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Integrated Approaches for Discovering Novel Drugs From Microbial Natural Products

  • Chapter
Natural Products

Abstract

Historically, nature has provided the source for the majority of the drugs in use today. This owes in large part to their structural complexity and clinical specificity. However, only a small percentage of known microbial secondary metabolites have been tested as natural-product drugs. Natural-product programs need to become more efficient, starting with the collection of environmental samples, selection of strains, metabolic expression, genetic exploitation, sample preparation and chemical dereplication. A renaissance of natural products-based drug discovery is coming because of the trend of combining the power of diversified but low-redundancy natural products with systems biology and novel assays. This review will focus on integrated approaches for diversifying microbial naturalproduct strains and extract libraries, while decreasing genetic and chemical redundancy. Increasing the quality and quantity of different chemical compounds tested in diverse biological systems should increase the chances of finding new leads for therapeutic agents.

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References

  1. Demain AL. Pharmaceutically active secondary metabolites of microorganisms. Appl Microbiol Biotechnol 1999;52:455–463.

    PubMed  CAS  Google Scholar 

  2. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identification of an 11-kDa FKBP12-rapamycinbinding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. PNAS1995;92:4947–4951.

    PubMed  CAS  Google Scholar 

  3. VanMiddlesworth F, Cannell RJP. Dereplication and partial identification of natural products. In: Cannell RJ, ed. Methods In Biotechnology, vol. 4: Natural Product Isolation. Humana Press, Inc., Totowa, NJ: 1998:279–327.

    Google Scholar 

  4. Urizar NL, Liverman AB, Dodds DT, et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 2002;296:1703–1706.

    PubMed  CAS  Google Scholar 

  5. Grabley S, Thiericke R. The impact of natural products on drug discovery. In: Grabley S, Thiericke R, eds. Drug Discovery From Nature. Springer, New York: 1999:3–37.

    Google Scholar 

  6. Che Y, Gloer J, Koster B, Malloch D. Decipinin A and decipienolides A and B: new bioactive metabolites from the coprophilous fungus Podospora decipiens. J Nat Prod 2002;65:916–919.

    PubMed  CAS  Google Scholar 

  7. Auerbach D, Thaminy S, Hottiger MO, Stagljar I. The post-genomic era of interactive proteomics: facts and perspectives. Proteomics. 2002;2:611–623.

    PubMed  CAS  Google Scholar 

  8. Fernandes P. Molecular recognition: identifying compounds and their targets. J Cell Biochem 2001;137:1–6.

    Google Scholar 

  9. Verdine G. The combinatorial chemistry of nature. Nature 1996;384(Supp):11–13.

    PubMed  CAS  Google Scholar 

  10. Breinbauer R, Vetter IR, Waldmann H. From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed Engl 2002;41:2879–2890.

    PubMed  Google Scholar 

  11. Czaran TL, Hoekstra RF, Pagie L. Chemical warfare between microbes promotes biodiversity. PNAS 2002;99:786–790.

    PubMed  CAS  Google Scholar 

  12. Harvey A. Strategies for discovery drugs from previously unexplored natural products. Drug Discov Today 2000;5:294–300.

    PubMed  Google Scholar 

  13. Firn RD, Jones CG. The evolution of secondary metabolism-a unifying model. Mol Microbiol 2000;37:989–994.

    PubMed  CAS  Google Scholar 

  14. Handelsman J, Rondon M, Brady S, Clardy J, Goodman R. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem Biol 1998;5:R245–R249.

    PubMed  CAS  Google Scholar 

  15. Monaghan RL, Polishook JD, Pecore VJ, Bills GF, Nallin M, Omstead S. Discovery of novel secondary metabolites from fungi—is it really a random walk through a random forest? Can J Bot 1995;73:S925–S931.

