Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

  • Brian O. Bachmann
  • Steven G. Van Lanen
  • Richard H. Baltz
Introductory Review

Abstract

Microbial genome mining is a rapidly developing approach to discover new and novel secondary metabolites for drug discovery. Many advances have been made in the past decade to facilitate genome mining, and these are reviewed in this Special Issue of the Journal of Industrial Microbiology and Biotechnology. In this Introductory Review, we discuss the concept of genome mining and why it is important for the revitalization of natural product discovery; what microbes show the most promise for focused genome mining; how microbial genomes can be mined; how genome mining can be leveraged with other technologies; how progress on genome mining can be accelerated; and who should fund future progress in this promising field. We direct interested readers to more focused reviews on the individual topics in this Special Issue for more detailed summaries on the current state-of-the-art.

Keywords

Combinatorial biosynthesis Genome mining Gifted microbes Heterologous expression Lasso peptides NRPS PKS Secondary metabolite Streptomyces 

References

  1. 1.
    Aigle B, Lautra S, Spiteller D, Dickschat JS, Challis GL, Leblond P, Pernodet J-L (2013) Genome mining of Streptomyces ambofaciens. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1379-y
  2. 2.
    Albright JC, Goering AW, Doroghazi JR, Metcalf WW, Kelleher NL (2013) Strain-specific proteogenomics accelerates discovery of natural products via their biosynthetic pathways. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1373-4
  3. 3.
    Almabruk KH, Lu W, Li Y, Abugreen M, Kelly JX, Mahmud T (2013) Mutasynthesis of fluorinated pactamycin analogues and their antimalarial activity. Org Lett 15:1678–1681PubMedCrossRefGoogle Scholar
  4. 4.
    Bachmann BO, McAlpine JB, Zazopoulos E, Farnet CM (2003) Polyene polyketides, process for their production and their use as a pharmaceutical. US Patent 7,375,088Google Scholar
  5. 5.
    Bachmann BO, McAlpine JB, Zazopoulos E, Farnet CM, Piraee M (2006) Farnesyl dibenzodiazepinone, and processes for its production. US Patent 7,101,872Google Scholar
  6. 6.
    Baltz RH (2005) Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News 55:186–196Google Scholar
  7. 7.
    Baltz RH (2006) Molecular engineering approaches to peptide, polyketide and other antibiotics. Nat Biotechnol 24:1533–1540PubMedCrossRefGoogle Scholar
  8. 8.
    Baltz RH (2008) Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol 8:557–563PubMedCrossRefGoogle Scholar
  9. 9.
    Baltz RH (2010) Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J Ind Microbiol Biotechnol 37:759–772PubMedCrossRefGoogle Scholar
  10. 10.
    Baltz RH (2010) Genomics and the ancient origins of the daptomycin biosynthetic gene cluster. J Antibiot 63:506–511PubMedCrossRefGoogle Scholar
  11. 11.
    Baltz RH (2011) Strain improvement in actinomycetes in the postgenomic era. J Ind Microbiol Biotechnol 38:657–666PubMedCrossRefGoogle Scholar
  12. 12.
    Baltz RH (2011) Function of MbtH homologs in non-ribosomal peptide biosynthesis and applications in secondary metabolite discovery. J Ind Microbiol Biotechnol 38:1747–1760PubMedCrossRefGoogle Scholar
  13. 13.
    Baltz RH (2012) Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways. ACS Synth Biol. doi:10.1021/sb3000673 PubMedGoogle Scholar
  14. 14.
    Baltz RH (2013) MbtH homology codes to identify gifted microbes for genome mining. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1360-9 Google Scholar
  15. 15.
    Bentley SD, Chater KF, Cerdeño-Tárraga AM et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147PubMedCrossRefGoogle Scholar
  16. 16.
    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. Nucl Acids Res 41:W204–W212PubMedCrossRefGoogle Scholar
  17. 17.
    Boddy CN (2013) Bioinformatics tools for genome mining of polyketide and non-ribosomal peptides. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1368-1 Google Scholar
  18. 18.
    Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–758PubMedCrossRefGoogle Scholar
  19. 19.
    Büssow K, Scheich C, Sievert V, Harttig U, Schultz J, Simon B, Bork P, Lehrach H, Heinemann U (2005) Structural genomics of human proteins—target selection and generation of a public catalogue of expression clones. Microb Cell Fact 4:21PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Challis G (2013) Exploitation of the Streptomyces coelicolor A3(2) genome sequence for discovery of new natural products and biosynthetic pathways. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1383-2
  21. 21.
    Challis GL, Ravel J (2000) Coelichelin, a new peptide siderophore encoded by the S. coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol Lett 187:111–114PubMedCrossRefGoogle Scholar
  22. 22.
    Cobb RE, Ning JC, Zhao H (2013) DNA assembly techniques for next generation combinatorial biosynthesis of natural products. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1358-3 PubMedGoogle Scholar
  23. 23.
    Corre C, Challis GL (2009) New natural product biosynthetic chemistry discovered by genome mining. Nat Prod Rep 26:977–986PubMedCrossRefGoogle Scholar
  24. 24.
    Deane CD, Mitchell DA (2013) Lessons learned from the transformation of natural product discovery to a genome-driven endeavor. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1361-8 PubMedGoogle Scholar
  25. 25.
    Demain AL (2013) Importance of microbial natural products and the need to revitalize their discovery. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1325-z PubMedGoogle Scholar
  26. 26.
    Derewacz DK, Goodwin CR, McNees CR, McLean JA, Bachmann BO (2013) Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism. Proc Natl Acad Sci USA 110:2336–2341PubMedCrossRefGoogle Scholar
  27. 27.
    Didelot X, Bowden R, Wilson DJ, Peto TE, Crook DW (2012) Transforming clinical microbiology with bacterial genome sequencing. Nat Rev Genet 13:601612CrossRefGoogle Scholar
  28. 28.
    Donadio S, Monciardini P, Sosio M (2007) Polyketide synthases and non-ribosomal peptide synthetases: the emerging view from bacterial genomics. Nat Prod Rep 24:1073–1109PubMedCrossRefGoogle Scholar
  29. 29.
    Du Y, Derewacz DK, Deguire SM, Teske J, Ravel J, Sulikowski GA, Bachmann BO (2011) Biosynthesis of the apoptolidins in Nocardiopsis sp. FU 40. Tetrahedron 67:6568–6575PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Farnet CM, Zazopoulos E (2005) Improving drug discovery from microorganisms. In: Zhang L, Demain AL (eds) Natural products: drug discovery and therapeutic medicine. Humana Press Inc, Totowa, pp 95–106CrossRefGoogle Scholar
  31. 31.
    Gantt RW, Peltier-Pain P, Thorson JS (2011) Enzymatic methods for glyco (diversification/randomization) of drugs and small molecules. Nat Prod Rep 28:1811–1853PubMedCrossRefGoogle Scholar
  32. 32.
    Genilloud O, González I, Salazar O, Martín J, Tormo JR, Vicente F (2011) Current approaches to exploit actinomycetes as a source of novel natural products. J Ind Microbiol Biotechnol 38:375–389PubMedCrossRefGoogle Scholar
  33. 33.
    Giddings LA, Newman DJ (2013) Microbial natural products: molecular blueprints for antitumor drugs. J Ind Microbiol Biotechnol 40:1181–1210PubMedCrossRefGoogle Scholar
  34. 34.
    Gomez-Escribano JP, Bibb MJ (2013) Heterologous expression of natural product biosynthetic gene clusters in S. coelicolor: from genome mining to manipulation of biosynthetic pathways. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1348-5 PubMedGoogle Scholar
  35. 35.
    Goodfellow M (2010) Selective isolation of Actinobacteria. In: Baltz RH, Davies JE, Demain AL (eds) Manual of industrial microbiology and biotechnology. American Society for Microbiology, Washington, pp 13–27Google Scholar
  36. 36.
    Gourdeau H, McAlpine JB, Ranger M, Simard B, Berger F, Beaudry F, Farnet CM, Falardeau P (2008) Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand. Cancer Chemother Pharmacol 61:911–921PubMedCrossRefGoogle Scholar
  37. 37.
