Pharmacologically Active Agents of Microbial Origin

Stephen K. Wrigley

doi:10.1128/9781555817770.ch32

Chapter 32 : Pharmacologically Active Agents of Microbial Origin

Author: Stephen K. Wrigley¹

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Cubist Pharmaceuticals (UK) Ltd., 545 Ipswich Road, Slough, Berkshire SL1 4EP, United Kingdom

Content Type: Monograph

Publication Year: 2004

Category: Environmental Microbiology; Applied and Industrial Microbiology

Book DOI: 10.1128/9781555817770

Chapter DOI: 10.1128/9781555817770.ch32

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Pharmacologically Active Agents of Microbial Origin, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817770/9781555812676_Chap32-1.gif /docserver/preview/fulltext/10.1128/9781555817770/9781555812676_Chap32-2.gif

Abstract:

Pharmacologically active natural products are generally classified as those useful for treating human diseases and disorders including hyperlipidemia, cancer, immunoregulatory disorders, inflammation, and neurological and metabolic diseases. This chapter reviews the discovery of pharmacologically active microbial metabolites, with an emphasis on recent developments, and considers the specific challenges involved in screening samples derived from microbial fermentations. It discusses high-throughput screening assays used for the discovery of pharmacologically active agents. It also gives specific examples of assays that have resulted in the discovery of new pharmacological agents of microbial origin. The chapter also reviews the selected pharmacologically active agents of microbial origin with utility or potential utility in the areas of immunosuppression, cancer, and cardiovascular and metabolic disease. The microbial products discussed in this chapter range from successful drugs to recently described lead compounds and provide ample testament to the ability of microbial secondary metabolism to provide compounds with real or potential therapeutic utility against a diverse and extensive range of pharmacological targets. The focus of many current microbial product screening operations is returning to antibiotic discovery. It is worth remembering that the discovery route of some very significant pharmacologically active agents of microbial origin has been indirect.

Citation: Wrigley S. 2004. Pharmacologically Active Agents of Microbial Origin, p 356-374. In Bull A (ed), Microbial Diversity and Bioprospecting. ASM Press, Washington, DC. doi: 10.1128/9781555817770.ch32

Highlighted Text: Show | Hide

Full text loading...

Figures

Pharmacologically Active Agents of Microbial Origin

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555817770.chap32-1,webId=/content/author/10.1128/9781555817770.chap32-1,properties={foaf_givenname=Stephen K., foaf_name=Stephen K. Wrigley, foaf_surname=Wrigley, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555817770.chap32-aff1]]}]]

/content/10.1128/9781555817770.chap32.fig32-1

Figure 1

Structures of the Memnoniella echinata metabolite L-671,776, (structure 1), the Favolaschia sp. metabolite 9-methoxystrobilurin E (structure 2), the actinomycete metabolite geldanamycin (structure 3), and the fungal metabolite monorden (radicicol) (structure 4).

10.1128/9781555817770/fig32-1_thmb.gif

10.1128/9781555817770/fig32-1.gif

Figure 1

/content/10.1128/9781555817770.chap32.fig32-2

Figure 2

Structures of the immunosuppressants, cyclosporin A (structure 1), from Tolypocladium inflatum; FK506 (structure 2) from Streptomyces tsukubaensis; and rapamycin (structure 3) from Streptomyces hygroscopicus.

10.1128/9781555817770/fig32-2_thmb.gif

10.1128/9781555817770/fig32-2.gif

Figure 2

/content/10.1128/9781555817770.chap32.fig32-3

Figure 3

Structures of the immunosuppressive lead compounds myriocin A (structure 1) from Isaria sinclairii; sanglifehrin A (structure 2) from a Streptomyces sp.; XR774 (structure 3) from Cladosporium cf. cladosporioides; and CJ-14,897 (structure 4) from a Marasmiellus sp.