    CAS  Google Scholar 

  16. Strobel G. Rainforest endophytes and bioactive products. Crit Rev Biotechnol 2002;22:315–333.

    PubMed  CAS  Google Scholar 

  17. Shrestha K, Strobel G, Shrivastava SP, Gewali M. Evidence for paclitaxel from three new endophytic fungi of Himalayan yew of Nepal. Planta Med 2001;67:374–376.

    PubMed  CAS  Google Scholar 

  18. Foissner W. Notes on the soil ciliate biota (Protozoa, Ciliophora) from the Shimba Hills in Kenya (Africa): diversity and description of three new genera and ten new species. Biodivers Conserv 1999;8:319–389.

    Google Scholar 

  19. Bull AT. Clean technology: industry and environment, a viable partnership? Biologist (London) 2000;47:61–64.

    CAS  Google Scholar 

  20. Staley J, Gosink J. Poles apart: biodiversity and biogeography of sea ice bacteria. Annu Rev Microbiol 1999;53:189–215.

    PubMed  CAS  Google Scholar 

  21. Doolittle W. Phylogenic classification and the universal tree. Science 1999;284:2124–2128.

    PubMed  CAS  Google Scholar 

  22. Tulp M, Bohlin L. Functional versus chemical diversity: is biodiversity important for drug discovery? Trends Pharmacol Sci 2002;23:225–231.

    PubMed  CAS  Google Scholar 

  23. Jensen PR, Fenical W. Strategies for the discovery of secondary metabolites from marine bacteria: ecological perspectives. Annu Rev Microbiol 1994;48:559–584.

    PubMed  CAS  Google Scholar 

  24. Proksch P, Edrada RA, Ebel R. Drugs from the sea-current status and microbiological implications. Appl Microbiol Biotechnol 2002;59:125–134.

    PubMed  CAS  Google Scholar 

  25. Mincer TJ, Jensen PR, Kauffman CA, Fenical W. Widespread and persistent populations of a major new marine actinomycete taxon in ocean sediments. Appl Environ Microbiol 2002;68: 5005–5011.

    PubMed  CAS  Google Scholar 

  26. Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora. Angew Chem Int Ed Engl 2003;42:355–357.

    PubMed  CAS  Google Scholar 

  27. Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the unseen majority. PNAS 1998;95: 6578–6583.

    PubMed  CAS  Google Scholar 

  28. Davidson SK, Allen SW, Lim GE, Anderson CM, Haygood MG. Evidence for the biosynthesis of bryostatins by the bacterial symbiont “Candidatus endobugula sertula” of the bryozoan Bugula neritina. Appl Environ Microbiol 2001;67:4531–4537.

    PubMed  CAS  Google Scholar 

  29. Zinniel D, Lambrecht P, Harris NB, et al. Isolation and characterization of endophytic colonizing bacteria from agronomic crops and prairie plants. Appl Environ Microbiol 2002;68:2198–2208.

    PubMed  CAS  Google Scholar 

  30. Castillo UF, Strobel GA, Ford EJ, et al. Munumbicins, wide-spectrum antibiotics produced by Streptomyces NRRL 30562, endophytic on Kennedia nigriscans. Microbiology 2002;148: 2675–2685.

    PubMed  CAS  Google Scholar 

  31. Ananda K, Sridhar K. Diversity of endophytic fungi in the roots of mangrove species on the west coast of India. Can J Microbiol 2002;48:871–878.

    PubMed  CAS  Google Scholar 

  32. Tan RX, Zou WX. Endophytes: a rich source of functional metabolites. Nat Prod Rep. 2001;18(4):448–459.

    PubMed  CAS  Google Scholar 

  33. Wei ZM, Laby RJ, Zumoff CH, et al. Harpin, elicitor of the hypersensitive response produced by the plant pathogen Erwinia amylovora. Science 1992;257:85–88.

