Advertisement

Culture-independent discovery of natural products from soil metagenomes

  • Micah Katz
  • Bradley M. Hover
  • Sean F. BradyEmail author
Natural Products

Abstract

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or “metagenomic,” methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth’s microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules.

Keywords

Metagenomics Drug discovery Natural products Culture-independent 

References

  1. 1.
    Aakvik T, Degnes KF, Dahlsrud R, Schmidt F, Dam R, Yu L, Volker U, Ellingsen TE, Valla S (2009) A plasmid RK2-based broad-host-range cloning vector useful for transfer of metagenomic libraries to a variety of bacterial species. FEMS Microbiol Lett 296:149–158. doi: 10.1111/j.1574-6968.2009.01639.x PubMedCrossRefGoogle Scholar
  2. 2.
    Abrudan MI, Smakman F, Grimbergen AJ, Westhoff S, Miller EL, van Wezel GP, Rozen DE (2015) Socially mediated induction and suppression of antibiosis during bacterial coexistence. Proc Natl Acad Sci USA 112:11054–11059. doi: 10.1073/pnas.1504076112 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Banik JJ, Brady SF (2008) Cloning and characterization of new glycopeptide gene clusters found in an environmental DNA megalibrary. Proc Natl Acad Sci USA 105:17273–17277. doi: 10.1073/pnas.0807564105 PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Banik JJ, Craig JW, Calle PY, Brady SF (2010) Tailoring enzyme-rich environmental DNA clones: a source of enzymes for generating libraries of unnatural natural products. J Am Chem Soc 132:15661–15670. doi: 10.1021/ja105825a PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O’Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J, Barrell BG, Parkhill J, Hopwood DA (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147. doi: 10.1038/417141a PubMedCrossRefGoogle Scholar
  6. 6.
    Biggins JB, Kang HS, Ternei MA, DeShazer D, Brady SF (2014) The chemical arsenal of Burkholderia pseudomallei is essential for pathogenicity. J Am Chem Soc 136:9484–9490. doi: 10.1021/ja504617n PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R, Takano E, Weber T (2013) antiSMASH 2.0–a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res 41:W204–W212. doi: 10.1093/nar/gkt449 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Brady SF (2007) Construction of soil environmental DNA cosmid libraries and screening for clones that produce biologically active small molecules. Nat Protoc 2:1297–1305. doi: 10.1038/nprot.2007.195 PubMedCrossRefGoogle Scholar
  9. 9.
    Brady SF, Bauer JD, Clarke-Pearson MF, Daniels R (2007) Natural products from isnA-containing biosynthetic gene clusters recovered from the genomes of cultured and uncultured bacteria. J Am Chem Soc 129:12102–12103. doi: 10.1021/ja075492v PubMedCrossRefGoogle Scholar
  10. 10.
    Brady SF, Chao CJ, Clardy J (2002) New natural product families from an environmental DNA (eDNA) gene cluster. J Am Chem Soc 124:9968–9969PubMedCrossRefGoogle Scholar
  11. 11.
    Brady SF, Chao CJ, Clardy J (2004) Long-chain N-acyltyrosine synthases from environmental DNA. Appl Environ Microbiol 70:6865–6870. doi: 10.1128/AEM.70.11.6865-6870.2004 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Brady SF, Chao CJ, Handelsman J, Clardy J (2001) Cloning and heterologous expression of a natural product biosynthetic gene cluster from eDNA. Org Lett 3:1981–1984PubMedCrossRefGoogle Scholar
  13. 13.
    Butler MS (2008) Natural products to drugs: natural product-derived compounds in clinical trials. Natural Prod Rep 25:475–516. doi: 10.1039/b514294f CrossRefGoogle Scholar
  14. 14.
    Chang FY, Brady SF (2011) Cloning and characterization of an environmental DNA-derived gene cluster that encodes the biosynthesis of the antitumor substance BE-54017. J Am Chem Soc 133:9996–9999. doi: 10.1021/ja2022653 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Chang FY, Brady SF (2013) Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening. Proc Natl Acad Sci USA 110:2478–2483. doi: 10.1073/pnas.1218073110 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Chang FY, Brady SF (2014) Characterization of an environmental DNA-derived gene cluster that encodes the bisindolylmaleimide methylarcyriarubin. Chembiochem Eur J Chem Biol 15:815–821. doi: 10.1002/cbic.201300756 CrossRefGoogle Scholar
  17. 17.