10.1128/9781555817770/fig32-3_thmb.gif

10.1128/9781555817770/fig32-3.gif

Figure 3

/content/10.1128/9781555817770.chap32.fig32-4

Figure 4

Structures of antitumor agents epothilone A (structure 1) from Sorangium cellulosum; fumagillin (structure 2) from Aspergillus fumigatus; calicheamicin γ (structure 3) from Micromonospora echinospora subsp. calichensis; and XR842 (structure 4) from Streptomyces cyaneus.

10.1128/9781555817770/fig32-4_thmb.gif

10.1128/9781555817770/fig32-4.gif

Figure 4

/content/10.1128/9781555817770.chap32.fig32-5

Figure 5

Structures of mechanism-based antitumor lead compounds UCN-01 (structure 1) from a Streptomyces sp.; clavaric acid (structure 2) from Clavariadelphus truncatus; chlorofusin (structure 3) from Microdocbium caespitosum; lactacystin (structure 4) from a Streptomyces sp.; and telemostatin (structure 5) from Streptomyces anulatus.

10.1128/9781555817770/fig32-5_thmb.gif

10.1128/9781555817770/fig32-5.gif

Figure 5

/content/10.1128/9781555817770.chap32.fig32-6

Figure 6

Structures of the cardiovascular drugs and lead compounds lovastatin (structure 1 ) from Aspergillus terreus; mevastatin (structure 2) from Penicillium citrinum and Penicillium brevicompactum; squalestatin SI from a Phoma sp. or zaragozic acid A from an unidentified fungus (structure 3); and pyripyropene A (structure 4) from Aspergillus fumigatus.

10.1128/9781555817770/fig32-6_thmb.gif

10.1128/9781555817770/fig32-6.gif

Figure 6

/content/10.1128/9781555817770.chap32.fig32-7

Figure 7

Structures of lipstatin (structure 1) from Streptomyces toxytricini; acarbose (structure 2) from an Actinoplanes sp.; and L-783,281 (structure 3) from a Pseudomassaria sp.

10.1128/9781555817770/fig32-7_thmb.gif

10.1128/9781555817770/fig32-7.gif

Figure 7

Structures of lipstatin (structure 1) from Streptomyces toxytricini; acarbose (structure 2) from an Actinoplanes sp.; and L-783,281 (structure 3) from a Pseudomassaria sp.

References

/content/book/10.1128/9781555817770.chap32

1. Ainsworth, A. M.,, S. K. Wrigley,, and U. Fauth,. 2001. Molecular and taxonomie diversity in drug discovery: experience of chemical and biological screening approaches, p. 131– 156. In S. B. Pointing, and K. D. Hyde (ed.), Bio-Exploitation of Filamentous Fungi, Fungal Diversity Research Series 6. Fungal Diversity Press, Hong Kong.

2. Alberts, A. W.,, J. Chen,, G. Kuron,, V. Hunt,, J. Huff,, C. Hoffman,, J. Rothrock,, M. Lopez,, H. Joshua,, E. Harris,, A. Patchett,, R. Monaghan,, S. Currie,, E. Stapley,, G. Albers-Schonberg,, O. Hensens,, J. Hirshfield,, K. Hoogsteen,, J. Liesch,, and J. Springer. 1980. Mevinolin: a highly competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a potent cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA 77: 3957– 3961.

3. Bergstrom, J. D.,, M. M. Kurtz,, D. J. Rew,, A. M. Amend,, J. D. Karkas,, R. G. Bostedor,, V. S. Bansal,, C. Dufresne,, F. L. Van-Middlesworth,, O. D. Hensens,, J. M. Liesch,, D. L. Zink,, K. E. Wilson,, J. Onishi,, J. A. Milligan,, G. Bills,, L. Kaplan,, M. Nallin Omstead,, R. G. Jenkins,, L. Huang,, M. S. Meinz,, L. Quinn,, R. W. Burg,, Y. L. Kong,, S. Mochales,, M. Mojena,, I. Martin,, F. Pelaez,, M. T. Diez,, and A. W. Alberts. 1993. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc. Natl. Acad. Sci. USA 90: 80– 84.