    PubMed  CAS  Google Scholar 

  34. Rikkinen J, Oksanen I, Lohtander K. Lichen guilds share related cyanobacterial symbionts. Science 2002;297:357.

    PubMed  CAS  Google Scholar 

  35. Ahmadjian V. Lichens. Annu Rev Microbiol 1965;19:1–20.

    PubMed  CAS  Google Scholar 

  36. Courtois S, Cappellano CM, Ball M, et al. Recombinant environmental libraries provide access to microbial diversity for drug discovery from natural products. Appl Environ Microbiol 2003;69:49–55.

    PubMed  CAS  Google Scholar 

  37. Kellenberger E. Exploring the unknown: the silent revolution of microbiology. EMBO Rep 2001;2:5–7.

    PubMed  CAS  Google Scholar 

  38. Hugenholtz P, Goebel BM, Pace NR. Impact of culture-independent studies on the emerging phylogenetic view of bacterial diversity. J Bacteriol 1998;180:4765–4774.

    PubMed  CAS  Google Scholar 

  39. Davies J. Millennium bugs. Trends Biochem Sci 1999;24:M2–M5.

    Google Scholar 

  40. Hunter-Cevera J, Belt A. Isolation of cultures. In: Demain AL, Davies J, eds. Manual of Industrial Microbiology and Biotechnology. American Society for Microbiology, Washington DC: 1999:3–20.

    Google Scholar 

  41. Bruns A, Cypionka H, Overmann J. Cyclic AMP and acyl homoserine lactones increase the cultivation efficiency of heterotrophic bacteria from the central Baltic Sea. Appl Environ Microbiol 2002;68:3978–3987.

    PubMed  CAS  Google Scholar 

  42. Kaeberlein T, Lewis K. Isolating “uncultivable” microorganisms in pure culture in a simulated natural environment. Science 2002;296:1127–1129.

    PubMed  CAS  Google Scholar 

  43. Brewer DG, Martin SE, Ordal ZJ. Beneficial effects of catalase or pyruvate in a most-probablenumber technique for the detection of Staphylococcus aureus. Appl Environ Microbiol 1977;34:797–800.

    PubMed  CAS  Google Scholar 

  44. Kalish H, Camp JE, Stepien M, Latos-Grazynski L, Balch AL. Reactivity of mono-meso-substituted iron(II) octaethylporphyrin complexes with hydrogen peroxide in the absence of dioxygen. Evidence for nucleophilic attack on the heme. J Am Chem Soc 2001;123:11,719–11,727.

    PubMed  CAS  Google Scholar 

  45. Ferenci T. Adaptation to life at micromolar nutrient levels: the regulation of Escherichia coli glucose transport by endoinduction and cAMP. FEMS Microbiol Rev 1996;18:301–317.

    PubMed  CAS  Google Scholar 

  46. Zengler K, Toledo G, Rappe M, et al. Cultivating the uncultured. PNAS 2002;99:15,681–15,686.

    PubMed  CAS  Google Scholar 

  47. Connon SA, Giovannoni SJ. High-throughput methods for culturing microorganisms in verylownutrient media yield diverse new marine isolates. Appl Environ Microbiol 2002;68: 3878–3885.

    PubMed  CAS  Google Scholar 

  48. Demain AL. Induction of secondary metabolism. Int Microbiol 1998;1:259–64.

    PubMed  CAS  Google Scholar 

  49. Demain AL. Microbial natural products: alive and well in 1998. Nat Biotechnol 1998;16:3–4.

    PubMed  CAS  Google Scholar 

  50. Horinouchi S. A microbial hormone, A-factor, as a master switch for morphological differentiation and secondary metabolism in Streptomyces griseus. Front Biosci 2002;7:2045–2057.

    Google Scholar 

  51. Betina V. Bioactive secondary metabolites of microorganisms. Progr Ind Microbiol 1994;30:5–14.

    Google Scholar 

  52. Luchese R, Harrigan W. Biosynthesis of aflatoxin-the role of nutritional factors. J Appl Bacteriol 1993;74:5–14.

    PubMed  CAS  Google Scholar 

  53. Boeck L, Christy KL. Production of anticapsine by Streptomyces griseoplanus. Appl Microbiol Biotechnol 1971;21:1075–1079.