    Chang FY, Ternei MA, Calle PY, Brady SF (2013) Discovery and synthetic refactoring of tryptophan dimer gene clusters from the environment. J Am Chem Soc 135:17906–17912. doi: 10.1021/ja408683p PubMedCrossRefGoogle Scholar
  18. 18.
    Chang FY, Ternei MA, Calle PY, Brady SF (2015) Targeted metagenomics: finding rare tryptophan dimer natural products in the environment. J Am Chem Soc 137:6044–6052. doi: 10.1021/jacs.5b01968 PubMedCrossRefGoogle Scholar
  19. 19.
    Charlop-Powers Z, Banik JJ, Owen JG, Craig JW, Brady SF (2013) Selective enrichment of environmental DNA libraries for genes encoding nonribosomal peptides and polyketides by phosphopantetheine transferase-dependent complementation of siderophore biosynthesis. ACS Chem Biol 8:138–143. doi: 10.1021/cb3004918 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Charlop-Powers Z, Owen JG, Reddy BV, Ternei MA, Brady SF (2014) Chemical-biogeographic survey of secondary metabolism in soil. Proc Natl Acad Sci USA 111:3757–3762. doi: 10.1073/pnas.1318021111 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Charlop-Powers Z, Owen JG, Reddy BV, Ternei MA, Guimaraes DO, de Frias UA, Pupo MT, Seepe P, Feng Z, Brady SF (2014) Global biogeographic sampling of bacterial secondary metabolism. eLife 4:e05048. doi: 10.7554/eLife.05048
  22. 22.
    Courtois S, Frostegard A, Goransson P, Depret G, Jeannin P, Simonet P (2001) Quantification of bacterial subgroups in soil: comparison of DNA extracted directly from soil or from cells previously released by density gradient centrifugation. Environ Microbiol 3:431–439PubMedCrossRefGoogle Scholar
  23. 23.
    Craig JW, Chang FY, Brady SF (2009) Natural products from environmental DNA hosted in Ralstonia metallidurans. ACS Chem Biol 4:23–28. doi: 10.1021/cb8002754 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Craig JW, Chang FY, Kim JH, Obiajulu SC, Brady SF (2010) Expanding small-molecule functional metagenomics through parallel screening of broad-host-range cosmid environmental DNA libraries in diverse proteobacteria. Appl Environ Microbiol 76:1633–1641. doi: 10.1128/AEM.02169-09 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Cueto M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J (2001) Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. J Nat Prod 64:1444–1446PubMedCrossRefGoogle Scholar
  26. 26.
    Davidson SK, Allen SW, Lim GE, Anderson CM, Haygood MG (2001) Evidence for the biosynthesis of bryostatins by the bacterial symbiont “Candidatus Endobugula sertula” of the bryozoan Bugula neritina. Appl Environ Microbiol 67:4531–4537PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Davidson SK, Haygood MG (1999) Identification of sibling species of the bryozoan Bugula neritina that produce different anticancer bryostatins and harbor distinct strains of the bacterial symbiont “Candidatus Endobugula sertula”. Biol Bull 196:273–280PubMedCrossRefGoogle Scholar
  28. 28.
    Donia MS, Ruffner DE, Cao S, Schmidt EW (2011) Accessing the hidden majority of marine natural products through metagenomics. ChemBioChem 12:1230–1236. doi: 10.1002/cbic.201000780 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Edlund A, Loesgen S, Fenical W, Jensen PR (2011) Geographic distribution of secondary metabolite genes in the marine actinomycete Salinispora arenicola. Appl Environ Microbiol 77:5916–5925. doi: 10.1128/AEM.00611-11 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Engel K, Pinnell L, Cheng J, Charles TC, Neufeld JD (2012) Nonlinear electrophoresis for purification of soil DNA for metagenomics. J Microbiol Methods 88:35–40. doi: 10.1016/j.mimet.2011.10.007 PubMedCrossRefGoogle Scholar
  31. 31.