4. Bindseil, K. U.,, J. Jakupovic,, D. Wolf,, J. Lavayre,, J. Leboul,, and D. van der Pyl. 2001. Pure compound libraries; a new perspective for natural product based drug discovery. Drug Discovery Today 6: 840– 847.

5. Bollag, D. M.,, P. A. McQueney,, J. Zhu,, O. Hensens,, L. Koupal,, J. Liesch,, M. Goetz,, E. Lazarides,, and C. M. Woods. 1995. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 55: 2325– 2333.

6. Borel, J. F.,, C. Feurer,, H. U. Gubler,, and H. Stahelin. 1976. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6: 468– 475.

7. Brown, A. G.,, T. C. Smale,, T. J. King,, R. Hasenkamp,, and R. H. Thompson. 1976. Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum. J. Chem. Soc. Perkin Trans. 1: 1165– 1170.

8. Cardenas, M. E.,, A. Sanfridson,, N. S. Cutler,, and J. Heitman. 1998. Signal-transduction cascades as targets for therapeutic intervention by natural products. Trends Biotechnol. 16: 427– 433.

9. Chang, R. S. L.,, V. J. Lotti,, R. L., Monaghan,, J. Birnbaum,, E. O. Stapley,, M. A. Goetz,, G. Albers-Schonberg,, A. A. Patchett,, J. M. Liesch,, O. D. Hensens,, and J. P. Springer. 1985. A potent non-peptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus. Science 230: 177– 179.

10. Chen, J. K.,, W. S. Lane,, and S. L. Schreiber. 1999. The identification of myriocin-binding proteins. Chem. Biol. 6: 221– 235.

11. Cragg, G. M.,, M. R. Boyd,, Y. F. Hallock,, D. J. Newman,, E. A. Sausville,, and M. K. Wolpert,. 2000. Natural products drug discovery at the National Cancer Institute. Past achievements and new directions for the new millennium, p. 22– 44. In S. K. Wrigley,, M. A. Hayes,, R. Thomas,, E. J. T. Chrystal,, and N. Nicholson (ed.), Biodiversity: New Leads for the Pharmaceutical and Agrochemical Industries. Royal Society of Chemistry, Cambridge, United Kingdom.

12. Dawson, M. J.,, J. E. Farthing,, P. S. Marshall,, R. F. Middleton,, M. J. O'Neill,, A. Shuttleworth,, C. Stylli,, R. M. Tait,, P. M. Taylor,, H. G. Wildman,, A. D. Buss,, D. Langley,, and M. V Hayes. 1992. The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity. J. Antibiot. 45: 639– 647.

13. Dick, L. R.,, A. A. Cmikshank,, A. T. Destree,, L. Grenier,, T. A. McCormack,, F. D. Melandri,, S. I. Nunes,, V. J. Palombella,, L. A. Parent,, L. Plamonden,, and R. L. Stein. 1997. Mechanistic studies on the inactivation of the proteasome by lactacystin in cultured cells. J. Biol. Chem. 272: 182– 188.

14. Drews, J. 2000. Drug discovery: a historical perspective. Science 287: 1960– 1964.

15. Duncan, S. J.,, M. A. Cooper,, and D. H. Williams. 2003. Binding of an inhibitor of the p53/MDM2 interaction to MDM2. Chem. Commun. 2003: 316– 317.

16. Duncan, S. J.,, S. Gruschow,, D. H. Williams,, C. McNicholas,, R. Purewal,, M. Hajek,, M. Gerlitz,, S. Martin,, S. K. Wrigley,, and M. Moore. 2001. Isolation and structure elucidation of chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp. J. Amer. Chem. Soc. 123: 554– 560.

17. Endo, A.,, and K. Hasumi. 1993. HMG-CoA reductase inhibitors. Nat. Prod. Rep. 10: 541– 550.

18. Fehr, T.,, V. F. J. Quesniaux,, J. J. Sanglier,, L. Obérer,, L. Gschwind,, M. Ponelle,, W. Schilling,, S. Wehrli,, A. Enz,, G. Zenke,, and W. Schuier. 1997. Cymbimicin A and B, two novel cyclophilin-binding structures isolated from actinomycetes. J. Antibiot. 50: 893– 899.