    CAS  Google Scholar 

  54. Aharonowitz Y. Nitrogen metabolite regulation of antibiotic biosynthesis. Annu Rev Microbiol 1980;34:209–233.

    PubMed  CAS  Google Scholar 

  55. Abbanat D, Maiese W. Biosynthesis of the pyrroindomycins by Streptomyces rugosporus LL-42D005; characterization of nutrient requirements. J Antibiot 1999;52:117–126.

    PubMed  CAS  Google Scholar 

  56. Gotoh T, Nakahara K, Hashimoto M, et al. Studies on a new immunoacrive peptide, FK-156. II Fermentation, extraction and chemical and biological characterization. J Antibiot 1982;35: 1286–1292.

    PubMed  CAS  Google Scholar 

  57. Shimada N, Hasegawa S, Harada T, Tomisawa T, Fuji A, Takita T. Oxetanocin, a novel nucleoside from bacteria. J Antibiot 1986;39:1623–1625.

    PubMed  CAS  Google Scholar 

  58. Weinberg E. Secondary metabolism: regulation by phosphate and trace elements. Folia Microbiol 1978;23:496–504.

    Article  CAS  Google Scholar 

  59. Barberel S, Walker J. The effect of aeration upon secondary metabolism of microorganisms. Biotechnol Genet Eng Rev 2000;17:281–323.

    PubMed  CAS  Google Scholar 

  60. Pfefferle C, Theobald U, Gurtler H, Fiedler H. Improved secondary metabolite production in the genus Streptosporangium by optimization of the fermentation conditions. J Biotechnol 2001;23:135–142.

    Google Scholar 

  61. Schimana J, Gebhardt K, Holtzel A, et al. Arymomycins A and B, bew biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tu6075. I Taxonomy, fermentation, isolation and biological activities. J Antibiot 2002;55:565–570.

    PubMed  CAS  Google Scholar 

  62. Saitoh K, Tenmyo O, Yamamoto S, Furumai T., Pramicidin S, a new pramicidin analog. I Taxonomy, fermentation and biological activities. J Antibiot 1993;46:580–588.

    PubMed  CAS  Google Scholar 

  63. Gerth K, Bedorf N HG, Irschik H, Reichenbach H. Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. J Antibiot 1996;49:560–563.

    PubMed  CAS  Google Scholar 

  64. Calvo AM, Wilson RA, Bok JW, Keller NP. Relationship between secondary metabolism and fungal development. Microbiol. Mol Biol Rev 2002;66:447–459.

    PubMed  CAS  Google Scholar 

  65. Robinson T, Singh D, Nigam P. Solid-state fermentation: a promising microbial technology for secondary metabolite production. Appl Microbiol Biotechnol 2001;55:284–289.

    PubMed  CAS  Google Scholar 

  66. Sandor E, Szentirmai A, Paul GC, Thomas CR, Pocsi L, Karaffa L. Analysis of the relationship between growth, cephalosporin C production, and fragmentation in Acremonium chrysogenum. Can J Microbiol 2001;47:801–806.

    PubMed  CAS  Google Scholar 

  67. Chen G, Wang YS, Li X, Waters B, Davies J. Enhanced production of microbial metabolites in the presence of dimethyl sulfoxyde. J Antibiot 2000;53:1145–1153.

    PubMed  CAS  Google Scholar 

  68. Minas W, Bailey JE, Duetz W. Streptomycetes in micro-cultures: growth, production of secondary metabolites, and storage and retrieval in the 96-well format. Antonie Van Leeuwenhoek 2000;78:297–305.

    PubMed  CAS  Google Scholar 

  69. Trujillo M, H.U., Gremlich, J.J. Sanglier. Selection strategy of traditional microorganisms for pharmacological screenings. Dev Ind Microb 1997;33: 35–42.

    Google Scholar 

  70. Schiewe HJ, Zeeck A. Cineromycins, gamma-butyrolactones and ansamycins by analysis of the secondary metabolite pattern created by a single strain of Streptomyces. J Antibiot 1999;52:635–642.