    Feng Z, Kallifidas D, Brady SF (2011) Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc Natl Acad Sci USA 108:12629–12634. doi: 10.1073/pnas.1103921108 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Feng Z, Kim JH, Brady SF (2010) Fluostatins produced by the heterologous expression of a TAR reassembled environmental DNA derived type II PKS gene cluster. J Am Chem Soc 132:11902–11903. doi: 10.1021/ja104550p PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ferrari BC, Binnerup SJ, Gillings M (2005) Microcolony cultivation on a soil substrate membrane system selects for previously uncultured soil bacteria. Appl Environ Microbiol 71:8714–8720. doi: 10.1128/AEM.71.12.8714-8720.2005 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Fleming A (2001) On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929. Bull World Health Organ 79(8):780–790PubMedCentralPubMedGoogle Scholar
  35. 35.
    Freeman MF, Gurgui C, Helf MJ, Morinaka BI, Uria AR, Oldham NJ, Sahl HG, Matsunaga S, Piel J (2012) Metagenome mining reveals polytheonamides as posttranslationally modified ribosomal peptides. Science 338:387–390. doi: 10.1126/science.1226121 PubMedCrossRefGoogle Scholar
  36. 36.
    Gabor EM, Alkema WB, Janssen DB (2004) Quantifying the accessibility of the metagenome by random expression cloning techniques. Environ Microbiol 6:879–886. doi: 10.1111/j.1462-2920.2004.00640.x PubMedCrossRefGoogle Scholar
  37. 37.
    Garcia JA, Fernandez-Guerra A, Casamayor EO (2011) A close relationship between primary nucleotides sequence structure and the composition of functional genes in the genome of prokaryotes. Mol Phylogenet Evol 61:650–658. doi: 10.1016/j.ympev.2011.08.011 PubMedCrossRefGoogle Scholar
  38. 38.
    Giovannoni SJ, Britschgi TB, Moyer CL, Field KG (1990) Genetic diversity in Sargasso Sea bacterioplankton. Nature 345:60–63. doi: 10.1038/345060a0 PubMedCrossRefGoogle Scholar
  39. 39.
    Gontang EA, Gaudencio SP, Fenical W, Jensen PR (2010) Sequence-based analysis of secondary-metabolite biosynthesis in marine actinobacteria. Appl Environ Microbiol 76:2487–2499. doi: 10.1128/AEM.02852-09 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Gregory MA, Till R, Smith MC (2003) Integration site for Streptomyces phage phiBT1 and development of site-specific integrating vectors. J Bacteriol 185:5320–5323PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Hamada T, Matsunaga S, Fujiwara M, Fujita K, Hirota H, Schmucki R, Guntert P, Fusetani N (2010) Solution structure of polytheonamide B, a highly cytotoxic nonribosomal polypeptide from marine sponge. J Am Chem Soc 132:12941–12945. doi: 10.1021/ja104616z PubMedCrossRefGoogle Scholar
  42. 42.
    Handelsman J, Rondon MR, Brady SF, Clardy J, Goodman RM (1998) Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem Biol 5:R245–R249PubMedCrossRefGoogle Scholar
  43. 43.
    Hildebrand M, Waggoner LE, Liu H, Sudek S, Allen S, Anderson C, Sherman DH, Haygood M (2004) bryA: an unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina. Chem Biol 11:1543–1552. doi: 10.1016/j.chembiol.2004.08.018 PubMedCrossRefGoogle Scholar
  44. 44.
    Hori M, Saito S, Shin YZ, Ozaki H, Fusetani N, Karaki H (1993) Mycalolide-B, a novel and specific inhibitor of actomyosin ATPase isolated from marine sponge. FEBS Lett 322:151–154PubMedCrossRefGoogle Scholar
  45. 45.
    Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531. doi: 10.1038/nbt820 PubMedCrossRefGoogle Scholar
  46. 46.