19. Franco, C. M. M.,, and L. E. L. Coutinho. 1991. Detection of novel secondary metabolites. Crit. Rev. Biotechnol. 11: 193– 276.

20. Fujita, T.,, K. Inoue,, S. Yamamoto,, T. Ikumoto,, S. Sasaki,, R. Toyama,, K. Chiba,, Y. Hoshino,, and T. Okumoto. 1994. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. 47: 208– 215.

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

22. Grabley, S.,, and R. Thiericke. 1999. Bioactive agents from natural sources: trends in discovery and application. Adv. Biochem. Eng. Biotechnol. 64: 101– 154.

23. Guerciolini, R. 1997. Mode of action of orlistat. Int. J. Obesity 21: S12– S23.

24. Hamann, P. R.,, and M. S. Berger,. 2002. Mylotarg: the first antibody-targeted chemotherapy agent, p. 239– 254. In M. sur (ed.), Cancer Drug Discovery and Development: Tumor Targeting in Cancer Therapy. Humana Press Inc., Totawa, N.J.

25. Hanada, M.,, K. Sugawara,, K. Kaneta,, S. Toda,, Y. Nishiyama,, K. Tomita,, H. Yamamoto,, M. Konishi,, and T. Oki. 1992. Epoxomicin, a new antitumour agent of microbial origin. J. Antibiot. 45: 1746– 1752.

26. Henkel, T.,, R. M. Brunne,, H. Muller,, and F. Reichel. 1999. Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew. Chem. Int. Ed. 38: 643– 647.

27. Hertzberg, R. P. 1993. Whole cell assays in screening for biologically active substances. Curr. Opin. Biotechnol. 4: 80– 84.

28. Hill, D. C.,, S. K. Wrigley,, and L. J. sur . 1998. Novel screen methodologies for identification of new microbial metabolites with pharmacological activity. Adv. Biochem. Eng. Biotechnol. 59: 73– 121.

29. Huang, S.,, and P. J. Houghten. 2002. Inhibitors of mammalian target of rapamycin as novel antitumour agents: from bench to clinic. Curr. Opin. Invest. Drugs 3: 295– 304.

30. Ichikawa, K.,, H. Hirai,, M. Ishiguro,, T. Kambara,, Y. Kato,, Y. I. Kim,, Y. Kojima,, V. Matsunaga,, H. Nishida,, Y. Shiomi,, N. Yoshikawa,, and N. Kojima. 2001a. Novel cytokine production inhibitors produced by a basidiomycete, Marasmiellus sp. J. Antibiot. 54: 703– 709.

31. Ichikawa, K.,, H. Hirai,, M. Ishiguro,, T. Kambara,, Y. Kato,, Y. J. Kim,, Y. Kojima,, Y, Matsunaga,, H. Nishida,, Y. Shiomi,, N. Yoshikawa,, L. H. Huang,, and N. Kojima. 2001b. Cytokine production inhibitors produced by a fungus, Oidiodendron griseum. J. Antibiot. 54: 697– 702.

32. Ingber, D.,, T. Fujita,, S. Kishimoto,, K. Sudo,, T. Kanamaru,, H. Brem,, and J. Folkman. 1990. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348: 555– 557.

33. Istvan, E. S.,, and J. Deisenhofer. 2001. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292: 1160– 1164.

34. Kakeya, H.,, S.-I. Kageyama,, L. Nie,, R. Onose,, G. Okada,, T. Beppu,, C. J. Norbury,, and H. Osada. 2001. Lucilactaene, a new cell cycle inhibitor in p53-transfected cancer cells, produced by a Fusarium sp . J. Antibiot. 54: 850– 854.