    PubMed  CAS  Google Scholar 

  71. Reichenbach H. Myxobacteria, producers of novel bioactive substances. J Ind Microbiol Biotechnol 2001;27:149–156.

    PubMed  CAS  Google Scholar 

  72. Hopwood D. Forty years of genetics with Streptomyces: from in vivo through in vitro to silico. Microbiology 1999;145:2183–2202.

    PubMed  CAS  Google Scholar 

  73. Kupfer D, Reece CA, Clifton SW, Roe BA, Prade RA. Multicellular ascomycetous fungal genomes contain more than 8000 genes. Fungal Genet Biol 1997;21:364–372.

    PubMed  CAS  Google Scholar 

  74. Pradella S, Hans A, Spoer C, Reichenbach H, Gerth K, Beyer S. Characterisation, genome size and genetic manipulation of the myxobacterium Sorangium cellulosim So ce56. Arch Microbiol 2002;178:484–492.

    PubMed  CAS  Google Scholar 

  75. Bentley S, Chater KF. Complete genome sequence of the model actinomycetes Streptomyces coelicolor A(3)2. Nature 2002;417:141–147.

    PubMed  Google Scholar 

  76. Omura S, Ikeda H, Ishikawa J, et al. Genome sequence of an industrial microorganism Streptomyces avermitilis deducing the ability of producing secondary metabolites. Proc Natl Acad Sci USA 2001;98:12,215–12,220.

    PubMed  CAS  Google Scholar 

  77. Silakowski B, Kunze B, Muller R. Multiple hybrid polyketide synthase/non-ribosomal peptide synthetase gene clusters in the myxobacterium Stigmatella aurantiaca. Gene 2001;275: 233–240.

    PubMed  CAS  Google Scholar 

  78. Pierceal, W., L. Zhang, and D. Hughes. Affinity capillary electrophoresis analyses of proteinprotein interactions in target-directed drug discovery. In Haian Fu (ed), “Methods in Molecular Biology, vol 261: Protein-Protein Interactions”, Humana, Totowa, NJ: 2003;187–197.

    Google Scholar 

  79. Bode HB, Bethe B, Hofs R, Zeeck A. Big effects from small changes: possible ways to explore nature’s chemical diversity. Chembiochem 2002;3:619–627.

    PubMed  CAS  Google Scholar 

  80. Wieling J, Dijkstra H, Mensink CK, et al. Chemometrics in bioanalytical sample preparation. A fractionated combined mixture and factorial design for the modelling of the recovery of five tricyclic amines from plasma after liquid-liquid extraction prior to high-performance liquid chromatography. J Chromatogr 1993;629:181–199.

    PubMed  CAS  Google Scholar 

  81. Degenkolb T, Heinze S, Schlegel B, Strobel G, Grafe U. Formation of new lipoaminopeptides, acremostatins A,B, and C, by co-cultivation of Acremonium sp. Tbp-5 and mycogene rosea DSM 12973. Biosci Biotechnol Biochem 2002;66:883–890.

    PubMed  CAS  Google Scholar 

  82. Kennedy J, Hutchinson CR. Nurturing nature: engineering new antibiotics. Nat Biotechnol 1999;17:538–539.

    PubMed  CAS  Google Scholar 

  83. Stokes HW, Holmes AJ, Nield BS, et al. Gene cassette PCR: sequence-independent recovery of entire genes from environmental DNA. Appl. Environ. Microbiol. 2001;67:5240–5246.

    PubMed  CAS  Google Scholar 

  84. Rondon MR, August PR, Bettermann AD, et al. Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms. Appl Environ Microbiol 2000;66:2541–2547.

    PubMed  CAS  Google Scholar 

  85. Zazopoulos E, Huang K, Staffa A, et al. A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nature Biotechnol 2003;21:187–190.