    Iqbal HA, Feng Z, Brady SF (2012) Biocatalysts and small molecule products from metagenomic studies. Curr Opin Chem Biol 16:109–116. doi: 10.1016/j.cbpa.2012.02.015 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Ji HF, Li XJ, Zhang HY (2009) Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Rep 10:194–200. doi: 10.1038/embor.2009.12 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Kakirde KS, Wild J, Godiska R, Mead DA, Wiggins AG, Goodman RM, Szybalski W, Liles MR (2011) Gram negative shuttle BAC vector for heterologous expression of metagenomic libraries. Gene 475:57–62. doi: 10.1016/j.gene.2010.11.004 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Kallifidas D, Brady SF (2012) Reassembly of functionally intact environmental DNA-derived biosynthetic gene clusters. Methods Enzymol 517:225–239. doi: 10.1016/B978-0-12-404634-4.00011-5 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Kallifidas D, Kang HS, Brady SF (2012) Tetarimycin A, an MRSA-active antibiotic identified through induced expression of environmental DNA gene clusters. J Am Chem Soc 134:19552–19555. doi: 10.1021/ja3093828 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Kampa A, Gagunashvili AN, Gulder TA, Morinaka BI, Daolio C, Godejohann M, Miao VP, Piel J, Andresson O (2013) Metagenomic natural product discovery in lichen provides evidence for a family of biosynthetic pathways in diverse symbioses. Proc Natl Acad Sci USA 110:E3129–E3137. doi: 10.1073/pnas.1305867110 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Kang HS, Brady SF (2013) Arimetamycin A: improving clinically relevant families of natural products through sequence-guided screening of soil metagenomes. Angew Chem 52:11063–11067. doi: 10.1002/anie.201305109 CrossRefGoogle Scholar
  53. 53.
    Kang HS, Brady SF (2014) Arixanthomycins A–C: phylogeny-guided discovery of biologically active eDNA-derived pentangular polyphenols. ACS Chem Biol 9:1267–1272. doi: 10.1021/cb500141b PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Kang HS, Brady SF (2014) Mining soil metagenomes to better understand the evolution of natural product structural diversity: pentangular polyphenols as a case study. J Am Chem Soc 136:18111–18119. doi: 10.1021/ja510606j PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kato Y, Fusetani N, Matsunaga S, Hashimoto K, Fujita S, Furuya T (1986) The bioactive marine metabolites. 16. calyculin-a, a novel antitumor metabolite from the marine sponge discodermia-calyx. J Am Chem Soc 108:2780–2781. doi: 10.1021/Ja00270a061 CrossRefGoogle Scholar
  56. 56.
    Kim JH, Feng Z, Bauer JD, Kallifidas D, Calle PY, Brady SF (2010) Cloning large natural product gene clusters from the environment: piecing environmental DNA gene clusters back together with TAR. Biopolymers 93:833–844. doi: 10.1002/bip.21450 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    King RW, Bauer JD, Brady SF (2009) An environmental DNA-derived type II polyketide biosynthetic pathway encodes the biosynthesis of the pentacyclic polyketide erdacin. Angew Chem 48:6257–6261. doi: 10.1002/anie.200901209 CrossRefGoogle Scholar
  58. 58.
    Kisselev AF (2008) Joining the army of proteasome inhibitors. Chem Biol 15:419–421. doi: 10.1016/j.chembiol.2008.04.010 PubMedCrossRefGoogle Scholar
  59. 59.
    Kisselev AF, van der Linden WA, Overkleeft HS (2012) Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol 19:99–115. doi: 10.1016/j.chembiol.2012.01.003 PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Lambalot RH, Gehring AM, Flugel RS, Zuber P, LaCelle M, Marahiel MA, Reid R, Khosla C, Walsh CT (1996) A new enzyme superfamily—the phosphopantetheinyl transferases. Chem Biol 3:923–936PubMedCrossRefGoogle Scholar
  61. 61.
    Laureti L, Song L, Huang S, Corre C, Leblond P, Challis GL, Aigle B (2011) Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens. Proc Natl Acad Sci USA 108:6258–6263. doi: 10.1073/pnas.1019077108 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Liles MR, Williamson LL, Rodbumrer J, Torsvik V, Goodman RM, Handelsman J (2008) Recovery, purification, and cloning of high-molecular-weight DNA from soil microorganisms. Appl Environ Microbiol 74:3302–3305. doi: 10.1128/AEM.02630-07 PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Luo Y, Huang H, Liang J, Wang M, Lu L, Shao Z, Cobb RE, Zhao H (2013) Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster. Nat Commun 4:2894. doi: 10.1038/ncomms3894 PubMedCentralPubMedGoogle Scholar
  64. 64.
