1887

Chapter 7 : Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways

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

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in
Zoomout

Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816827/9781555815127_Chap07-1.gif /docserver/preview/fulltext/10.1128/9781555816827/9781555815127_Chap07-2.gif

Abstract:

This chapter concentrates on the methodological approaches used to access the products of silent biosynthetic pathways (SBPs), and presents a number of important case studies that are intended to help one evaluate the advantages and disadvantages of each technique. Usage of the term ‘’silent’’ throughout this chapter is intended to include the broad range of suppressive transcriptional, translational, and biosynthetic mechanisms responsible for inhibiting microbial secondary-metabolite formation. During the preparation of this chapter, the authors have found it extremely useful to consider each method in its chronological context. An exciting new dimension in SBP studies is the emergence of novel mechanism-based and other hybrid techniques that meld the technological simplicity of culture manipulation strategies with recent breakthroughs in the understanding of microbial molecular biology. Although significant insight from genome mining was used to advance this discovery, this work serves as a testament to the fact that, in the absence of similar guiding factors, culture modification strategies will continue to involve significant guesswork regarding which culture amendments will provide access to SBPs. Genomic technologies are expected to facilitate the sequencing of microbial genomes at even greater rates, which is anticipated to provide natural products researchers with unprecedented capacity for identifying SBPs. Currently available techniques for investigating SBPs fall into three discrete categories: (i) culture-dependent, (ii) genomics- driven, and (iii) mechanism-based and hybrid approaches. Each of these method sets present unique advantages and disadvantages for studying SBPs.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7

Key Concept Ranking

High-Performance Liquid Chromatography
0.43999872
0.43999872
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Timeline illustrating significant events related to the field of SBP studies. Note the substantial surge in the number of experimental methods and techniques for investigating SBPs that were developed during the past several years.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Representative microbial compounds identified by use of early culture manipulation techniques.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Compounds obtained from sp. F-24′707 by use of culture manipulation.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

Compounds obtained from DSM7428 by use of culture manipulation.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5
FIGURE 5

Examples of natural products obtained by manipulating microbial culture conditions.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6
FIGURE 6

Examples demonstrating the use of coculture techniques to induce the production of microbial natural products.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 7
FIGURE 7

Combined approach leading to the discovery of coelichelin from

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 8
FIGURE 8

Examples of microbial metabolites whose structures were predicted based on genome scanning. The structure of each metabolite was later confirmed by isolation and characterization using NMR and mass spectrometric analyses.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 9
FIGURE 9

Examples of SBP-derived natural products that were identified by use of heterologous expression techniques.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 10
FIGURE 10

Compounds obtained from SBPs following activation using promoter/activator manipulation.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 11
FIGURE 11

Natural products obtained by using the chemical epigenetic induction of SBPs.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 12
FIGURE 12

Overview of the genomisotopic method and its application to the study of the orfamide gene cluster in Pf-5.