    Gross H, Stockwell VO, Henkels MD, Nowak-Thompson B, Loper JE, Gerwick WH (2007) The genomisotopic approach: a systematic method to isolate products of orphan biosynthetic gene clusters. Chem Biol 14:53–63PubMedCrossRefGoogle Scholar
  38. 38.
    Herbst DA, Boll B, Zocher G, Stehle T, Heide L (2013) Structural basis of the interaction of MbtH-like proteins, putative regulators of non-ribosomal peptide biosynthesis, with adenylating enzymes. J Biol Chem 288:1991–2003PubMedCrossRefGoogle Scholar
  39. 39.
    Hou Y, Braun DR, Michel CR, Klassen JL, Adnani N, Wyche TP, Bugni TS (2012) Microbial strain prioritization using metabolomics tools for the discovery of natural products. Anal Chem 84:4277–4283PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ikeda H, Shin-Ya K, Ōmura S (2013) Genome mining of the Streptomyces avermitilis genome and development of genome-minimized hosts for heterologous expression of biosynthetic gene clusters. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1327-x PubMedGoogle Scholar
  41. 41.
    Iqbal HA, Feng Z, Brady SF (2012) Biocatalysts and small molecule products from metagenomic studies. Curr Opin Chem Biol 16:109–116PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Jensen PR, Chavarria K, Fenical W, Moore BS, Ziemert N (2013) Challenges and triumphs to genomics-based natural product discovery. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1353-8 PubMedGoogle Scholar
  43. 43.
    Jensen PR, Mincer TJ, Williams PG, Fenical W (2005) Marine actinomycete diversity and natural product discovery. Antonie Van Leeuwenhoek 87:43–48PubMedCrossRefGoogle Scholar
  44. 44.
    Ju K-S, Doraghazi JR, Metcalf WW (2013) Genomics enabled discovery of phosphonate natural products and their biosynthetic pathways. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1375-2
  45. 45.
    Kaysser L, Bernhardt P, Nam SJ, Loesgen S, Ruby JG, Skewes-Cox P, Jensen PR, Fenical W, Moore BS (2012) Merochlorins A–D, cyclic meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium-dependent chloroperoxidases. J Am Chem Soc 134:11988–11991PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Krug D, Zurek G, Schneider B, Garcia R, Müller R (2008) Efficient mining of myxobacterial metabolite profiles enabled by liquid chromatography-electrospray ionization-time-of-flight mass spectrometry and compound-based principal component analysis. Anal Chim Act 624:97–106CrossRefGoogle Scholar
  47. 47.
    Land M, Lapidus A, Mayilraj S (2009) Complete genome sequence of Actinosynnema mirum type strain (101). Stand Genom Sci 1:46–53CrossRefGoogle Scholar
  48. 48.
    Lautru S, Deeth RJ, Bailey LM, Challis GL (2005) Discovery of a new peptide natural product by S. coelicolor genome mining. Nat Chem Biol 1:265–269PubMedCrossRefGoogle Scholar
  49. 49.
    Liu X, Cheng Y-Q (2013) Genome-guided discovery of diverse natural products from Burkholderia sp. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1376-1 Google Scholar
  50. 50.
    Lu W, Roongsawang N, Mahmud T (2011) Biosynthetic studies and genetic engineering of pactamycin analogs with improved selectivity toward malarial parasites. Chem Biol 18:425–431PubMedCrossRefGoogle Scholar
  51. 51.
    Luzhetskyy A, Rebets Y, Brötz E, Tokovenko B (2013) Actinomycetes biosynthetic potential: how to bridge in silico and in vivo. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1352-9 PubMedGoogle Scholar
  52. 52.
    Maksimov MO, Link AJ (2013) Prospecting genomes for lasso peptides. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1357-4
  53. 53.
    McAlpine JB, Bachmann BO, Piraee M, Tremblay S, Alarco AM, Zazopoulos E, Farnet CM (2005) Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. J Nat Prod 68:493–496PubMedCrossRefGoogle Scholar
  54. 54.
    McMahon MD, Rush JS, Thomas MG (2012) Analyses of MbtB, MbtE, and MbtF suggest revisions to the mycobactin biosynthesis pathway in Mycobacterium tuberculosis. 194:2809–2818Google Scholar
  55. 55.
    Molinski TF (2010) Microscale methodology for structure elucidation of natural products. Curr Opin Biotechnol 21:819–826PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Molinski TF (2010) NMR of natural products at the nanomole-scale. Nat Prod Rep 27:321–329PubMedCrossRefGoogle Scholar
