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Developing a new resource for drug discovery: marine actinomycete bacteria

Abstract

Natural products are both a fundamental source of new chemical diversity and an integral component of today's pharmaceutical compendium. Yet interest in natural-product drug discovery has waned, in part owing to diminishing returns from traditional resources such as soil bacteria. The oceans cover 70% of the Earth's surface and harbor most of the planet's biodiversity. Although marine plants and invertebrates have received considerable attention as a resource for natural-product discovery, the microbiological component of this diversity remains relatively unexplored. Recent studies have revealed that select groups of marine actinomycetes are a robust source of new natural products. Members of the genus Salinispora have proven to be a particularly rich source of new chemical structures, including the potent proteasome inhibitor salinosporamide A, and other distinct groups are yielding new classes of terpenoids, amino acid–derived metabolites and polyene macrolides. The continued development of improved cultivation methods and technologies for accessing deep-sea environments promises to provide access to this significant new source of chemical diversity.

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Figure 1: Radial tree depicting the phylogenetic relationships of 13 groups of marine-derived actinomycetes within six different families.
Figure 2: Structures and biosynthesis of metabolites from Salinispora tropica.
Figure 3: Representations, based on X-ray data, of the CT-L active site of the yeast 20S proteasome complexed with salinosporamide A (Sal A).
Figure 4
Figure 5: Representative structures (15, 16 and 17) of the numerous polyene-polyol antibiotics produced by the Marinispora group.
Figure 6: Structures of the antibiotic abyssomycin C (23) and the anticancer drug candidate thiocoraline (24).

References

  1. Newman, D.J., Cragg, G.M. & Snader, K.M. Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod. 66, 1022–1037 (2003).

    Article  CAS  Google Scholar 

  2. Koehn, F.E. & Carter, G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4, 206–220 (2005).

    Article  CAS  Google Scholar 

  3. Clardy, J. & Walsh, C. Lessons from natural molecules. Nature 432, 829–837 (2004).

    Article  CAS  Google Scholar 

  4. Walsh, C. Where will new antibiotics come from? Nat. Rev. Microbiol. 1, 65–70 (2003).

    Article  CAS  Google Scholar 

  5. Goodfellow, M. & Haynes, J.A. in Biological, Biochemical, and Biomedical Aspects of Actinomycetes (eds. Ortiz-Ortiz, L., Bojalil, L.F. & Yakoleff, V.) 453–472 (Academic, Orlando, Florida, 1984).

    Book  Google Scholar 

  6. ZoBell, C.E. Marine Microbiology (Chronica Botanica Co., Waltham, Massachusetts, 1946).

    Google Scholar 

  7. Amann, R.I., Ludwig, W. & Schleifer, K.-H. Phylogenetic identification and in situ detection of individual microbial cells without cultivation. Microbiol. Rev. 59, 143–169 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Venter, J.C. et al. Environmental genome shotgun sequencing of the Sargasso Sea. Science 304, 66–74 (2004).

    Article  CAS  Google Scholar 

  9. Lam, K.S. Discovery of novel metabolites from marine actinomycetes. Curr. Opin. Microbiol. 9, 245–251 (2006).

    Article  CAS  Google Scholar 

  10. Bérdy, J. Bioactive microbial metabolites. J. Antibiot. (Tokyo) 58, 1–26 (2005).

    Article  Google Scholar 

  11. Weyland, H. Actinomycetes in North Sea and Atlantic Ocean sediments. Nature 223, 858 (1969).

    Article  CAS  Google Scholar 

  12. Pathom-aree, W. et al. Diversity of actinomycetes isolated from the Challenger Deep sediment (10,898 m) from the Mariana Trench. Extremophiles 10, 181–189 (2006).

    Article  CAS  Google Scholar 

  13. Helmke, E. & Weyland, H. Rhodococcus marinonascens sp. nov., an actinomycete from the sea. Int. J. Syst. Bacteriol. 34, 127–138 (1984).

    Article  Google Scholar 

  14. Han, S.K., Nedashkovzkaya, O.I., Mikhailov, V.V., Kim, S.B. & Bae, K.S. Salinibacterium amurkyense gen. nov., sp. nov., a novel genus of the family Microbacteriaceae from the marine environment. Int. J. Syst. Evol. Microbiol. 53, 2061–2066 (2003).

    Article  CAS  Google Scholar 

  15. Yi, H., Schumann, P., Sohn, K. & Chun, J. Serinicoccus marinus gen. nov., sp. nov., a novel actinomycete with L-ornithine and L-serine in the pedtidoglycan. Int. J. Syst. Evol. Microbiol. 54, 1585–1589 (2004).

    Article  CAS  Google Scholar 

  16. Maldonado, L. et al. Salinispora gen nov., a home for obligate marine actinomycetes belonging to the family Micromonosporaceae. Int. J. Sys. Evol. Microbiol. 55, 1759–1766 (2005).