35. Kelland, L. R.,, S. Y. Sharp,, P. M. Rogers,, T. G. Myers,, and P. Workman. 1999. DT-diaphorase expression and tumor cell sensitivity to 17-allylamino,17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J. Natl. Cancer Inst. 91: 1940– 1949.

36. Kino, T.,, H. Hatanaka,, M. Hashimoto,, M. Nishiyama,, T. Goto,, M. Okuhara,, M. Kohsaka,, H. Aoki,, and H. Imanako. 1987a. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J. Antibiot. 40: 1249– 1255.

37. Kino, T.,, H. Hatanuka,, S. Miyata,, N. Inamura,, M. Nishiyama,, T. Yajima,, T. Goto,, M. Okuhara,, M. Kohsaka,, H. Aoki,, and T. Ochiai. 1987b. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro.. J. Antibiot 40: 1256– 1265.

38. Kulanthaivel, P.,, Y. F. Hallock,, C. Boros,, S. M. Hamilton,, W. P. Janzen,, L. M. Ballas,, C. R. Loomis,, and J. B. Jiang. 1993. Balanol: a novel and potent inhibitor of protein kinase C from the fungus Verticillium balanoides. J. Am. Chem. Soc. 115: 6452– 6453.

39. Kureishi, Y.,, Z. Luo,, I. Shiojima,, A. Bialik,, D. Fulton,, D. J Lefer,, W. C. Sessa,, and K. Walsh. 2000. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat. Med. 6: 1004– 1010.

40. Lam, Y. K. T.,, C. F. Wichmann,, M. S. Meinz,, L. Guariglia,, R. A. Giacobbe,, S. Mochales,, I. Kong,, S. S. Honeycutt,, D. Zink,, G. F. Bills,, L. Huang,, R. W. Burg,, R. L. Monaghan,, R. Jackson,, G. Reid,, J. J. Maguire,, A. T. McKnight, and C. I. Ragan. 1992. A novel inositol mono-phosphatase inhibitor from Memnoniella echinata. Producing organism, fermentation, isolation, physico-chemical and in vitro biological properties. J. Antibiot. 45: 1397– 1403.

41. Laube, H. 2002. Acarbose: an update of its therapeutic use in diabetes treatment. Clin. Drug Invest. 22: 141– 156.

42. Lee, F. Y. F.,, R. Borzilleri,, C. R. Fairchild,, S.-H. Kim,, B. H. Long,, C. Reventos-Suarez,, G. D. Vite,, W. C. Rose,, and R. A. Kramer. 2001. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin. Cancer Res. 7: 1429– 1437.

43. Lee, M. D.,, F. E. Durr,, L. M. Hinman,, P. R. Hamann,, and G. A. Ellestad. 1993. The calicheamicins. Adv. Med. Chem. 2: 31– 66.

44. Lingham, R. B.,, K. C. Silverman,, H. Jayasuriya,, B. M. Kim,, S. E. Arno,, F. R. Wilson,, D. J. Raw,, M. D. Schaber,, J. D. Bergstrom,, K. S. Koblan,, S. L. Graham,, N. E. Kohi,, J. B. Gibbs,, and S. B. Singh. 1998. Clavarie acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase. J. Med. Chem. 41: 4492– 4501.

45. MacAllan, D. September 1997. Dual label solid phase binding assay. International patent application WO 9816833.

46. MacAllan, D.,, J. Sohal,, C. Walker,, D. Hill,, and M. Moore. 1997. Development of a novel TNFa ligand-receptor binding assay for screening NatChem™ libraries. J. Recept. Sig. Trans. Res. 17: 521– 529.

47. Mann, J. 2001. Natural products as immunosuppressive agents. Nat. Prod. Rep. 18: 417– 430.

48. Meng, L.,, R. Mohan,, B. H. B. Kwok,, M. Eloffson,, N. Sin,, and C. M. Crews. 1999. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo anti-inflammatory activity. Proc. Natl. Acad. Sci. USA 96: 10403– 10408.