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555816827.ch07
1. Aceti, D. J., and, W. C. Champness. 1998. Transcriptional regulation of Streptomyces coelicolor pathway-specific antibiotic regulators by the absA and absB loci. J. Bacteriol. 180:31003106.
2. Amagata, T.,, M. Tanaka,, T. Yamada,, M. Doi,, K. Minoura,, H. Ohishi,, T. Yamori, and, A. Numata. 2007. Variation in cytostatic constituents of a sponge-derived Gymnascella dankaliensis by manipulating the carbon source. J. Nat. Prod. 70:17311740.
3. Angell, S.,, B. J. Bench,, H. Williams, and, C. M. H. Wata-nabe. 2006. Pyocyanin isolated from a marine microbial population: synergistic production between two distinct bacterial species and mode of action. Chem. Biol. 13:13491359.
4. Ashley, J. N.,, B. C. Hobbs, and, H. Raistrick. 1937. Studies in the biochemistry of micro-organisms: the crystalline colouring matters of Fusarium culmorum (W. G. Smith) Sacc. and related forms. Biochem. J. 31:385397.
5. Baltz, R. H. 2008. Renaissance in antibacterial discovery from actinomycetes. Curr. Opin. Pharmacol. 8:557563.
6. Banskota, A. H.,, J. B. McAlpine,, D. Sorensen,, M. Aoui-date,, M. Piraee,, A.-M. Alarco,, S. Omura,, K. Shiomi,, C. M. Farnet, and, E. Zazopoulos. 2006. Isolation and identification of three new 5-alkenyl-3,3(2H)-furanones from two Streptomyces species using a genomic screening approach. J. Antibiot. 59:168176.
7. Banskota, A. H.,, J. B. McAlpine,, D. Sorensen,, A. Ibrahim,, M. Aouidate,, M. Piraee,, A.-M. Alarco,, C. M. Farnet, and, E. Zazopoulos. 2006. Genomic analyses lead to novel secondary metabolites. J. Antibiot. 59:533542.
8. Bentley, S. D.,, K. F. Chater,, A. M. Cerdeno-Tarraga,, G. L. Challis,, N. R. Thomson,, K. D. James,, D. E. Harris,, M. A. Quail,, H. Kieser,, D. Harper,, A. Bateman,, S. Brown,, G. Chandra,, C. W. Chen,, M. Collins,, A. Cronin,, A. Fraser,, A. Goble,, J. Hidalgo,, T. Hornsby,, S. Howarth,, C. H. Huang,, T. Kieser,, L. Larke,, L. Murphy,, K. Oliver,, S. O’Neil,, E. Rabbinowitsch,, M. A. Rajandream,, K. Rutherford,, S. Rutter,, K. Seeger,, D. Saunders,, S. Sharp,, R. Squares,, S. Squares,, K. Taylor,, T. Warren,, A. Wietzorrek,, J. Woodward,, B. G. Barrell,, J. Parkhill, and, D. A. Hopwood. 2002. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141147.
9. Bergmann, S.,, J. Schumann,, K. Scherlach,, C. Lange,, A. A. Brakhage, and, C. Hertweck. 2007. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 3:213217.
10. Bills, G. F.,, G. Platas,, A. Fillola,, M. R. Jiménez,, J. Collado,, F. Vicente,, J. Martín,, A. González,, J. Bur-Zimmermann,, J. R. Tormo, and, F. Peláez. 2008. Enhancement of antibiotic and secondary metabolite detection from filamentous fungi by growth on nutritional arrays. J. Appl. Microbiol. 104:16441658.
11. Bitzer, J.,, T. Grosse,, L. Z. Wang,, S. Lang,, W. Beil, and, A. Zeeck. 2006. New aminophenoxazinones from a marine Halomonas sp.: fermentation, structure elucidation, and biological activity. J. Antibiot. 59:8692.
12. Bode, H. B.,, B. Bethe,, R. Höfs, and, A. Zeeck. 2002. Big effects from small changes: possible ways to explore nature’s chemical diversity. ChemBioChem 3:619627.
13. Bode, H. B., and, R. Müller. 2005. The impact of bacterial genomics on natural product research. Angew. Chem. Int. Ed. 44:68286846.
14. Bode, H. B.,, M. Walker, and, A. Zeeck. 2000. Secondary metabolites by chemical screening. 42. Cladospirones B to I from Sphaeropsidales sp F-24′707 by variation of culture conditions. Eur. J. Org. Chem. 2000:31853193.
15. Bode, H. B., and, A. Zeeck. 2000. Sphaerolone and dihydrosphaerolone, two bisnaphthyl-pigments from the fungus Sphaeropsidales sp. F-24′707. Phytochemistry 54:597601.
16. Boelker, M.,, C. W. Basse, and, J. Schirawski. 2008. Ustilago maydis secondary metabolism: from genomics to biochemistry. Fungal Genet. Biol. 45:S88S93.
