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Biodiversity, chemical diversity and drug discovery

  • Sheo B. Singh
  • Fernando Pelaez
Part of the Progress in Drug Research book series (PDR, volume 65)

Abstract

Drugs developed from microbial natural products are in the fundaments of modern pharmaceutical companies. Despite decades of research, all evidences suggest that there must remain many interesting natural molecules with potential therapeutic application yet to be discovered. Any efforts to successfully exploit the chemical diversity of microbial secondary metabolites need to rely heavily on a good understanding of microbial diversity, being the working hypothesis that maximizing biological diversity is the key strategy to maximizing chemical diversity. This chapter presents an overview of diverse topics related with this basic principle, always in relation with the discovery of novel secondary metabolites. The types of microorganisms more frequently used for natural products discovery are briefly reviewed, as well as the differences between terrestrial and marine habitats as sources of bioactive secondary metabolite producers. The concepts about microbial diversity as applied to prokaryotes have evolved in the last years, but recent data suggest the existence of true biogeographic patterns of bacterial diversity, which are also discussed. Special attention is dedicated to the existing strategies to exploit the microbial diversity that is not easy to tackle by conventional approaches. This refers explicitly to the current attempts to isolate and cultivate the previously uncultured bacteria, including the application of high throughput techniques. Likewise, the advances of microbial molecular biology has allowed the development of metagenomic approaches, i.e., the expression of biosynthetic pathways directly obtained from environmental DNA and cloned in a suitable host, as another way of accessing microbial genetic resources. Also, approaches relying on the genomics of metabolite producers are reviewed.

Keywords

Microbial Diversity Appl Environ Natural Product Research Marine Actinomycete Natural Product Discovery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2003) Marine natural products. Nat Prod Rep 20: 1–48PubMedCrossRefGoogle Scholar
  2. 2.
    Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2004) Marine natural products. Nat Prod Rep 21: 1–49PubMedCrossRefGoogle Scholar
  3. 3.
    Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2005) Marine natural products. Nat Prod Rep 22: 15–61PubMedCrossRefGoogle Scholar
  4. 4.
    Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2006) Marine natural products. Nat Prod Rep 23: 26–78PubMedCrossRefGoogle Scholar
  5. 5.
    Berdy J (2005) Bioactive microbial metabolites. J Antibiot (Tokyo) 58: 1–26Google Scholar
  6. 6.
    Ward BB (2002) How many species of prokaryotes are there? Proc Natl Acad Sci USA 99: 10234–10236PubMedCrossRefGoogle Scholar
  7. 7.
    Curtis TP, Sloan WT, Scannell JW (2002) Estimating prokaryotic diversity and its limits, Proc Natl Acad Sci USA 99: 10494–10499PubMedCrossRefGoogle Scholar
  8. 8.
    Pedros-Alio C (2006) Marine microbial diversity: can it be determined? Trends Microbiol 14: 257–263PubMedCrossRefGoogle Scholar
  9. 9.
    Hawksworth DL (1991) The fungal dimension of biodiversity, magnitude, significance and conservation. Mycological Res 95: 641–655Google Scholar
  10. 10.
    Watve MG, Tickoo R, Jog MM, Bhole BD (2001) How many antibiotics are produced by the genus Streptomyces? Arch Microbiol 176: 386–390PubMedCrossRefGoogle Scholar
  11. 11.
    Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R et al (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441: 358–361PubMedCrossRefGoogle Scholar
  12. 12.
    Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417: 141–147PubMedCrossRefGoogle Scholar
  13. 13.
    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: 526–531PubMedCrossRefGoogle Scholar
  14. 14.
    Dean RA, Talbot NJ, Ebbole DJ, Farman ML, Mitchell TK, Orbach MJ, Thon M, Kulkarni R, Xu JR, Pan H et al (2005) The genome sequence of the rice blast fungus Magnaporthe grisea. Nature 434: 980–986PubMedCrossRefGoogle Scholar
  15. 15.