49. Minagawa, K.,, S. Kouzuki,, K. Nomura,, T. Yamaguchi,, Y. Kawamura,, K. Matsushima,, H. Tani,, K. Ishii,, T. Tanimoto,, and T. Kamigauchi. 2001. Bisabosquals, novel squalene synthase inhibitors. I. Taxonomy, fermentation, isolation and biological properties. J. Antibiot. 54: 890– 895.

50. Momose, I.,, R. Sekizawa,, H. Hashizume,, N. Kinoshita,, Y. Homma,, M. Hamada,, H. Iinuma,, and T. Takeuchi. 2001. Tyropeptins A and B, new proteasome inhibitors produced by Kitasatosporia sp. MK993-dF2. I. Taxonomy, isolation, physico-chemical properties and biological activities. J. Antibiot. 54: 997– 1003.

51. Morris, R. E.,, and B. M. Meiser. 1989. Identification of a new pharmacologie action for an old compound. Med. Sci. Res. 17: 877– 878.

52. Muller, L.,, B. Junge,, W. Frommer,, D. Schmidt,, and E. Truscheit,. 1980. Acarbose (BAY g 5421) and homologous α-glucosidase inhibitors from actinoplanaceae, p. 109– 122. In V. Brodberk (ed.), Enzyme Inhibitors. Proceedings of the Meeting. Verlag Chemie, Weinheim, Germany.

53. Mundy, G.,, R. Garrett,, S. Harris,, J. Chan,, D. Chen,, G. Rossini,, B. Boyce,, M. Zhao,, and G. Gutierrez. 1999. Stimulation of bone formation in vitro and in rodents by statins. Science 286: 1946– 1949.

54. Newman, D. J.,, G. M. Cragg,, and K. M. Snader. 2000. The influence of natural products upon drug discovery. Nat. Prod. Rep. 17: 215– 234.

55. Nie, L.,, M. Ueki,, H. Kakeya,, and H. Osada. 2001. A facile and effective screening method for p21 WAF1 promoter activators from microbial metabolites. J. Antibiot. 54: 783– 788.

56. Nisbet, L. J.,, and Porter, N,. 1989. The impact of pharmacology and molecular biology on the exploitation of microbial products, p. 309– 342. In S. Banmberg,, I. Hunter,, and M. Rhodes (ed.), Society for General Microbiology Symposium, 44. Cambridge University Press, Cambridge, United Kingdom.

57. Ōmura, S.,, T. Fujimoto,, K. Otoguro,, K. Matsuzaki,, R. Moriguchi,, H. Tanaka,, and Y. Sasaki. 1991. Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. J. Antibiot. 44: 113– 116.

58. Ōmura, S.,, Y. Sasaki,, Y. Iwai,, and H. Takeshima. 1995a. Stau-rosporine, a potentially important gift from a microorganism. J. Antibiot. 48: 535– 548.

59. Ōmura, S.,, H. Tomoda,, and T. Sunazuka,. 1995b. ACAT inhibitors from microorganisms, p. 37– 49. In W. Kuhn, and H.-P. Fiedler (ed.), Sekundarmetabolismus bei Mikroorganismen. Attempto Verlag, Tubingen, Germany.

60. Rawlins, P.,, T. Mander,, R. Sadhegi,, S. Hill,, G. Gammon,, B. Foxwell,, S. Wrigley,, and M. Moore. 1999. Inhibition of endotoxin-induced TNFα production in macrophages by 5Z-7- oxo-zeaenol and other fungal resorcylic acid lactones. Int. J. Immunopharmacol. 21: 799– 814.

61. Rishton, G. M. 1997. Reactive compounds and in vitro false positives in HTS. Drug Discovery Today 2: 382– 384.

62. Roe, S. M.,, C. Prodromou,, R. O'Brien,, J. E. Ladbury,, P. W. Piper,, and L. H. Pearl. 1999. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin. J. Med. Cbem. 42: 260– 266.