17. Bok, J. W., and, N. P. Keller. 2004. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3:527535.
18. Brakhage, A. A.,, J. Schuemann,, S. Bergmann,, K. Scherlach,, V. Schroeckh, and, C. Hertweck. 2008. Activation of fungal silent gene clusters: a new avenue to drug discovery. Prog. Drug Res. 66:312.
19. Burgess, J. G.,, E. M. Jordan,, M. Bregu,, A. Mearns-Spragg, and, K. G. Boyd. 1999. Microbial antagonism: a neglected avenue of natural products research. J. Biotechnol. 70:2732.
20. Butler, A. R., and, E. Cundliffe. 2001. Influence of dimethylsulfoxide on tylosin production in Streptomyces fradiae. J. Ind. Microbiol. Biotechnol. 27:4651.
21. Calam, C. T., and, D. J. D. Hockenhull. 1949. The production of penicillin in surface culture, using chemically defined media. J. Gen. Microbiol. 3:1931.
22. Challis, G. L. 2008. Genome mining for novel natural product discovery. J. Med. Chem. 51:26182628.
23. Challis, G. L. 2008. Mining microbial genomes for new natural products and biosynthetic pathways. Microbiology 154:15551569.
24. Challis, G. L., and, D. A. Hopwood. 2003. Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc. Natl. Acad. Sci. USA 100:1455514561.
25. Challis, G. L., and, J. Ravel. 2000. Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiol. Lett. 187:111114.
26. Chen, G. H.,, G. Y. S. Wang,, X. Li,, B. Waters, and, J. Davies. 2000. Enhanced production of microbial metabolites in the presence of dimethyl sulfoxide. J. Antibiot. 53:11451153.
27. Chen, L.,, Y. Lu,, J. Chen,, W. Zhang,, D. Shu,, Z. Qin,, S. Yang, and, W. Jiang. 2008. Characterization of a negative regulator AveI for avermectin biosynthesis in Streptomyces aver-mitilis NRRL8165. Appl. Microbiol. Biotechnol. 80:277286.
28. Chiang, Y.-M.,, E. Szewczyk,, A. D. Davidson,, N. Keller,, B. R. Oakley, and, C. C. C. Wang. 2009. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J. Am. Chem. Soc. 131:29652970.
29. Christian, O. E.,, J. Compton,, K. R. Christian,, S. L. Mooberry,, F. A. Valeriote, and, P. Crews. 2005. Using jasplakinolide to turn on pathways that enable the isolation of new chaetoglobosins from Phomospis asparagi. J. Nat. Prod. 68:15921597.
30. Cueto, M.,, P. R. Jensen,, C. Kauffman,, W. Fenical,, E. Lobkovsky, and, J. Clardy. 2001. Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. J. Nat. Prod. 64:14441446.
31. Curtin, T.,, G. Fitzgerald, and, J. Reilly. 1940. Production of phoenicine on synthetic media: Penicillium phoeniceum Van Beyma. 2. Penicillium rubrum Grasberger-Stoll. Biochem. J. 34:16051610.
32. Davey, V. F., and, M. J. Johnson. 1953. Penicillin production in corn steep media with continuous carbohydrate addition. Appl. Microbiol. 1:208211.
33. Davies, J. 2006. Are antibiotics naturally antibiotics? J. Ind. Microbiol. Biotechnol. 33:496499.
34. Dean, R. A.,, N. J. Talbot,, D. J. Ebbole,, M. L. Farman,, T. K. Mitchell,, M. J. Orbach,, M. Thon,, R. Kulkarni,, J. R. Xu,, H. Q. Pan,, N. D. Read,, Y. H. Lee,, I. Carbone,, D. Brown,, Y. Y. Oh,, N. Donofrio,, J. S. Jeong,, D. M. Soanes,, S. Djonovic,, E. Kolomiets,, C. Rehmeyer,, W. X. Li,, M. Harding,, S. Kim,, M. H. Lebrun,, H. Bohnert,, S. Coughlan,, J. Butler,, S. Calvo,, L. J. Ma,, R. Nicol,, S. Purcell,, C. Nusbaum,, J. E. Galagan, and, B. W. Birren. 2005. The genome sequence of the rice blast fungus Mag-naporthe grisea. Nature 434:980986.
35. Degenkolb, T.,, S. Heinze,, B. Schlegel,, G. Strobel,, Gr. Auml, and, U. Fe. 2002. Formation of new lipoamino-peptides, acremostatins A, B, and C, by co-cultivation of Acremonium sp. Tbp-5 and Mycogone rosea DSM 12973. Biosci. Biotechnol. Biochem. 66:883886.
36. Doull, J. L.,, S. W. Ayer,, A. K. Singh, and, P. Thibault. 1993. Production of a novel polyketide antibiotic, jado-mycin B, by Streptomyces venezuelae following heat-shock. J. Antibiot. 46:869871.