    Zengler K, Paradkar A, Keller M (2005) New methods to access microbial diversity for small molecule discovery. In: L Zhang, AL Demain (eds): Natural products drug discovery and therapeutic medicine. Humana Press, Totowa, New Jersey, 275–293Google Scholar
  16. 16.
    Pelaez F, Genilloud O (2003) Discovering new drugs from microbial natural products. In: JL Barredo (ed): Microorganisms for health care, foods and enzyme production. Research Signpost, Trivendrum, 1–22Google Scholar
  17. 17.
    Harvey A (2000) Strategies for discovering drugs from previously unexplored natural products. DrugDiscov Today 5: 294–300CrossRefGoogle Scholar
  18. 18.
    Sielaff H, Christiansen G, Schwecke T (2006) Natural products from cyanobacteria: Exploiting a new source for drug discovery. IDrugs 9: 119–127PubMedGoogle Scholar
  19. 19.
    Ehrenreich IM, Waterbury JB, Webb EA (2005) Distribution and diversity of natural product genes in marine and freshwater cyanobacterial cultures and genomes. Appl Environ Microbiol 71: 7401–7413PubMedCrossRefGoogle Scholar
  20. 20.
    Burja AM, Banaigs B, About-Mansour E, Burgess JG, Wright P (2001) Marine cyanobacteria — a prolific source of natural products. Tetrahedron 57: 9347–9377CrossRefGoogle Scholar
  21. 21.
    Harada K (2004) Production of secondary metabolites by freshwater cyanobacteria. Chem Pharm Bull (Tokyo) 52: 889–899CrossRefGoogle Scholar
  22. 22.
    Simmons TL, Andrianasolo E, McPhail K, Flatt P, Gerwick WH (2005) Marine natural products as anticancer drugs. Mol Cancer Ther 4: 333–342PubMedGoogle Scholar
  23. 23.
    Gerth K, Pradella S, Perlova O, Beyer S, Muller R (2003) Myxobacteria: proficient producers of novel natural products with various biological activities — past and future biotechnological aspects with the focus on the genus Sorangium. J Biotechnol 106: 233–253PubMedCrossRefGoogle Scholar
  24. 24.
    Reichenbach H (2001) Myxobacteria, producers of novel bioactive substances. J Ind Microbiol Biotechnol 27: 149–156PubMedCrossRefGoogle Scholar
  25. 25.
    Reichenbach H (1999) The ecology of the myxobacteria. Environ Microbiol 1: 15–21PubMedCrossRefGoogle Scholar
  26. 26.
    Gaspari F, Paitan Y, Mainini M, Losi D, Ron EZ, Marinelli F (2005) Myxobacteria isolated in Israel as potential source of new anti-infectives. J Appl Microbiol 98: 429–439PubMedCrossRefGoogle Scholar
  27. 27.
    Burja A, Wright P (2003) Look first to nature before invention industrial applications for marine cyanobacteria. SIM News 53: 4–9Google Scholar
  28. 28.
    Pelaez F (2006) The historical delivery of antibiotics from microbial natural products — can history repeat? Biochem Pharmacol 71: 981–990PubMedCrossRefGoogle Scholar
  29. 29.
    Chen XH, Vater J, Piel J, Franke P, Scholz R, Schneider K, Koumoutsi A, Hitzeroth G, Grammel N, Strittmatter AW et al (2006) Structural and functional characterization of three polyketide synthase gene clusters in Bacillus amyloliquefaciens FZB 42. J Bacteriol 188: 4024–4036PubMedCrossRefGoogle Scholar
  30. 30.
    Walsh C (2003) Antibiotics actions, origins, resistance. ASP Press, Washington, DCGoogle Scholar
  31. 31.
    Shivas RG, Hyde KD (1997) Biodiversity of plant pathogenic fungi in the tropics. In: KD Hyde (ed): Biodiversity of tropical microfungi. Hong Kong University Press, Hong Kong, 47–56Google Scholar
  32. 32.