    CAS  Google Scholar 

  86. Xue Q, Ashley G, Hutchinson CR, Santi DV. A multiplasmid approach to preparing large libraries of polyketides. PNAS 1999;96:11,740–11,745.

    PubMed  CAS  Google Scholar 

  87. McDaniel R, Thamchaipenet A, Gustafsson C, et al. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products. PNAS 1999;96:1846–1851.

    PubMed  CAS  Google Scholar 

  88. Hopwood DA, Malpartida F, Kieser HM, et al. Production of “hybrid” antibiotics by genetic engineering. Nature 1985;314:642–644.

    PubMed  CAS  Google Scholar 

  89. Seow K, Meurer G, Gerlitz M, Wendt-Pienkowski E, Hutchinson C, Davies J. 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 1997;179:7360–7368.

    PubMed  CAS  Google Scholar 

  90. Christiansen G, Fastner J, Erhard M, Borner T, Dittmann E. Microcystin biosynthesis in Planktothrix: genes, evolution, and manipulation. J Bacteriol 2003;185:564–572.

    PubMed  CAS  Google Scholar 

  91. Walsh CT. Combinatorial biosynthesis of antibiotics: challenges and opportunities. Chembiochem 2002;3:125–134.

    PubMed  Google Scholar 

  92. Rix U, Fischer C, Remsing LL, Rohr J. Modification of post-PKS tailoring steps through combinatorial biosynthesis. Nat Prod Rep 2002;19:542–580.

    PubMed  CAS  Google Scholar 

  93. Zhang YX, Perry K, Vinci VA, Powell K, Stemmer WP, del Cardayre SB. Genome shuffling leads to rapid phenotypic improvement in bacteria. Nature 2002;415:644–646.

    PubMed  CAS  Google Scholar 

  94. Cohan FM. Bacterial species and speciation. Syst Biol 2001;50:513–524.

    PubMed  CAS  Google Scholar 

  95. Goodfellow M, Freeman R. Curie-point pyrolysis mass spectrometry as a tool in clinical microbiology. Zentralbl Bakteriol 1997;285:133–156.

    PubMed  CAS  Google Scholar 

  96. Bastert J, Korting HC, Traenkle P, Schmalreck AF. Identification of dermatophytes by Fourier transform infrared spectroscopy (FT-IR). Mycoses 1999;42:525–528.

    PubMed  CAS  Google Scholar 

  97. Brandao PF, Torimura M, Kurane R, Bull AT. Dereplication for biotechnology screening: PyMS analysis and PCR-RFLP-SSCP (PRS) profiling of 16S rRNA genes of marine and terrestrial actinomycetes. Appl Microbiol Biotechnol 2002;58:77–83.

    PubMed  CAS  Google Scholar 

  98. Brandao PF, Clapp JP, Bull AT. Discrimination and taxonomy of geographically diverse strains of nitrile-metabolizing actinomycetes using chemometric and molecular sequencing techniques. Environ Microbiol 2002;4:262–276.

    PubMed  CAS  Google Scholar 

  99. Vermis K, Vandekerckhove C, Nelis HJ, Vandamme PA. Evaluation of restriction fragment length polymorphism analysis of 16S rDNA as a tool for genomovar characterisation within the Burkholderia cepacia complex. FEMS Microbiol Lett 2002;214:1–5.

    PubMed  CAS  Google Scholar 

  100. Schloter M, Lebuhn M, Heulin T, Hartmann A. Ecology and evolution of bacterial microdiversity. FEMS Microbiol Rev 2000;24:647–660.

    PubMed  CAS  Google Scholar 

  101. von Wintzingerode F, Bocker S, Schlotelburg C, et al. Base-specific fragmentation of amplified 16S rRNA genes analyzed by mass spectrometry: a tool for rapid bacterial identification. PNAS2002;99:7039–7044.

    Google Scholar 

  102. Nielsen NP, Smedsgaard J, Frisvad JC. Full second-order chromatographic/spectrometric data matrices for automated sample identification and component analysis by non-data-reducing image analysis. Anal Chem 1999;71:727–735.