37. Firn, R. D., and, C. G. Jones. 2000. The evolution of secondary metabolism—a unifying model. Mol. Microbiol. 37:989994.
38. Fisch, K. M.,, A. F. Gillaspy,, M. Gipson,, J. C. Henrikson,, A. R. Hoover,, L. Jackson,, F. Z. Najar,, H. Wägele, and, R. H. Cichewicz. 2009. Chemical induction of silent pathway transcription in Aspergillus niger. J. Ind. Microbiol. Biotechnol. 36:11991213.
39. Fox, E. M., and, B. J. Howlett. 2008. Secondary metabolism: regulation and role in fungal biology. Curr. Opin. Microbiol. 11:481487.
40. Fuchser, J., and, A. Zeeck. 1997. Secondary metabolites by chemical screening. 34. Aspinolides and aspinonene/aspyrone co-metabolites, new pentaketides produced by Aspergillus ochraceus. Liebigs Ann. Rec. 1997:8795.
41. Galagan, J. E.,, S. E. Calvo,, K. A. Borkovich,, E. U. Selker,, N. D. Read,, D. Jaffe,, W. FitzHugh,, L. J. Ma,, S. Smirnov,, S. Purcell,, B. Rehman,, T. Elkins,, R. Engels,, S. G. Wang,, C. B. Nielsen,, J. Butler,, M. Endrizzi,, D. Y. Qui,, P. Ianakiev,, D. B. Pedersen,, M. A. Nelson,, M. Werner-Washburne,, C. P. Selitrennikoff,, J. A. Kinsey,, E. L. Braun,, A. Zelter,, U. Schulte,, G. O. Kothe,, G. Jedd,, W. Mewes,, C. Staben,, E. Marcotte,, D. Greenberg,, A. Roy,, K. Foley,, J. Naylor,, N. Stabge-Thomann,, R. Barrett,, S. Gnerre,, M. Kamal,, M. Kamvysselis,, E. Mauceli,, C. Bielke,, S. Rudd,, D. Frishman,, S. Krystofova,, C. Rasmussen,, R. L. Metzenberg,, D. D. Perkins,, S. Kroken,, C. Cogoni,, G. Macino,, D. Catcheside,, W. X. Li,, R. J. Pratt,, S. A. Osmani,, C. P. C. DeSouza,, L. Glass,, M. J. Orbach,, J. A. Berglund,, R. Voelker,, O. Yarden,, M. Plamann,, S. Seller,, J. Dunlap,, A. Radford,, R. Aramayo,, D. O. Natvig,, L. A. Alex,, G. Mannhaupt,, D. J. Ebbole,, M. Freitag,, I. Paulsen,, M. S. Sachs,, E. S. Lander,, C. Nusbaum, and, B. Birren. 2003. The genome sequence of the filamentous fungus Neurospora crassa. Nature 422:859868.
42. Galagan, J. E.,, S. E. Calvo,, C. Cuomo,, L. J. Ma,, J. R. Wortman,, S. Batzoglou,, S. I. Lee,, M. Basturkmen,, C. C. Spevak,, J. Clutterbuck,, V. Kapitonov,, J. Jurka,, C. Scazzocchio,, M. Farman,, J. Butler,, S. Purcell,, S. Harris,, G. H. Braus,, O. Draht,, S. Busch,, C. D’Enfert,, C. Bouchier,, G. H. Goldman,, D. Bell-Pedersen,, S. Griffiths-Jones,, J. H. Doonan,, J. Yu,, K. Vienken,, A. Pain,, M. Freitag,, E. U. Selker,, D. B. Archer,, M. A. Penalva,, B. R. Oakley,, M. Momany,, T. Tanaka,, T. Kumagai,, K. Asai,, M. Machida,, W. C. Nierman,, D. W. Denning,, M. Caddick,, M. Hynes,, M. Paoletti,, R. Fischer,, B. Miller,, P. Dyer,, M. S. Sachs,, S. A. Osmani, and, B. W. Birren. 2005. Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438:11051115.
43. Gloer, J. B. 2007. Applications of fungal ecology in the search for new bioactive natural products, p. 257283. In C. P. Kubicek and, I. S. Druzhinina (ed.), The Mycota. Springer, Berlin, Germany.
44. Gross, F.,, N. Luniak,, O. Perlova,, N. Gaitatzis,, H. Jenke-Kodama,, K. Gerth,, D. Gottschalk,, E. Dittmann, and, R. Müller. 2006. Bacterial type III polyketide synthases: phylogenetic analysis and potential for the production of novel secondary metabolites by heterologous expression in pseudomonads. Arch. Microbiol. 185:2838.
45. Gross, H. 2007. Strategies to unravel the function of orphan biosynthesis pathways: recent examples and future prospects. Appl. Microbiol. Biotechnol. 75:267277.
46. Gross, H.,, V. O. Stockwell,, M. D. Henkels,, B. Nowak-Thompson,, J. E. Loper, and, W. H. Gerwick. 2007. The gen-omisotopic approach: a systematic method to isolate products of orphan biosynthetic gene clusters. Chem. Biol. 14:5363.