    Collado J, Platas G, Pelaez F (2001) Identification of an endophytic Nodulisporium sp from Quercus ilex in central Spain as the anamorph of Biscogniauxia mediterranea by rDNA sequencing analysis and effect of different ecological factors on distribution of the fungus. Mycologia 93: 875–886CrossRefGoogle Scholar
  33. 33.
    Rodrigues KF, Petrini O (1997) Biodiversity of endophytic fungi in tropical regions. In: KD Hyde (eds): Biodiversity of tropical microfungi. Hong Kong University Press, Hong Kong, 57–69Google Scholar
  34. 34.
    Polishook J, Pelaez F, Platas G, Ondeyka JG, Dombrowski AW, Teran AM (2001) Biogeography and relatedness of Nodulisporium strains producing nodulisporic acid. Mycologia 93: 1125–1137CrossRefGoogle Scholar
  35. 35.
    Martiny JB, Bohannan BJ, Brown JH, Colwell RK, Fuhrman JA, Green JL, Horner-Devine MC, Kane M, Krumins JA, Kuske CR et al (2006) Microbial biogeography: putting micro-organisms on the map. Nat Rev Microbiol 4: 102–112PubMedCrossRefGoogle Scholar
  36. 36.
    Fierer N, Jackson RB (2006) The diversity and biogeography of soil bacterial communities. Proc Natl Acad Sci USA 103: 626–631PubMedCrossRefGoogle Scholar
  37. 37.
    Finlay BJ (2002) Global dispersal of free-living microbial eukaryote species. Science 296: 1061–1063PubMedCrossRefGoogle Scholar
  38. 38.
    Bell T, Ager D, Song JI, Newman JA, Thompson IP, Lilley AK, van der Gast CJ (2005) Larger islands house more bacterial taxa. Science 308: 1884PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang L (2005) Integrated approaches for discovering novel drugs from microbial natural products. In: L Zhang, AL Demain (eds): Natural products drug discovery and therapeutic medicine. Humana Press, Totowa, New Jersey, 33–55Google Scholar
  40. 40.
    Bills GF, Platas G, Pelaez F, Masurekar P (1999) Reclassification of a pneumocandin-producing anamorph, Glea lozoyensis gen et sp nov, previously identified as Zalerion arboricola. Mycol Res 103: 179–192CrossRefGoogle Scholar
  41. 41.
    Pelaez F, Cabello A, Platas G, Diez MT, Gonzalez del Val A, Basilio A, Martan I, Vicente F, Bills GE, Giacobbe RA et al (2000) The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst Appl Microbiol 23: 333–343PubMedGoogle Scholar
  42. 42.
    Basilio A, Justice M, Harris G, Bills G, Collado J, de la Cruz M, Diez MT, Hernandez P, Liberator P, Nielsen Kahn J et al (2006) The discovery of moriniafungin, a novel sordarin derivative produced by Morinia pestalozzioides. BioorgMed Chem 14: 560–566CrossRefGoogle Scholar
  43. 43.
    Bills GF, Dombrowski AW, Pelaez F, Polishook J, An Z (2002) Recent and future discoveries of pharmacologically active metabolites from tropical fungi. In: R Walting, JC Fran-kland, AM Ainsworth, S Isaac, CH Robinson (eds): Tropical mycology. CABI Publishing, CAB International, Wallingford, UK, 165–194Google Scholar
  44. 44.
    Salituro GM, Pelaez F, Zhang BB (2001) Discovery of a small molecule insulin receptor activator. Recent Prog Horm Res 56: 107–126PubMedCrossRefGoogle Scholar
  45. 45.
    Strobel G, Daisy B, Castillo U (2005) Novel natural products from rainforest endophytes. Humana Press, Totowa, New JerseyGoogle Scholar
  46. 46.
    Ruibal C, Platas G, Bills GF (2005) Isolation and characterization of melanized fungi from limestone formations in Mallorca. Mycological Prog 4: 23–38CrossRefGoogle Scholar
  47. 47.
    Salazar O, Valverde A, Genilloud O (2006) Real-time PCR for the detection and quantification of geodermatophilaceae from stone samples and identification of new members of the genus Blastococcus. Appl Environ Microbiol 72: 346–352PubMedCrossRefGoogle Scholar
  48. 48.