    MacNeil IA, Tiong CL, Minor C, August PR, Grossman TH, Loiacono KA, Lynch BA, Phillips T, Narula S, Sundaramoorthi R, Tyler A, Aldredge T, Long H, Gilman M, Holt D, Osburne MS (2001) Expression and isolation of antimicrobial small molecules from soil DNA libraries. J Mol Microbiol Biotechnol 3:301–308PubMedGoogle Scholar
  65. 65.
    Maplestone RA, Stone MJ, Williams DH (1992) The evolutionary role of secondary metabolites–a review. Gene 115:151–157PubMedCrossRefGoogle Scholar
  66. 66.
    Matzanke BF, Muller GI, Raymond KN (1984) Hydroxamate siderophore mediated iron uptake in E. coli: stereospecific recognition of ferric rhodotorulic acid. Biochem Biophys Res Commun 121:922–930PubMedCrossRefGoogle Scholar
  67. 67.
    Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, Weber T, Takano E, Breitling R (2011) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39:W339–W346. doi: 10.1093/nar/gkr466 PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Milshteyn A, Schneider JS, Brady SF (2014) Mining the metabiome: identifying novel natural products from microbial communities. Chem Biol 21:1211–1223. doi: 10.1016/j.chembiol.2014.08.006 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Montiel D, Kang H-S, Chang F-Y, Charlop-Powers Z, Brady SF (2015) Yeast homologous recombination-based promoter engineering for the activation of silent natural product biosynthetic gene clusters. Proc Natl Acad Sci 112:8953–8958. doi: 10.1073/pnas.1507606112 PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Moore JM, Bradshaw E, Seipke RF, Hutchings MI, McArthur M (2012) Use and discovery of chemical elicitors that stimulate biosynthetic gene clusters in Streptomyces bacteria. Methods Enzymol 517:367–385. doi: 10.1016/B978-0-12-404634-4.00018-8 PubMedCrossRefGoogle Scholar
  71. 71.
    Nakano H, Omura S (2009) Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine. J Antibiot 62:17–26. doi: 10.1038/ja.2008.4 PubMedCrossRefGoogle Scholar
  72. 72.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Natl Prod 75:311–335. doi: 10.1021/np200906s CrossRefGoogle Scholar
  73. 73.
    Olano C, Garcia I, Gonzalez A, Rodriguez M, Rozas D, Rubio J, Sanchez-Hidalgo M, Brana AF, Mendez C, Salas JA (2014) Activation and identification of five clusters for secondary metabolites in Streptomyces albus J1074. Microb Biotechnol 7:242–256. doi: 10.1111/1751-7915.12116 PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Owen JG, Charlop-Powers Z, Smith AG, Ternei MA, Calle PY, Reddy BV, Montiel D, Brady SF (2015) Multiplexed metagenome mining using short DNA sequence tags facilitates targeted discovery of epoxyketone proteasome inhibitors. Proc Natl Acad Sci USA 112:4221–4226. doi: 10.1073/pnas.1501124112 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Owen JG, Reddy BV, Ternei MA, Charlop-Powers Z, Calle PY, Kim JH, Brady SF (2013) Mapping gene clusters within arrayed metagenomic libraries to expand the structural diversity of biomedically relevant natural products. Proc Natl Acad Sci USA 110:11797–11802. doi: 10.1073/pnas.1222159110 PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Pel J, Broemeling D, Mai L, Poon HL, Tropini G, Warren RL, Holt RA, Marziali A (2009) Nonlinear electrophoretic response yields a unique parameter for separation of biomolecules. Proc Natl Acad Sci USA 106:14796–14801. doi: 10.1073/pnas.0907402106 PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Pettit GR (1991) The bryostatins. Fortschritte der Chemie organischer Naturstoffe = Progress in the chemistry of organic natural products Progres dans la chimie des substances organiques naturelles 57:153–195Google Scholar
  78. 78.