47. Henrikson, J. C.,, A. R. Hoover,, P. M. Joyner, and, R. H. Cichewicz. 2009. A chemical epigenetics approach for engineering the in situ biosynthesis of a cryptic natural product from Aspergillus niger. Org. Biomol. Chem. 7:435438.
48. Hofs, R.,, M. Walker, and, A. Zeeck. 2000. Hexacyclinic acid, a polyketide from Streptomyces with a novel carbon skeleton. Angew. Chem. Int. Ed. 39:32583261.
49. Horinouchi, S. 2007. Mining and polishing of the treasure trove in the bacterial genus Streptomyces. Biosci. Biotechnol. Biochem. 71:283299.
50. Ikeda, H.,, J. Ishikawa,, A. Hanamoto,, M. Shinose,, H. Kikuchi,, T. Shiba,, Y. Sakaki,, M. Hattori, and, S. Omura. 2003. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat. Biotechnol. 21:526531.
51. Jarvis, F. G., and, M. J. Johnson. 1947. The role of the constituents of synthetic media for penicillin production. J. Am. Chem. Soc. 69:30103017.
52. Kamper, J.,, R. Kahmann,, M. Bolker,, L. J. Ma,, T. Brefort,, B. J. Saville,, F. Banuett,, J. W. Kronstad,, S. E. Gold,, O. Muller,, M. H. Perlin,, H. A. B. Wosten,, R. de Vries,, J. Ruiz-Herrera,, C. G. Reynaga-Pena,, K. Snetselaar,, M. McCann,, J. Perez-Martin,, M. Feldbrugge,, C. W. Basse,, G. Steinberg,, J. I. Ibeas,, W. Holloman,, P. Guzman,, M. Farman,, J. E. Stajich,, R. Sentandreu,, J. M. Gonzalez-Prieto,, J. C. Kennell,, L. Molina,, J. Schirawski,, A. Mendoza-Mendoza,, D. Greilinger,, K. Munch,, N. Rossel,, M. Scherer,, M. Vranes,, O. Ladendorf,, V. Vincon,, U. Fuchs,, B. Sandrock,, S. Meng,, E. C. H. Ho,, M. J. Cahill,, K. J. Boyce,, J. Klose,, S. J. Klosterman,, H. J. Deelstra,, L. Ortiz-Castellanos,, W. X. Li,, P. Sanchez-Alonso,, P. H. Schreier,, I. Hauser-Hahn,, M. Vaupel,, E. Koopmann,, G. Friedrich,, H. Voss,, T. Schluter,, J. Margolis,, D. Platt,, C. Swimmer,, A. Gnirke,, F. Chen,, V. Vysotskaia,, G. Mannhaupt,, U. Guldener,, M. Munsterkotter,, D. Haase,, M. Oesterheld,, H. W. Mewes,, E. W. Mauceli,, D. DeCaprio,, C. M. Wade,, J. Butler,, S. Young,, D. B. Jaffe,, S. Calvo,, C. Nusbaum,, J. Galagan, and, B. W. Birren. 2006. Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis. Nature 444:97101.
53. Kawai, K.,, G. Wang,, S. Okamoto, and, K. Ochi. 2007. The rare earth, scandium, causes antibiotic overproduction in Streptomyces spp. FEMS Microbiol. Lett. 274:311315.
54. Keller, N. P.,, G. Turner, and, J. W. Bennett. 2005. Fungal secondary metabolism—from biochemistry to genomics. Nat. Rev. Microbiol. 3:937947.
55. Lautru, S.,, R. J. Deeth,, L. M. Bailey, and, G. L. Challis. 2005. Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat. Chem. Biol. 1:265269.
56. Lee, B.-N.,, S. Kroken,, D. Y. T. Chou,, B. Robbertse,, O. C. Yoder, and, B. G. Turgeon. 2005. Functional analysis of all nonribosomal peptide synthetases in Cochliobolus heterostrophus reveals a factor, NPS6, involved in virulence and resistance to oxidative stress. Eukaryot. Cell 4:545555.
57. Lin, X.,, R. Hopson, and, D. E. Cane. 2006. Genome mining in Streptomyces coelicolor: molecular cloning and characterization of a new sesquiterpene synthase. J. Am. Chem. Soc. 128:60226023.
58. Lin, Z.,, T. Zhu,, H. Wei,, G. Zhang,, H. Wang, and, Q. Gu. 2009. Spicochalasin A and new aspochalasins from the marine-derived fungus Spicaria elegans. Eur. J. Org. Chem. 2009:30453051.
59. Machida, M.,, K. Asai,, M. Sano,, T. Tanaka,, T. Kumagai,, G. Terai,, K. I. Kusumoto,, T. Arima,, O. Akita,, Y. Kashiwagi,, K. Abe,, K. Gomi,, H. Horiuchi,, K. Kitamoto,, T. Kobayashi,, M. Takeuchi,, D. W. Denning,, J. E. Galagan,, W. C. Nierman,, J. J. Yu,, D. B. Archer,, J. W. Bennett,, D. Bhatnagar,, T. E. Cleveland,, N. D. Fedorova,, O. Gotoh,, H. Horikawa,, A. Hosoyama,, M. Ichinomiya,, R. Igarashi,, K. Iwashita,, P. R. Juvvadi,, M. Kato,, Y. Kato,, T. Kin,, A. Kokubun,, H. Maeda,, N. Maeyama,, J. Maruyama,, H. Nagasaki,, T. Nakajima,, K. Oda,, K. Okada,, I. Paulsen,, K. Sakamoto,, T. Sawano,, M. Takahashi,, K. Takase,, Y. Terabayashi,, J. R. Wortman,, O. Yamada,, Y. Yamagata,, H. Anazawa,, Y. Hata,, Y. Koide,, T. Komori,, Y. Koyama,, T. Minetoki,, S. Suharnan,, A. Tanaka,, K. Isono,, S. Kuhara,, N. Ogasawara, and, H. Kikuchi. 2005. Genome sequencing and analysis of Aspergillus oryzae. Nature 438:11571161.