    Gonzalez I, Ayuso-Sacido A, Anderson A, Genilloud O (2005) Actinomycetes isolated from lichens: evaluation of their diversity and detection of biosynthetic gene sequences. FEMS Microbiol Ecol 54: 401–415PubMedCrossRefGoogle Scholar
  49. 49.
    Gebhardt K, Schimana J, Muller J, Fiedler HP, Kallenborn HG, Holzenkampfer M, Krastel P, Zeeck A, Vater J, Holtzel A et al (2002) Screening for biologically active metabolites with endosymbiotic bacilli isolated from arthropods. FEMS Microbiol Lett 217: 199–205PubMedCrossRefGoogle Scholar
  50. 50.
    Piel J, Hui D, Wen G, Butzke D, Platzer M, Fusetani N, Matsunaga S (2004) Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei. Proc Natl Acad Sci USA 101: 16222–16227PubMedCrossRefGoogle Scholar
  51. 51.
    Schirmer A, Gadkari R, Reeves CD, Ibrahim F, DeLong EF, Hutchinson CR (2005) Metagenomic analysis reveals diverse polyketide synthase gene clusters in microorganisms associated with the marine sponge Discodermia dissoluta. Appl Environ Microbiol 71: 4840–4849PubMedCrossRefGoogle Scholar
  52. 52.
    Kohlmeyer K, Kohlmeyer E (1979) Marine mycology. Academic Press, LondonGoogle Scholar
  53. 53.
    Bhaduri P, Mohammad BT, Wright PC (2006) The current status of natural products from marine fungi and their potential as anti-infective agents. J Ind Microbiol Biotechnol 33: 325–337CrossRefGoogle Scholar
  54. 54.
    Fenical W (1993) Chemical studies of marine bacteria: developing a new resource. Chem Rev 93: 1673–1683CrossRefGoogle Scholar
  55. 55.
    Mincer TJ, Jensen PR, Kauffman CA, Fenical W (2002) Widespread and persistent populations of a major new marine actinomycete taxon in ocean sediments. Appl Environ Microbiol 68: 5005–5011PubMedCrossRefGoogle Scholar
  56. 56.
    Helmke E, Weyland H (1984) Rhodococcus marinonascens sp nov, an actinomycete from the sea. Int J Syst Bacteriol 34: 127–134CrossRefGoogle Scholar
  57. 57.
    Magarvey NA, Keller JM, Bernan V, Dworkin M, Sherman DH (2004) Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites. Appl Environ Microbiol 70: 7520–7529PubMedCrossRefGoogle Scholar
  58. 58.
    Jensen PR, Fenical W (2005) New natural-product diversity from marine actinomycetes. In: L Zhang, AL Demain (eds): Natural products drug discovery and therapeutic medicine. Humana Press, Totowa, New Jersey, 315–328Google Scholar
  59. 59.
    Jensen PR, Mincer TJ, Williams PG, Fenical W (2005) Marine actinomycete diversity and natural product discovery. Antonie Van Leeuwenhoek 87: 43–48PubMedCrossRefGoogle Scholar
  60. 60.
    Jensen PR, Gontang E, Mafnas C, Mincer TJ, Fenical W (2005) Culturable marine actinomycete diversity from tropical Pacific Ocean sediments. Environ Microbiol 7: 1039–1048PubMedCrossRefGoogle Scholar
  61. 61.
    Kim TK, Garson MJ, Fuerst JA (2005) Marine actinomycetes related to the’ salinospora’ group from the Great Barrier Reef sponge Pseudoceratina clavata. Environ Microbiol 7: 509–518PubMedCrossRefGoogle Scholar
  62. 62.
    Williams PG, Buchanan GO, Feling RH, Kauffman CA, Jensen PR, Fenical W (2005) New cytotoxic salinosporamides from the marine Actinomycete Salinispora tropica. J Org Chem 70: 6196–6203PubMedCrossRefGoogle Scholar
  63. 63.