  57. 57.
    Moree WJ, Phelan VV, Wu CH, Bandeira N, Cornett DS, Duggan BM, Dorrestein PC (2012) Interkingdom metabolic transformations captured by microbial imaging mass spectrometry. Proc Natl Acad Sci USA 109:13811–13816PubMedCrossRefGoogle Scholar
  58. 58.
    Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1362–1384PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Nolan M, Sikorski J, Jando M et al (2010) Complete genome sequence of Streptosporangium roseum type strain (NI 9100). Stand Genom Sci 2:29–37CrossRefGoogle Scholar
  61. 61.
    Ochi K, Tanaka Y, Tojo S (2013) Activating the expression of bacterial cryptic genes by rpoB mutations in RNA polymerase or by rare earth elements. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1349-4 PubMedGoogle Scholar
  62. 62.
    Owen JG, Reddy BV, Ternel MA, Charlop-Powers Z, Calle PY, Kim JH, Brady SF (2013) Mapping gene clusters within arrayed metagenomic libraries to expand the structural diversity of bio-medically relevant natural products. Proc Nat Acad Sci USA 110:11797–11802PubMedCrossRefGoogle Scholar
  63. 63.
    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 78:3744–3755PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Roden J, Dienstmann R, Serra V, Tabernero J (2013) Development of PI3 K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10:143–153CrossRefGoogle Scholar
  65. 65.
    Temme K, Zhao D, Voigt CA (2012) Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca. Proc Nat Acad Sci USA 109:7085–7090PubMedCrossRefGoogle Scholar
  66. 66.
    Ouyang Z, Takats Z, Blake TA, Gologan B, Guymon AJ, Wiseman JM, Oliver JC, Davisson VJ, Cooks RG (2003) Preparing protein microarrays by soft-landing of mass-selected ions. Science 301:1351–1354PubMedCrossRefGoogle Scholar
  67. 67.
    Vizcaino MI, Guo X, Crawford JM (2013) Merging chemical ecology with bacterial genome mining for secondary metabolite discovery. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1356-5 PubMedGoogle Scholar
  68. 68.
    Wang J, Soisson SM, Young K et al (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441:358–361PubMedCrossRefGoogle Scholar
  69. 69.
    Weissman KJ, Müller R (2010) Myxobacterial secondary metabolites: bioactivities and modes-of-action. Nat Prod Rep 27:1276–1295PubMedCrossRefGoogle Scholar
  70. 70.
    Wong FT, Khosla C (2012) Combinatorial biosynthesis of polyketides––a perspective. Curr Opin Chem Biol 16:117–123PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Yea SS, Fruman DA (2013) Achieving cancer cell death with PI3 K/mTOR-targeted therapies. Ann NY Acad Sci 1280:15–18PubMedCrossRefGoogle Scholar
  72. 72.
    Yoon V, Nodwell JR (2013) Activating secondary metabolism with stress and chemicals. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1387-y
  73. 73.
    Zazopoulos E, Huang K, Staffa A, Liu W, Bachmann BO, Nonaka K, Ahlert J, Thorson JS, Shen B, Farnet CM (2003) A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol 21:187–190PubMedCrossRefGoogle Scholar
  74. 74.
    Zerikly M, Challis GL (2009) Strategies for the discovery of new natural products by genome mining. ChemBioChem 10:625–633PubMedCrossRefGoogle Scholar
  75. 75.
    Zhu F, Qin C, Tao L et al (2011) Clustered patterns of species origins of nature-derived drugs and clues for future bio-prospecting. Proc Nat Acad Sci USA 31:12943–12948CrossRefGoogle Scholar
  76. 76.
    Zhu H, Sandiford SK, van Wezel GP (2013) Triggers and cues that activate antibiotic production by actinomycetes. J Ind Microbiol Biotechnol. doi:10.1007/s10295-013-1309-z Google Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2013

Authors and Affiliations

  • Brian O. Bachmann
    • 1
  • Steven G. Van Lanen
    • 2
  • Richard H. Baltz
    • 3
  1. 1.Department of ChemistryVanderbilt UniversityNashvilleUSA
  2. 2.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA
  3. 3.CognoGen Biotechnology ConsultingSarasotaUSA

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