60. MacLean, D.,, J. D. Jones, and, D. J. Studholme. 2009. Application of “next-generation” sequencing technologies to microbial genetics. Nat. Rev. Microbiol. 7:287296.
61. Maldonado, A.,, J. L. Ruiz-Barba, and, R. Jimenez-Diaz. 2003. Purification and genetic characterization of plan-taricin NC8, a novel coculture-inducible two-peptide bacteriocin from Lactobacillus plantarum NC8. Appl. Environ. Microbiol. 69:383389.
62. Mardis, E. R. 2008. The impact of next-generation sequencing technology on genetics. Trends Genet. 24:133141.
63. McAlpine, J. B.,, B. O. Bachmann,, M. Piraee,, S. Tremblay,, A.-M. Alarco,, E. Zazopoulos, and, C. M. Farnet. 2005. Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. J. Nat. Prod. 68:493496.
64. Mearns-Spragg, A.,, M. Bregu,, K. G. Boyd, and, J. G. Burgess. 1998. Cross-species induction and enhancement of antimicrobial activity produced by epibiotic bacteria from marine algae and invertebrates, after exposure to terrestrial bacteria. Lett. Appl. Microbiol. 27:142146.
65. Nierman, W. C.,, A. Pain,, M. J. Anderson,, J. R. Wortman,, H. S. Kim,, J. Arroyo,, M. Berriman,, K. Abe,, D. B. Archer,, C. Bermejo,, J. Bennett,, P. Bowyer,, D. Chen,, M. Collins,, R. Coulsen,, R. Davies,, P. S. Dyer,, M. Farman,, N. Fedorova,, N. Fedorova,, T. V. Feldblyum,, R. Fischer,, N. Fosker,, A. Fraser,, J. L. Garcia,, M. J. Garcia,, A. Goble,, G. H. Goldman,, K. Gomi,, S. Griffith-Jones,, R. Gwilliam,, B. Haas,, H. Haas,, D. Harris,, H. Horiuchi,, J. Huang,, S. Humphray,, J. Jimenez,, N. Keller,, H. Khouri,, K. Kitamoto,, T. Kobayashi,, S. Konzack,, R. Kulkarni,, T. Kumagai,, A. Lafton,, J.-P. Latge,, W. Li,, A. Lord,, C. Lu,, W. H. Majoros,, G. S. May,, B. L. Miller,, Y. Mohamoud,, M. Molina,, M. Monod,, I. Mouyna,, S. Mulligan,, L. Murphy,, S. O’Neil,, I. Paulsen,, M. A. Penalva,, M. Pertea,, C. Price,, B. L. Pritchard,, M. A. Quail,, E. Rabbinowitsch,, N. Rawlins,, M.-A. Rajandream,, U. Reichard,, H. Renauld,, G. D. Robson,, S. R. de Cordoba,, J. M. Rodriguez-Pena,, C. M. Ronning,, S. Rutter,, S. L. Salzberg,, M. Sanchez,, J. C. Sanchez-Ferrero,, D. Saunders,, K. Seeger,, R. Squares,, S. Squares,, M. Takeuchi,, F. Tekaia,, G. Turner,, C. R. V. de Aldana,, J. Weidman,, O. White,, J. Woodward,, J.-H. Yu,, C. Fraser,, J. E. Galagan,, K. Asai,, M. Machida,, N. Hall,, B. Barrell, and, D. W. Denning. 2005. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438:11511156.
66. Oh, D.-C.,, P. R. Jensen,, C. A. Kauffman, and, W. Fenical. 2005. Libertellenones A-D: induction of cytotoxic diterpe-noid biosynthesis by marine microbial competition. Bioorg. Med. Chem. 13:52675273.
67. Oh, D. C.,, C. A. Kauffman,, P. R. Jensen, and, W. Fenical. 2007. Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing co-culture. J. Nat. Prod. 70:515520.
68. Omura, S.,, H. Ikeda,, J. Ishikawa,, A. Hanamoto,, C. Takahashi,, M. Shinose,, Y. Takahashi,, H. Horikawa,, H. Nakazawa,, T. Osonoe,, H. Kikuchi,, T. Shiba,, Y. Sakaki, and, M. Hattori. 2001. Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc. Natl. Acad. Sci. USA 98:1221512220.
69. Onaka, H.,, N. Ando,, T. Nihira,, Y. Yamada,, T. Beppu, and, S. Horinouchi. 1995. Cloning and characterization of the A-factor receptor gene from Streptomyces griseus. J. Bacteriol. 177:60836092.
70. Palmu, K.,, K. Ishida,, P. Mäntsälä,, C. Hertweck, and, M. Metsä-Ketelä. 2007. Artificial reconstruction of two cryptic angucycline antibiotic biosynthetic pathways. ChemBioChem 8:15771584.