    Buchanan GO, Williams PG, Feling RH, Kauffman CA, Jensen PR, Fenical W (2005) Sporolides A and B: structurally unprecedented halogenated macrolides from the marine actinomycete Salinispora tropica. Org Lett 7: 2731–2734PubMedCrossRefGoogle Scholar
  64. 64.
    Soria-Mercado IE, Prieto-Davo A, Jensen PR, Fenical W (2005) Antibiotic terpenoid chloro-dihydroquinones from a new marine actinomycete. J Nat Prod 68: 904–910PubMedCrossRefGoogle Scholar
  65. 65.
    Kwon HC, Kauffman CA, Jensen PR, Fenical W (2006) Marinomycins A-D, antitumorantibiotics of a new structure class from a marine actinomycete of the recently discovered genus ‘marinispora’. J Am Chem Soc 128: 1622–1632PubMedCrossRefGoogle Scholar
  66. 66.
    Kim TK, Hewavitharana AK, Shaw PN, Fuerst JA (2006) Discovery of a new source of rifamycin antibiotics in marine sponge actinobacteria by phylogenetic prediction. Appl Environ Microbiol 72: 2118–2125PubMedCrossRefGoogle Scholar
  67. 67.
    Okuda T, Ando K, Bills G (2004) Fungal germplasm for drug discovery and industrial applications In: Z An (ed): Handbook of industrial mycology. Marcel Dekker Inc, New York 123–166Google Scholar
  68. 68.
    Bills GF, Pelaez F, Polishook J, Diez MT, Harris GH, Clapp WH, Dufresne C, Byrne KM, Nallin-Omstead M, Jenkins RG et al (1994) Distribution of zaragozic acids (squalestatins) among filamentous ascomycetes. Mycol Res 98: 733–739CrossRefGoogle Scholar
  69. 69.
    Vilella D, Sanchez M, Platas G, Salazar O, Genilloud O, Royo I, Cascales C, Martin I, Diez T, Silverman KC et al (2000) Inhibitors of farnesylation of Ras from a microbial natural products screening program. J Ind Microbiol Biotechnol 25: 315–327PubMedCrossRefGoogle Scholar
  70. 70.
    Torsvik V, Ovreas L, Thingstad TF (2002) Prokaryotic diversity — magnitude, dynamics, and controlling factors. Science 296: 1064–1066PubMedCrossRefGoogle Scholar
  71. 71.
    Torsvik V, Ovreas L (2002) Microbial diversity and function in soil: from genes to ecosystems. Curr Opin Microbiol 5: 240–245PubMedCrossRefGoogle Scholar
  72. 72.
    Gans J, Wolinsky M, Dunbar J (2005) Computational improvements reveal great bacterial diversity and high metal toxicity in soil. Science 309: 1387–1390PubMedCrossRefGoogle Scholar
  73. 73.
    Hughes JB, Hellmann JJ, Ricketts TH, Bohannan BJ (2001) Counting the uncountable: statistical approaches to estimating microbial diversity. Appl Environ Microbiol 67: 4399–4406PubMedCrossRefGoogle Scholar
  74. 74.
    de Vargas C, Norris R, Zaninetti L, Gibb SW, Pawlowski J (1999) Molecular evidence of cryptic speciation in planktonic foraminifers and their relation to oceanic provinces. Proc Natl Acad Sci USA 96: 2864–2868PubMedCrossRefGoogle Scholar
  75. 75.
    Keller M, Zengler K (2004) Tapping into microbial diversity. Nat Rev Microbiol 2: 141–150PubMedCrossRefGoogle Scholar
  76. 76.
    Janssen PH, Yates PS, Grinton BE, Taylor PM, Sait M (2002) 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: 2391–2396PubMedCrossRefGoogle Scholar
  77. 77.
    Bruns A, Cypionka H, Overmann J (2002) Cyclic AMP and acyl homoserine lactones increase the cultivation efficiency of heterotrophic bacteria from the central Baltic Sea. Appl Environ Microbiol 68: 3978–3987PubMedCrossRefGoogle Scholar
  78. 78.