63. Sadhegi, R.,, P. Depledge,, P. Rawlins,, N. Dhanjal,, A. Manie,, S. Wrigley,, B. Foxwell,, and M. Moore. 2001. Differential regulation of CD3- and CD28-induced IL-2 and IFNγ production by a novel tyrosine kinase inhibitor XR774 from Cladosporium cf. cladosporioides. Int. Immunopharmacol. 1: 33– 48.

64. Sanglier, J.-J.,, V. Quesniaux,, T. Fehr,, H. Hofmann,, M. Mahnke,, K. Memmert,, W. Schuier,, G. Zenke,, L. Gschwind,, C. Maurer,, and W. Schilling. 1999. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110.1. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 52: 466– 473.

65. Sekizawa, R.,, I. Momose,, N. Kinoshita,, H. Naganawa,, M. Hamada,, Y. Muraoka,, H. Iinuma,, and T. Takeuchi. 2001. Isolation and structure elucidation of phepropeptins A, B, and C, and D, new proteasome inhibitors, produced by Streptomyces sp. J. Antibiot. 54: 874– 881.

66. Shin-ya, K.,, K. Wierzba,, K. Matsuo,, T. Ohtani,, Y. Yamada,, K. Furihata,, Y. Hayakawa,, and H. Seto. 2001. Telemostatin, a novel telomerase inhibitor from Streptomyces anulatus. J. Am. Chem. Soc. 123: 1262– 1263.

67. Shu, Y.-Z. 1998. Recent natural products based drug development: a pharmaceutical industry perspective. J. Nat. Prod. 61: 1053– 1071.

68. Sievers, T. M.,, S. J. Rossi,, R. M. Ghobrial,, E. Arriola,, P. Nishimura,, M. Kawano,, and C. D. Holt. 1997. Mycophenolate mofetil. Pharmacotherapy 17: 1178– 1197.

69. Simons, M. 2000. Molecular multitasking: statins lead to more arteries, less plaque. Nat. Med. 6: 965– 966.

70. Sin, N.,, L. Meng,, M. Q. W. Wang,, J. J. Wen,, W. G. Bornmann,, and C. M. Crews. 1997. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc. Natl. Acad. Sci. USA 94: 6099– 6103.

71. Stahelin, H. F. 1996. The history of cyclosporin A (Sandimmune®) revisited: another point of view. Experientia 52: 5– 13.

72. Takahashi, I.,, Y. Saitoh,, M. Yoshida,, H. Sano,, H. Nakano,, M. Morimoto,, and T. Tamaoki. 1989. UCN-01 and UCN-02, new selective inhibitors of protein kinase C II. Purification, physico-chemical properties, structural determination and biological activities. J. Antibiot. 42: 571– 576.

73. Takeuchi, T.,, H. Iinuma,, S. Kunimoto,, T. Masuda,, M. Ishizuka,, M. Takeuchi,, M. Hamada,, H. Naganawa,, S. Kondo, and H. Umezawa. 1981. A new antitumor antibiotic, spergualin: isolation and antitumor activity. J. Antibiot. 34: 1619– 1621.

74. Ueki, M.,, T. Teruya,, L. Nie,, R. Usami,, M. Yoshida,, and H. Osada. 2001. A new trichostatin derivative, trichostatin RK, from Streptomyces sp. RK98-A74. J. Antibiot. 54: 1093– 1095.

75. Umezawa, H. 1982. Low-molecular-weight enzyme inhibitors of microbial origin. Ann. Rev. Microbiol. 36: 75– 99.

76. Umezawa, H.,, M. Imoto,, T. Sawa,, K. Isshiki,, N. Matsuda,, T. Uchida,, H. Iinuma,, M. Hamada,, and T. Takeuchi. 1986. Studies on a new epidermal growth factor-receptor kinase inhibitor, erbstatin, produced by MH453-hF3. J. Antibiot. 39: 170– 173.

77. Vertesy, L.,, H. Kogler,, A. Markus,, M. Schiell,, M. Vogel,, and J. Wink. 2001. Memnopeptide A, a novel terpene peptide from Memnoniella with an activating effect on SERCA2. J. Antibiot. 54: 771– 782.