    Article  CAS  Google Scholar 

  17. Jensen, P.R., Dwight, R. & Fenical, W. Distribution of actinomycetes in near-shore tropical marine sediments. Appl. Environ. Microbiol. 57, 1102–1108 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mincer, T.J., Jensen, P.R., Kauffman, C.A. & Fenical, W. Widespread and persistent populations of a major new marine actinomycete taxon in ocean sediments. Appl. Environ. Microbiol. 68, 5005–5011 (2002).

    Article  CAS  Google Scholar 

  19. Feling, R.H. et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinispora. Angew. Chem. Int. Edn. Engl. 42, 355–357 (2003).

    Article  CAS  Google Scholar 

  20. Omura, S. et al. Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. J. Antibiot. (Tokyo) 44, 113–116 (1991).

    Article  CAS  Google Scholar 

  21. Chauhan, D. et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myelome cells with mechanisms distinct from bortezomib. Cancer Cell 8, 407–419 (2005).

    Article  CAS  Google Scholar 

  22. Groll, M., Huber, R. & Potts, B.C.M. Crystal structure of salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J. Am. Chem. Soc. 128, 5136–5141 (2006).

    Article  CAS  Google Scholar 

  23. Macherla, V.R. et al. Structure-activity relationship studies of Salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J. Med. Chem. 48, 3684–3687 (2005).

    Article  CAS  Google Scholar 

  24. Williams, P.G. et al. New cytotoxic salinosporamides from the marine actinomycete Salinispora tropica. J. Org. Chem. 70, 6196–6203 (2005).

    Article  CAS  Google Scholar 

  25. Reddy, L.R., Saravanan, P. & Corey, E.J. A simple stereocontrolled synthesis of salinosporamide A. J. Am. Chem. Soc. 126, 6230–6231 (2004).

    Article  CAS  Google Scholar 

  26. Endo, A. & Danishefsky, S.J. Total synthesis of salinosporamide A. J. Am. Chem. Soc. 127, 8298–8299 (2005).

    Article  CAS  Google Scholar 

  27. Mulholland, N.P., Pattenden, G. & Walters, I.A.S. A concise total synthesis of salinosporamide A. Org. Biomol. Chem. 4, 2845–2846 (2006).

    Article  CAS  Google Scholar 

  28. Buchanan, G.O. et al. Sporolides A and B: structurally unprecedented halogenated macrolides from the marine actinomycete Salinispora tropica. Org. Lett. 7, 2731–2734 (2005).

    Article  CAS  Google Scholar 

  29. Jensen, P.R. & Mafnas, C. Biogeography of the marine actinomycete Salinispora. Environ. Microbiol. 8, 1881–1888 (2006).

    Article  CAS  Google Scholar 

  30. Kim, T.K., Hewavitharana, A.K., Shaw, P.N. & Fuerst, J.A. Discovery of a new source of rifamycin antibiotics in marine sponge actinobacteria by phylogenetic prediction. Appl. Environ. Microbiol. 72, 2118–2125 (2006).

    Article  CAS  Google Scholar 

  31. Renner, M.K. et al. Cyclomarins A-C, New anti-inflammatory cyclic peptides produced by a marine bacterium (Streptomyces sp.). J. Am. Chem. Soc. 121, 11273–11276 (1999).

    Article  CAS  Google Scholar 

  32. He, H. et al. Lomaiviticins A and B, potent antitumor antibiotics from Micromonospora lomaivitiensis. J. Am. Chem. Soc. 123, 5362–5363 (2001).

    Article  CAS  Google Scholar 

  33. Charan, R.D. et al. Diazepinomicin, a new antimicrobial alkaloid from a marine Micromonospora sp. J. Nat. Prod. 67, 1431–1433 (2004).

    Article  CAS  Google Scholar 

  34. Bernan, V.S., Greenstein, M. & Carter, G.T. Mining marine microorganisms as a source of new antimicrobials and antifungals. Curr. Med. Chem. Anti-infective Agents 3, 181–195 (2004).

    Article  CAS  Google Scholar 

  35. Oh, D.C., Williams, P.G., Kauffman, C.A., Jensen, P.R. & Fenical, W. Cyanosporasides A and B, chloro- and cyano-cyclopenta[a]indene glycosides from the marine actinomycete “Salinispora pacifica”. Org. Lett. 8, 1021–1024 (2006).

    Article  CAS  Google Scholar 

  36. Liu, W. et al. Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model. Proc. Natl. Acad. Sci. USA 100, 11959–11963 (2003).

    Article  CAS  Google Scholar 

  37. Larsen, T.O., Smedsgaard, J., Nielsen, K.F., Hansen, M.E. & Frisvad, J.C. Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat. Prod. Rep. 22, 672–695 (2005).

    Article  CAS  Google Scholar 

  38. Ward, A.C. & Bora, N. Diversity and biogeography of marine actinobacteria. Curr. Opin. Microbiol. 9, 279–286 (2006).

    Article  CAS  Google Scholar 

  39. Kwon, H.C., Kauffman, C.A., Jensen, P.R. & Fenical, W. Marinomycins A-D, antitumor antibiotics of a new structure class from a amrine actinomycete of the recently discovered genus “Marinispora”. J. Am. Chem. Soc. 128, 1622–1632 (2006).