    Kaeberlein T, Lewis K, Epstein SS (2002) Isolating ‘uncultivable’ microorganisms in pure culture in a simulated natural environment. Science 296: 1127–1129PubMedCrossRefGoogle Scholar
  79. 79.
    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: 8714–8720PubMedCrossRefGoogle Scholar
  80. 80.
    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
  81. 81.
    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: R245–249PubMedCrossRefGoogle Scholar
  82. 82.
    Rondon MR, August PR, Bettermann AD, Brady SF, Grossman TH, Liles MR, Loiacono KA, Lynch BA, MacNeil IA, Minor C et al (2000) Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms. Appl Environ Microbiol 66: 2541–2547PubMedCrossRefGoogle Scholar
  83. 83.
    Handelsman J (2005) How to find new antibiotics. The Scientist October 10: 20–21Google Scholar
  84. 84.
    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
  85. 85.
    Brady SF, Clardy J (2000) Long-chain N-acyl amino acid antibiotics isolated from heterologously expressed environmental DNA. J Am Chem Soc 122: 12903–12904CrossRefGoogle Scholar
  86. 86.
    Brady SF, Chao CJ, Clardy J (2004) Long-chain N-acyltyrosine synthases from environmental DNA. Appl Environ Microbiol 70: 6865–6870PubMedCrossRefGoogle Scholar
  87. 87.
    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
  88. 88.
    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
  89. 89.
    Brady SF, Clardy J (2003) Synthesis of long-chain fatty acid enol esters isolated from an environmental DNA clone. Org Lett 5: 121–124PubMedCrossRefGoogle Scholar
  90. 90.
    Brady SF, Clardy J (2004) Palmitoylputrescine, an antibiotic isolated from the heterologous expression of DNA extracted from bromeliad tank water. J Nat Prod 67: 1283–1286PubMedCrossRefGoogle Scholar
  91. 91.
    Brady SF, Clardy J (2005) N-acyl derivatives of arginine and tryptophan isolated from environmental DNA expressed in Escherichia coli. Org Lett 7: 3613–3616PubMedCrossRefGoogle Scholar
  92. 92.
    Brady SF, Clardy J (2005) Cloning and heterologous expression of isocyanide biosynthetic genes from environmental DNA. Angew Chem IntEdEngl 44: 7063–7065CrossRefGoogle Scholar
  93. 93.
    Brady SF, Clardy J (2005) Systematic investigation of the Escherichia coli metabolome for the biosynthetic origin of an isocyanide carbon atom. Angew Chem Int Ed Engl 44: 7045–7048PubMedCrossRefGoogle Scholar
  94. 94.
    Gillespie DE, Brady SF, Bettermann AD, Cianciotto NP, Liles MR, Rondon MR, Clardy J, Goodman RM, Handelsman J (2002) Isolation of antibiotics turbomycin a and B from a metagenomic library of soil microbial DNA. Appl Environ Microbiol 68: 4301–4306PubMedCrossRefGoogle Scholar
  95. 95.
    An Z, Harris GH, Zink D, Giacobbe RA, Lu P, Sangari R, Svetnik V, Gunter B, Liaw A, Masurekar P et al (2005) Expression of cosmid-size DNA of slow-growing fungi in Aspergillus nidulans for secondary metabolite screening. In: Z An (ed): Handbook of industrial mycology. Marcel Dekker, New York, 167–186Google Scholar
  96. 96.
    Button DK, Schut F, Quang P, Martin R, Robertson BR (1993) Viability and isolation of marine bacteria by dilution culture: theory, procedures, and initial results. Appl Environ Microbiol 59: 881–891PubMedGoogle Scholar
  97. 97.
    Connon SA, Giovannoni SJ (2002) High-throughput methods for culturing microorganisms in very-low-nutrient media yield diverse new marine isolates. Appl Environ Microbiol 68: 3878–3885PubMedCrossRefGoogle Scholar
  98. 98.