    Rappe MS, Giovannoni SJ (2003) The uncultured microbial majority. Annu Rev Microbiol 57:369–394. doi: 10.1146/annurev.micro.57.030502.090759 PubMedCrossRefGoogle Scholar
  79. 79.
    Reddy BV, Kallifidas D, Kim JH, Charlop-Powers Z, Feng Z, Brady SF (2012) Natural product biosynthetic gene diversity in geographically distinct soil microbiomes. Appl Environ Microbiol 78:3744–3752. doi: 10.1128/AEM.00102-12 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Reddy BV, Milshteyn A, Charlop-Powers Z, Brady SF (2014) eSNaPD: a versatile, web-based bioinformatics platform for surveying and mining natural product biosynthetic diversity from metagenomes. Chem Biol 21:1023–1033. doi: 10.1016/j.chembiol.2014.06.007 PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Roesch LF, Fulthorpe RR, Riva A, Casella G, Hadwin AK, Kent AD, Daroub SH, Camargo FA, Farmerie WG, Triplett EW (2007) Pyrosequencing enumerates and contrasts soil microbial diversity. ISME J 1:283–290. doi: 10.1038/ismej.2007.53 PubMedCentralPubMedGoogle Scholar
  82. 82.
    Rondon MR, August PR, Bettermann AD, Brady SF, Grossman TH, Liles MR, Loiacono KA, Lynch BA, MacNeil IA, Minor C, Tiong CL, Gilman M, Osburne MS, Clardy J, Handelsman J, Goodman RM (2000) Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms. Appl Environ Microbiol 66:2541–2547PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Rondon MR, Raffel SJ, Goodman RM, Handelsman J (1999) Toward functional genomics in bacteria: analysis of gene expression in Escherichia coli from a bacterial artificial chromosome library of Bacillus cereus. Proc Natl Acad Sci USA 96:6451–6455PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Seow KT, Meurer G, Gerlitz M, Wendt-Pienkowski E, Hutchinson CR, Davies J (1997) A study of iterative type II polyketide synthases, using bacterial genes cloned from soil DNA: a means to access and use genes from uncultured microorganisms. J Bacteriol 179:7360–7368PubMedCentralPubMedGoogle Scholar
  85. 85.
    Shao Z, Rao G, Li C, Abil Z, Luo Y, Zhao H (2013) Refactoring the silent spectinabilin gene cluster using a plug-and-play scaffold. ACS synthetic biology 2:662–669. doi: 10.1021/sb400058n PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Starcevic A, Zucko J, Simunkovic J, Long PF, Cullum J, Hranueli D (2008) ClustScan: an integrated program package for the semi-automatic annotation of modular biosynthetic gene clusters and in silico prediction of novel chemical structures. Nucleic Acids Res 36:6882–6892. doi: 10.1093/nar/gkn685 PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Stevens DC, Conway KR, Pearce N, Villegas-Penaranda LR, Garza AG, Boddy CN (2013) Alternative sigma factor over-expression enables heterologous expression of a type II polyketide biosynthetic pathway in Escherichia coli. PLoS One 8:e64858. doi: 10.1371/journal.pone.0064858 PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Torsvik V, Goksoyr J, Daae FL (1990) High diversity in DNA of soil bacteria. Appl Environ Microbiol 56:782–787PubMedCentralPubMedGoogle Scholar
  89. 89.
    Torsvik V, Salte K, Sorheim R, Goksoyr J (1990) Comparison of phenotypic diversity and DNA heterogeneity in a population of soil bacteria. Appl Environ Microbiol 56:776–781PubMedCentralPubMedGoogle Scholar
  90. 90.
    Trindade M, van Zyl LJ, Navarro-Fernandez J, Abd Elrazak A (2015) Targeted metagenomics as a tool to tap into marine natural product diversity for the discovery and production of drug candidates. Front Microbiol 6:890. doi: 10.3389/fmicb.2015.00890 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Tringe SG, von Mering C, Kobayashi A, Salamov AA, Chen K, Chang HW, Podar M, Short JM, Mathur EJ, Detter JC, Bork P, Hugenholtz P, Rubin EM (2005) Comparative metagenomics of microbial communities. Science 308:554–557. doi: 10.1126/science.1107851 PubMedCrossRefGoogle Scholar
  92. 92.
