  10. 10.
    Fenical W, Jensen PR (2006) Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol 2:666–673PubMedCrossRefGoogle Scholar
  11. 11.
    Fenical W, Jensen PR, Palladino MA, Lam KS, Lloyd GK, Potts BC (2009) Discovery and development of the anticancer agent salinosporamide A (NPI-0052). Bioorg Med Chem 17:2175–2180PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Freel KC, Nam S-J, Fenical W, Jensen PR (2011) Evolution of secondary metabolite genes in three closely related marine actinomycete species. Appl Environ Microbiol 77:7261–7270PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Gust B, Challis GL, Fowler K, Kieser T, Chater KF (2003) PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc Natl Acad Sci 100:1541–1546PubMedCrossRefGoogle Scholar
  14. 14.
    Jensen PR, Williams PG, Oh DC, Zeigler L, Fenical W (2007) Species-specific secondary metabolite production in marine actinomycetes of the genus Salinispora. Appl Environ Microbiol 73:1146–1152PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Kieser T, Bibb MJ, Buttner MJ, Chater KF, Hopwood DA (2000) Practical Streptomyces genetics. John Innes Foundation, NorwichGoogle Scholar
  16. 16.
    Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4:206–220PubMedCrossRefGoogle Scholar
  17. 17.
    Lane AL, Nam S-J, Fukuda T, Yamanaka K, Kauffman CA, Jensen PR et al (2013) Structures and comparative characterization of biosynthetic gene clusters for cyanosporasides, enediyne-derived natural products from marine actinomycetes. J Am Chem Soc 135:4171–4174PubMedCrossRefGoogle Scholar
  18. 18.
    Lautru S, Deeth RJ, Bailey LM, Challis GL (2005) Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat Chem Biol 1:265–269PubMedCrossRefGoogle Scholar
  19. 19.
    Lechner A, Eustáquio A, Gulder TAM, Hafner M, Moore BS (2011) Selective overproduction of the proteasome inhibitor salinosporamide A via precursor pathway regulation. Chem Biol 18:1527–1536PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Maldonado LA, Fenical W, Jensen PR, Kauffman CA, Mincer TJ, Ward AC et al (2005) Salinispora arenicola gen. nov., sp. nov. and Salinispora tropica sp. nov., obligate marine actinomycetes belonging to the family Micromonosporaceae. Int J Syst Evol Microbiol 55:1759–1766PubMedCrossRefGoogle Scholar
  21. 21.
    Medema MH, Takano E, Breitling R (2013) Detecting sequence homology at the gene cluster level with MultiGeneBlast. Mol Biol Evol 30:1218–1223PubMedCrossRefGoogle Scholar
  22. 22.
    Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA et al (2011) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39:W339–W346PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Natural Product Reports 26:1362–1384PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Penn K, Jenkins C, Nett M, Udwary DW, Gontang EA, McGlinchey RP et al (2009) Genomic islands link secondary metabolism to functional adaptation in marine Actinobacteria. ISME J 3:1193–1203PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Ross AC, Xu Y, Lu L, Kersten RD, Shao Z, Al-Suwailem AM et al (2012) Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria. J Am Chem Soc 135:1155–1162CrossRefGoogle Scholar
  26. 26.
    Schultz AW, Oh DC, Carney JR, Williamson RT, Udwary DW, Jensen PR et al (2008) Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin. J Am Chem Soc 130:4507–4516PubMedCrossRefGoogle Scholar
  27. 27.
    Siegl T, Tokovenko B, Myronovskyi M, Luzhetskyy A (2013) Design, construction and characterisation of a synthetic promoter library for fine-tuned gene expression in actinomycetes. Metab Eng 19:98–106PubMedCrossRefGoogle Scholar
  28. 28.
    Udwary DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W et al (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc Natl Acad Sci 104:10376–10381PubMedCrossRefGoogle Scholar
  29. 29.
    Wilson MC, Gulder TAM, Mahmud T, Moore BS (2010) Shared biosynthesis of the saliniketals and rifamycins in Salinispora arenicola is controlled by the sare1259-encoded cytochrome P450. J Am Chem Soc 132:12757–12765PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Yamanaka K, Ryan KS, Gulder TAM, Hughes CC, Moore BS (2012) Flavoenzyme-catalyzed atropo-selective N,C-bipyrrole homocoupling in marinopyrrole biosynthesis. J Am Chem Soc 134:12434–12437PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Ziemert N, Jensen PR (2012) Phylogenetic approaches to natural product structure prediction. Methods Enzymol 517:161–182PubMedGoogle Scholar
  32. 32.
    Ziemert N, Podell S, Penn K, Badger JH, Allen E, Jensen PR (2012) The natural product domain seeker NaPDoS: a phylogeny-based bioinformatic tool to classify secondary metabolite gene diversity. PLoS ONE 7:e34064PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2013

Authors and Affiliations

  • Paul R. Jensen
    • 1
  • Krystle L. Chavarria
    • 1
  • William Fenical
    • 1
  • Bradley S. Moore
    • 1
  • Nadine Ziemert
    • 1
  1. 1.Scripps Institution of OceanographyUniversity of California, San DiegoLa JollaUSA

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