    Rappe MS, Connon SA, Vergin KL, Giovannoni SJ (2002) Cultivation of the ubiquitous SAR11 marine bacterioplankton clade. Nature 418: 630–633PubMedCrossRefGoogle Scholar
  99. 99.
    Bruns A, Hoffelner H, Overmann J (2003) A novel approach for the high throughput cultivation assays and the isolation of planktonic bacteria. FEMS Microbiol Ecol 45: 161–171CrossRefPubMedGoogle Scholar
  100. 100.
    Gich F, Schubert K, Bruns A, Hoffelner H, Overmann J (2005) Specific detection, isolation, and characterization of selected, previously uncultured members of the freshwater bacterioplankton community. Appl Environ Microbiol 71: 5908–5919PubMedCrossRefGoogle Scholar
  101. 101.
    Zengler K, Toledo G, Rappe M, Elkins J, Mathur EJ, Short JM, Keller M (2002) Cultivating the uncultured. Proc Natl Acad Sci USA 99: 15681–15686PubMedCrossRefGoogle Scholar
  102. 102.
    Farnet CM, Zazopoulos E (2005) Improving drug discovery from microorganisms. In: L Zhang L, AL Demain (eds): Natural products drug discovery and therapeutic medicine. Humana Press, Totowa, New Jersey, 95–106Google Scholar
  103. 103.
    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
  104. 104.
    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
  105. 105.
    Minas W, Bailey JE, Duetz W (2000) Streptomycetes in micro-cultures: growth, production of secondary metabolites, and storage and retrieval in the 96-well format. Antonie Van Leeuwenhoek 78: 297–305PubMedCrossRefGoogle Scholar
  106. 106.
    Duetz WA, Ruedi L, Hermann R, O’Connor K, Buchs J, Witholt B (2000) Methods for intense aeration, growth, storage, and replication of bacterial strains in microtiter plates. Appl Environ Microbiol 66: 2641–2646PubMedCrossRefGoogle Scholar
  107. 107.
    Ortholand JY, Ganesan A (2004) Natural products and combinatorial chemistry: back to the future. Curr Opin Chem Biol 8: 271–280PubMedCrossRefGoogle Scholar
  108. 108.
    Feher M, Schmidt JM (2003) Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43: 218–227PubMedCrossRefGoogle Scholar
  109. 109.
    Tosteson MT, Scriven DR, Bharadwaj AK, Kishi Y, Tosteson DC (1995) Interaction of palytoxin with red cells: structure-function studies. Toxicon 33: 799–807PubMedCrossRefGoogle Scholar
  110. 110.
    Baryza JL, Brenner SE, Craske ML, Meyer T, Wender PA (2004) Simplified analogs of bryostatin with anticancer activity display greater potency for translocation of PKCdelta-GFP. Chem Biol 11: 1261–1267PubMedCrossRefGoogle Scholar
  111. 111.
    Wender PA, Hinkle KW, Koehler MF, Lippa B (1999) The rational design of potential chemotherapeutic agents: synthesis of bryostatin analogues. Med Res Rev 19: 388–407PubMedCrossRefGoogle Scholar
  112. 112.
    Davies J (2006) Are antibiotics naturally antibiotics? J Ind Microbiol Biotechnol 33: 496–499PubMedCrossRefGoogle Scholar
  113. 113.
    Clardy J, Walsh C (2004) Lessons from natural molecules. Nature 432: 829–837PubMedCrossRefGoogle Scholar
  114. 114.
    Singh SB, Barrett JF (2006) Empirical antibacterial drug discovery — foundation in natural products. Biochem Pharmacol 71: 1006–1015PubMedCrossRefGoogle Scholar
  115. 115.
    Lipinski CA (2003) Chris Lipinski discusses life and chemistry after the Rule of Five. Drug Discov Today 8: 12–16PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel (Switzerland) 2008

Authors and Affiliations

  • Sheo B. Singh
    • 1
  • Fernando Pelaez
    • 2
  1. 1.Merck Research LaboratoriesRahwayNew JerseyUSA
  2. 2.Centro de Investigación BásicaMerck, Sharp & Dohme de EspañaMadridSpain

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