    Article  CAS  Google Scholar 

  40. Schlegel, R., Thrum, H., Zielinski, J. & Borowski, E.J. The structure of roflamycin, a new polyene macrolide antifungal antibiotic. J. Antibiot. (Tokyo) 34, 122–123 (1981).

    Article  CAS  Google Scholar 

  41. Rychnovsky, S.D., Greisgraber, G. & Schlegel, R. Stereochemical determination of roflamycoin: 13C acetonide analysis and synthetic correlation. J. Am. Chem. Soc. 117, 197–210 (1995).

    Article  CAS  Google Scholar 

  42. Neu, H.C. The crisis in antibiotic resistance. Science 257, 1064–1073 (1992).

    Article  CAS  Google Scholar 

  43. Pathirana, C., Jensen, P.R. & Fenical, W. Marinone and debromomarinone, two phenylated napthoquinones from a marine actinomycete. Tetrahedron Lett. 33, 7663–7666 (1992).

    Article  CAS  Google Scholar 

  44. Soria-Mercardo, I.E., Prieto-Davo, A., Jensen, P.R. & Fenical, W. Antibiotic terpenoid chloro-dihydroquinones from a new marine actinomycete. J. Nat. Prod. 68, 904–910 (2005).

    Article  Google Scholar 

  45. Gribble, G.W. in The Handbook of Environmental Chemistry, Vol. 3, Part P, 1–15 (Springer-Verlag, Berlin, 2003).

    Google Scholar 

  46. Carter-Franklin, J.N., Parrish, J.D., Tschirret-Guth, R.A., Little, R.D. & Butler, A. Vanadium haloperoxidase-catalyzed bromination and cyclization of terpenes. J. Am. Chem. Soc. 125, 3688–3689 (2003).

    Article  CAS  Google Scholar 

  47. Magarvey, N.A., Keller, J.M., Bernan, V., Dworkin, M. & Sherman, D.H. Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites. Appl. Environ. Microbiol. 70, 7520–7529 (2004).

    Article  CAS  Google Scholar 

  48. Fiedler, H.-P. et al. Marine actinomycetes as a source of novel secondary metabolites. Antonie Van Leeuwenhoek 87, 37–42 (2005).

    Article  CAS  Google Scholar 

  49. Bister, B. et al. Abyssomicin C - a polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor of the para-aminobenzoic acid/tetrahydrofolate biosynthesis pathway. Angew. Chem. Int. Edn. Engl. 43, 2574–2576 (2004).

    Article  CAS  Google Scholar 

  50. Newman, D.J. & Cragg, G.M. Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67, 1216–1238 (2004).

    Article  CAS  Google Scholar 

  51. Stach, J.E.M. et al. Statistical approaches for estimating actinobcterial diversity in marine sediments. Appl. Environ. Microbiol. 69, 6189–6200 (2003).

    Article  CAS  Google Scholar 

  52. Naumann, K. Influence of chlorine substituents on biological activity of chemicals. J. Prakt. Chem. 341, 417–435 (1999).

    Article  CAS  Google Scholar 

  53. Harris, C., Kannan, R., Kopecka, H. & Harris, T.M. The role of the chlorine substituents in the antibiotic vancomycin: preparation and characterization of mono- and didechlorovancomycin. J. Am. Chem. Soc. 107, 6652–6658 (1985).

    Article  CAS  Google Scholar 

  54. Pfeifer, B.A. & Khosla, C. Biosynthesis of polyketides in heterologous hosts. Microbiol. Mol. Biol. Rev. 65, 106–118 (2001).

    Article  CAS  Google Scholar 

  55. Walsh, C.T. Combinatorial biosynthesis of antibiotics: challenges and opportunities. ChemBioChem 3, 125–134 (2002).

    Article  Google Scholar 

  56. Janssen, P.H., Yates, P.S., Grinton, B.E., Taylor, P.M. & Sait, M. Improved culturability of soil bacteria and isolation in pure culture of novel members of the Divisions Acidobacteria, Actinobacteria, Proteobacteria, and Verrucomicrobia. Appl. Environ. Microbiol. 68, 2391–2396 (2002).

    Article  CAS  Google Scholar 

  57. Challis, G.L. & Ravel, J. Coelichen, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol. Lett. 187, 111–114 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the US National Institutes of Health, National Cancer Institute for generous continuing support of this research under grants CA44848, CA052955 and CA048112. Support from the NCI allowed the unusual marine microbiology described herein to be explored. We thank V. Bernan (Wyeth Research Laboratories) for S. pacifica sequence data.

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Correspondence to William Fenical.

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W.F. and P.J. are founders of and consultants to Nereus Pharmaceuticals.

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Fenical, W., Jensen, P. Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol 2, 666–673 (2006). https://doi.org/10.1038/nchembio841

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