71. Paranagama, P. A.,, E. M. K. Wijeratne, and, A. A. L. Gunatilaka. 2007. Uncovering biosynthetic potential of plant-associated fungi: effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii. J. Nat. Prod. 70:19391945.
72. Pel, H. J.,, J. H. de Winde,, D. B. Archer,, P. S. Dyer,, G. Hofmann,, P. J. Schaap,, G. Turner,, R. P. de Vries,, R. Albang,, K. Albermann,, M. R. Andersen,, J. D. Bendtsen,, J. A. E. Benen,, M. van den Berg,, S. Breestraat,, M. X. Caddick,, R. Contreras,, M. Cornell,, P. M. Coutinho,, E. G. J. Danchin,, A. J. M. Debets,, P. Dekker,, P. W. M. van Dijck,, A. van Dijk,, L. Dijkhuizen,, A. J. M. Driessen,, C. d’Enfert,, S. Geysens,, C. Goosen,, G. S. P. Groot,, P. W. J. de Groot,, T. Guillemette,, B. Henrissat,, M. Herweijer,, J. P. T. W. van den Hombergh,, C. A. M. J. J. van den Hondel,, R. T. J. M. van der Heijden,, R. M. van der Kaaij,, F. M. Klis,, H. J. Kools,, C. P. Kubicek,, P. A. van Kuyk,, J. Lauber,, X. Lu,, M. J. E. C. van der Maarel,, R. Meulenberg,, H. Menke,, M. A. Mortimer,, J. Nielsen,, S. G. Oliver,, M. Olsthoorn,, K. Pal,, N. N. M. E. van Peij,, A. F. J. Ram,, U. Rinas,, J. A. Roubos,, C. M. J. Sagt,, M. Schmoll,, J. Sun,, D. Ussery,, J. Varga,, W. Vervecken,, P. J. J. van de Vondervoort,, H. Wedler,, H. A. B. Wosten,, A.-P. Zeng., A. J. J. van Ooyen,, J. Visser, and, H. Stam. 2007. Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88. Nat. Biotechnol. 25:221231.
73. Penttinen, P.,, J. Pelkonen,, K. Huttunen, and, M.-R. Hirvonen. 2006. Co-cultivation of Streptomyces californi-cus and Stachybotrys chartarum stimulates the production of cytostatic compound(s) with immunotoxic properties. Toxicol. Appl. Pharmacol. 217:342351.
74. Perrin, R. M.,, N. D. Fedorova,, J. W. Bok,, R. A. Cramer,, J. R. Wortman,, H. S. Kim,, W. C. Nierman, and, N. P. Keller. 2007. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 3:508517.
75. Pirt, S. J., and, R. C. Righelato. 1967. Effect of growth rate on the synthesis of penicillin by Penicillium chrysogenum in batch and chemostat cultures. Appl. Microbiol. 15:12841290.
76. Porges, N. 1932. Chemical composition of Aspergillus niger as modified by zinc sulphate. Bot. Gaz. 94:197.
77. Rokem, J. S.,, A. E. Lantz, and, J. Nielsen. 2007. Systems biology of antibiotic production by microorganisms. Nat. Prod. Rep. 24:12621287.
78. Scherlach, K., and, C. Hertweck. 2009. Triggering cryptic natural product biosynthesis in microorganisms. Org. Biomol. Chem. 7:17531760.
79. Schiewe, H. J., and, A. Zeeck. 1999. Cineromycins, gamma-butyrolactones and ansamycins by analysis of the secondary metabolite pattern created by a single strain of Streptomyces. J. Antibiot. 52:635642.
80. Schneider, P.,, M. Misiek, and, D. Hoffmeister. 2008. In vivo and in vitro production options for fungal secondary metabolites. Mol. Pharm. 5:234242.
81. Schumann, J., and, C. Hertweck. 2006. Advances in cloning, functional analysis and heterologous expression of fungal polyketide synthase genes. J. Biotechnol. 124:690703.
82. Seibert, S. F.,, A. Krick,, E. Eguereva,, S. Kehraus, and, G. M. Konig. 2007. Ascospiroketals A and B, unprecedented cycloethers from the marine-derived fungus Ascochyta salicorniae. Org. Lett. 9:239242.
83. Shao, H.-J.,, X.-D. Qin,, Z.-J. Dong,, H.-B. Zhang, and, J.-K. Liu. 2008. Induced daldinin A, B, C with a new skeleton from cultures of the ascomycete Daldinia concentrica. J. Antibiot. 61:115119.
84. Shwartzman, G. 1944. Enhanced production of penicillin in fluid medium containing cellophane. Science 100:390392.
85. Singh, S. B., and, F. Pelaez. 2008. Biodiversity, chemical diversity and drug discovery, p. 141174. In F. Peterson and, R. Amstutz (ed.), Natural Compounds as Drugs, vol. I. Birkhäuser, Basel, Switzerland.