78. Vezina, C.,, A. Kudelski,, and S. N. Sehgal. 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28: 721– 726.

79. Vilella, D.,, M. Sanchez,, G. Platas,, O. Salazar,, O. Genilloud,, I. Royo,, C. Cascales,, I. Martin,, T. Diez,, K. C. Silverman,, R. B. Lingham,, S. B. Singh,, H. Jayasuriya,, and F. Pelaez. 2000. Inhibitors of farnesylation of Ras from a microbial natural products screening program. J. Ind. Microbiol. Biotecbnol. 25: 315– 327.

80. Watanabe, S.,, H. Hirai,, M. Ishiguro,, T. Kambara,, Y. Kojima,, T. Matsunaga,, H. Nishida,, Y. Suzuki,, A. Sugiura,, H. J. Harwood, Jr.,, L. H. Huang,, and N. Kojima. 2001. CJ-15,183, a new inhibitor of squalene synthase produced by a fungus, Aspergillus aculeatus. J. Antibiot. 54: 904– 910.

81. Weibel, E. K.,, P. Hadvary,, E. Hochuli,, E. Kupfer,, and H. Lengsfeld. 1987. Lipstatin, an inhibitor of pancreatic lipase produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J. Antibiot. 40: 1081– 1085.

82. Williams, D. H.,, M. J. Stone,, P. R. Hauck,, and S. K. Rahman. 1989. Why are secondary metabolites (natural products) biosynthesized? J. Nat. Prod. 52: 1189– 1208.

83. Wood, K. A.,, D. A. Kau,, S. K. Wrigley,, R. Beneyto,, D. V. Renno,, A. M. Ainsworth,, J. Penn,, D. Hill,, J. Killacky,, and P. Depledge. 1996. Novel 9-methoxyacrylates of the 9-methoxystrobilurin and oudemansin classes produced by the basidiomycete Favolaschia pustulosa. J. Nat. Prod. 59: 646– 649.

84. Wrigley, S. K.,, R. Sadhegi,, S. Bahl,, A. J. Whiting,, A. M. Ainsworth,, S. M. Martin,, W. Katzer,, R. Ford,, D. A. Kau,, N. Robinson,, M. A. Hayes,, C. Elcock,, T. Mander,, and M. Moore. 1999. A novel (65)-4,6-dimethyldodeca-2 E,4 E-dienoylester of phomalactone and related α-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity. J. Antibiot. 52: 862– 872.

85. Wrigley, S. K.,, A. M. Ainsworth,, D. A. Kau,, S. M. Martin,, S. Bahl,, J. S. Tang,, D. J. Hardick,, P. Rawlins,, R. Sadhegi,, and M. Moore. 2001. Novel reduced benzo[j]fluoranthen-3-ones from Cladosporium cf. cladosporioides with cytokine production and tyrosine kinase inhibitory propertiers. J. Antibiot. 54: 479– 488.

86. Zhang, B.,, G. Salituro,, D. Szalkowski,, Z. Li,, Y. Zhang,, I. Royo,, D. Vilella,, M. T. Diez,, F. Pelaez,, C. Ruby,, R. L. Kendall,, X. Mao,, P. Griffin,, J. Calaycay,, J. R. Zierath,, J. V. Heck,, R. G. Smith,, and D. E. Moller. 1999. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 284: 974– 977.

87. Zhang, L.-H.,, and J. O. Liu. 2001. Sanglifehrin a, a novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependant T cell proliferation at the G 1 phase of the cell cycle. J. Immunol. 166: 5611– 5618.

88. Zhao, A.,, S. H. Lee,, M. Mojena,, R. G. Jenkins,, D. R. Patrick,, H. E. Huber,, M. A. Goetz,, O. D. Hensens,, D. L. Zink,, D. Vilella,, A. W. Dombrowski,, R. B. Lingham,, and L. Huang. 1999. Resorcyclic acid lactones: naturally occurring and potent inhibitors of MEK. J. Antibiot. 52: 1086– 1094.