    PubMed  CAS  Google Scholar 

  103. Smedsgaard J. Micro-scale extraction procedure for standardized screening of fungal metabolite production in cultures. J Chromatogr A 1997;760:264–270.

    PubMed  CAS  Google Scholar 

  104. Yurek DA, Branch DL, Kuo MS. Development of a system to evaluate compound identity, purity, and concentration in a single experiment and its application in quality assessment of combinatorial libraries and screening hits. J Comb Chem 2002;4:138–148.

    PubMed  CAS  Google Scholar 

  105. Higgs RE, Zahn JA, Gygi JD, Hilton MD. Rapid method to estimate the presence of secondary metabolites in microbial extracts. Appl Environ Microbiol 2001;67:371–376.

    PubMed  CAS  Google Scholar 

  106. Zahn JA, Higgs RE, Hilton MD. Use of direct-infusion electrospray mass spectrometry to guide empirical development of improved conditions for expression of secondary metabolites from actinomycetes. Appl Environ Microbiol 2001;67:377–386.

    PubMed  CAS  Google Scholar 

  107. Cremin PA, Zeng L. High-throughput analysis of natural product compound libraries by parallel LC-MS evaporative light scattering detection. Anal Chem 2002;74:5492–5500.

    PubMed  CAS  Google Scholar 

  108. Bobzin SC, Yang S, Kasten TP. LC-NMR: a new tool to expedite the dereplication and identification of natural products. J Ind Microbiol Biotechnol 2000;25:342–345.

    PubMed  CAS  Google Scholar 

  109. Bobzin SC, Yang S, Kasten TP. Application of liquid chromatography-nuclear magnetic resonance spectroscopy to the identification of natural products. J Chromatogr B Biomed Sci Appl 2000;748:259–267.

    PubMed  CAS  Google Scholar 

  110. Schultz M, Tsaklakidis C. Nach Chem Tech Lab 1997;45:159–165.

    Google Scholar 

  111. Garcia JB, Tormo JR. HPLC Studio: a novel software utility to perform HPLC chromatogram comparison for screening purposes J Biomol Screen 2003;8(3):305–315

    PubMed  CAS  Google Scholar 

  112. Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981-2002. J Nat Prod 2003;66(7):1022–1037

    PubMed  CAS  Google Scholar 

  113. Martinez A, Kolvek SJ, Tiong Yip CL, et al. Genetically modified bacterial strains and novel shuttle BAC vectors for constructing environmental libraries and detecting heterologous natural products in multiple expression hosts. Appl Environ Microbiol 2004;70:2452–2463.

    PubMed  CAS  Google Scholar 

  114. Tormo JR, García JB, DeAntonio M, et al. A method for the selection of production media for actinomycete strains based on their metabolite HPLC profiles. J Ind Mic Biotech 2003;30: 582–588.

    CAS  Google Scholar 

  115. Knight V, Sanglier JJ, DiTullio D, et al. Diversifying microbial natural products for drug discovery. Appl Microbiol Biotech 2003;62:446–458.

    CAS  Google Scholar 

  116. Woese CR. Bacterial evolution. Microbiol Rev 1987;51:221–271.

    PubMed  CAS  Google Scholar 

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  1. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Lixin Zhang PhD

  2. SynerZ Pharmaceuticals Inc., Lexington, MA

    Lixin Zhang PhD

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  1. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    Lixin Zhang PhD

  2. SynerZ Pharmaceuticals Inc., Lexington, MA

    Lixin Zhang PhD

  3. Charles A. Dana Research Institute (R.I.S.E.), Drew University, Madison, NJ

    Arnold L. Demain PhD

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Zhang, L. (2005). Integrated Approaches for Discovering Novel Drugs From Microbial Natural Products. In: Zhang, L., Demain, A.L. (eds) Natural Products. Humana Press. https://doi.org/10.1007/978-1-59259-976-9_2

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