86. Steinberg, R. A. 1919. A study of some factors in the chemical stimulation of the growth of Aspergillus niger. Am. J. Bot. 6:330356.
87. Steinberg, R. A. 1919. A study of some factors in the chemical stimulation of the growth of Aspergillus niger. Am. J. Bot. 6:357372.
88. Stone, R. W., and, M. A. Farrell. 1946. Synthetic media for penicillin production. Science 104:445446.
89. Udwary, D. W.,, L. Zeigler,, R. N. Asolkar,, V. Singan,, A. Lapidus,, W. Fenical,, P. R. Jensen, and, B. S. Moore. 2007. Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl. Acad. Sci. USA 104:1037610381.
90. Ueda, K.,, S. Kawai,, H. Ogawa,, A. Kiyama,, T. Kubota,, H. Kawanobe, and, T. Beppu. 2000. Wide distribution of interspecific stimulatory events on antibiotic production and sporulation among Streptomyces species. J. Antibiot. 53:979982.
91. Uguru, G. C.,, K. E. Stephens,, J. A. Stead,, J. E. Towle,, S. Baumberg, and, K. J. McDowall. 2005. Transcriptional activation of the pathway-specific regulator of the acti-norhodin biosynthetic genes in Streptomyces coelicolor. Mol. Microbiol. 58:131150.
92. van den Berg, M. A.,, R. Albang,, K. Albermann,, J. H. Badger,, J.-M. Daran,, A. J. M Driessen,, C. Garcia-Estrada,, N. D. Fedorova,, D. M. Harris,, W. H. M. Heijne,, V. Joardar,, J. A. K. W Kiel,, A. Kovalchuk,, J. F. Martin,, W. C. Nierman,, J. G. Nijland,, J. T. Pronk,, J. A. Roubos,, I. J. van der Klei,, N. N. M. E. van Peij,, M. Veenhuis,, H. von Dohren,, C. Wagner,, J. Wortman, and, R. A. L. Bovenberg. 2008. Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum. Nat. Biotechnol. 26:11611168.
93. Van Lanen, S. G., and, B. Shen. 2006. Microbial genom-ics for the improvement of natural product discovery. Curr. Opin. Microbiol. 9:252260.
94. Waksman, S. A.,, E. S. Horning, and, E. L. Spencer. 1943. Two antagonistic fungi, Aspergillus fumigatus and Aspergillus clavatus, and their antibiotic substances. J. Bacteriol. 45:233248.
95. Wilkinson, B., and, J. Micklefield. 2007. Mining and engineering natural-product biosynthetic pathways. Nat. Chem. Biol. 3:379386.
96. Williams, R. B.,, J. C. Henrikson,, A. R. Hoover,, A. E. Lee, and, R. H. Cichewicz. 2008. Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem. 6:18951897.
97. Yu, J.-H., and, N. Keller. 2005. Regulation of secondary metabolism in filamentous fungi. Annu. Rev. Phytopathol. 43:437458.
98. Zazopoulos, E.,, K. Huang,, A. Staffa,, W. Liu,, B. O. Bachmann,, K. Nonaka,, J. Ahlert,, J. S. Thorson,, B. Shen, and, C. M. Farnet. 2003. A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat. Biotechnol. 21:187190.
99. Zerikly, M., and, G. L. Challis. 2009. Strategies for the discovery of new natural products by genome mining. ChemBioChem 10:625633.

Tables

Generic image for table
TABLE 1

Numbers of PKS, NRPS, and HPN gene clusters in selected bacteria and fungi

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Generic image for table
TABLE 2

Examples of some reported culture manipulation techniques

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Generic image for table
TABLE 3

Examples of cocultivation methods for investigating SBPs in microorganisms

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Generic image for table
TABLE 4

Examples of online resources providing archiving of microbial genomic data

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7
Generic image for table
TABLE 5

Summary of the major strengths and weaknesses of methods for investigating microbial SBPs

Citation: Cichewicz R, Henrikson J, Wang X, Branscum K. 2010. Strategies for Accessing Microbial Secondary Metabolites from Silent Biosynthetic Pathways, p 78-95. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch7

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error