    Uchiyama T, Miyazaki K (2010) Product-induced gene expression, a product-responsive reporter assay used to screen metagenomic libraries for enzyme-encoding genes. Appl Environ Microbiol 76:7029–7035. doi: 10.1128/AEM.00464-10 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Wakimoto T, Egami Y, Nakashima Y, Wakimoto Y, Mori T, Awakawa T, Ito T, Kenmoku H, Asakawa Y, Piel J, Abe I (2014) Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont. Nat Chem Biol 10:648. doi: 10.1038/NCHEMBIO.1573 PubMedCrossRefGoogle Scholar
  94. 94.
    Wang GY, Graziani E, Waters B, Pan W, Li X, McDermott J, Meurer G, Saxena G, Andersen RJ, Davies J (2000) Novel natural products from soil DNA libraries in a streptomycete host. Org Lett 2:2401–2404PubMedCrossRefGoogle Scholar
  95. 95.
    Wang K, Li G, Yu SQ, Zhang CT, Liu YH (2010) A novel metagenome-derived beta-galactosidase: gene cloning, overexpression, purification and characterization. Appl Microbiol Biotechnol 88:155–165. doi: 10.1007/s00253-010-2744-7 PubMedCrossRefGoogle Scholar
  96. 96.
    Wang Q, Wu H, Wang A, Du P, Pei X, Li H, Yin X, Huang L, Xiong X (2010) Prospecting metagenomic enzyme subfamily genes for DNA family shuffling by a novel PCR-based approach. J Biol Chem 285:41509–41516. doi: 10.1074/jbc.M110.139659 PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Wexler M, Johnston AW (2010) Wide host-range cloning for functional metagenomics. Methods Mol Biol 668:77–96. doi: 10.1007/978-1-60761-823-2_5 PubMedCrossRefGoogle Scholar
  98. 98.
    Wilson MC, Mori T, Ruckert C, Uria AR, Helf MJ, Takada K, Gernert C, Steffens UA, Heycke N, Schmitt S, Rinke C, Helfrich EJ, Brachmann AO, Gurgui C, Wakimoto T, Kracht M, Crusemann M, Hentschel U, Abe I, Matsunaga S, Kalinowski J, Takeyama H, Piel J (2014) An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 506:58–62. doi: 10.1038/nature12959 PubMedCrossRefGoogle Scholar
  99. 99.
    Woo SS, Jiang J, Gill BS, Paterson AH, Wing RA (1994) Construction and characterization of a bacterial artificial chromosome library of Sorghum bicolor. Nucleic Acids Res 22:4922–4931PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Woodhouse JN, Fan L, Brown MV, Thomas T, Neilan BA (2013) Deep sequencing of non-ribosomal peptide synthetases and polyketide synthases from the microbiomes of Australian marine sponges. ISME J 7:1842–1851. doi: 10.1038/ismej.2013.65 PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Yamanaka K, Reynolds KA, Kersten RD, Ryan KS, Gonzalez DJ, Nizet V, Dorrestein PC, Moore BS (2014) Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc Natl Acad Sci USA 111:1957–1962. doi: 10.1073/pnas.1319584111 PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Yao J, Fan XJ, Lu Y, Liu YH (2011) Isolation and characterization of a novel tannase from a metagenomic library. J Agric Food Chem 59:3812–3818. doi: 10.1021/jf104394m PubMedCrossRefGoogle Scholar
  103. 103.
    Yap WH, Li X, Soong TW, Davies JE (1996) Genetic diversity of soil microorganisms assessed by analysis of hsp70 (dnaK) sequences. J Ind Microbiol 17:179–184CrossRefGoogle Scholar
  104. 104.
    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:e34064. doi: 10.1371/journal.pone.0034064 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2015

Authors and Affiliations

  1. 1.Laboratory of Genetically Encoded Small Molecules, Howard Hughes Medical InstituteThe Rockefeller UniversityNew YorkUSA

Personalised recommendations