The sound of silence: Activating silent biosynthetic gene clusters in marine microorganisms

Marine Drugs

Volumn 13, Issue 8, 2015, Pages 4754-4783

  Reen, F Jerry ^a   Romano, Stefano ^a   Dobson, Alan D W ^a   O'Gara, Fergal ^a,b  

^a UNIVERSITY COLLEGE CORK   (Ireland)

^b CURTIN UNIVERSITY   (Australia)

Author keywords

Bioactive gene clusters; Cryptic; Heterologous expression; Metagenomics; Non ribosomal peptide synthases; Polyketide synthases; Silent

Indexed keywords

ANGUCYCLINONE; APOSPHAERIN B; ASPINOLIDE DERIVATIVE; ASPINONENE; CHAXALACTIN A; CHAXALACTIN B; CHAXALACTIN C; CYTOSPORONE F; CYTOSPORONE G; CYTOSPORONE H; CYTOSPORONE I; EMODIN; LIBERTELLENONE A; LIBERTELLENONE B; LIBERTELLENONE C; LIBERTELLENONE D; MARINAMIDE A; MARINAMIDE B; MONODICTYPHENONE; NATURAL PRODUCT; PESTALONE; QUADRISEPTIN A; REGULATOR PROTEIN; SPECTINABILIN; TAROMYCIN A; UNCLASSIFIED DRUG; BIOLOGICAL PRODUCT;

ACTINOBACTERIA; ASPERGILLUS FUMIGATUS; ASPERGILLUS NIDULANS; ASPERGILLUS NIGER; ASPERGILLUS OCHRACEUS; BACILLUS AMYLOLIQUEFACIENS; BURKHOLDERIA CEPACIA; BURKHOLDERIA THAILANDENSIS; CELL METABOLISM; COMBINATORIAL CHEMISTRY; DEUTEROMYCETES; ELECTROSPRAY MASS SPECTROMETRY; ENTEROBACTER; EPIGENETICS; GENE CLUSTER; GENETIC ENGINEERING; MARINE SPECIES; MATRIX ASSISTED LASER DESORPTION IONIZATION TIME OF FLIGHT MASS SPECTROMETRY; METABOLITE; METABOLOME; MICROORGANISM; NONHUMAN; PECTOBACTERIUM CAROTOVORUM; PROMOTER REGION; PSEUDOMONAS AERUGINOSA; REVIEW; RIBOSOME; STREPTOMYCES; AQUATIC SPECIES; BIOSYNTHESIS; ECOSYSTEM; GENE EXPRESSION REGULATION; GENETICS; HUMAN; METABOLISM; MULTIGENE FAMILY;

AQUATIC ORGANISMS; BIOLOGICAL PRODUCTS; BIOSYNTHETIC PATHWAYS; ECOSYSTEM; GENE EXPRESSION REGULATION; HUMANS; MULTIGENE FAMILY;

EID: 84940398939     PISSN: None     EISSN: 16603397     Source Type: Journal    
DOI: 10.3390/md13084754     Document Type: Review

References (157)

1. Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311-335.
2. Brakhage, A. A.; Schroeckh, V. Fungal secondary metabolites-Strategies to activate silent gene clusters. Fungal Genet. Biol. 2011, 48, 15-22.
3. Lazzarini, A.; Cavaletti, L.; Toppo, G.; Marinelli, F. Rare genera of actinomycetes as potential producers of new antibiotics. Anton. Leeuw. 2000, 78, 399-405.
4. Yamanaka, K.; Reynolds, K. A.; Kersten, R. D.; Ryan, K. S.; Gonzalez, D. J.; Nizet, V.; Dorrestein, P. C.; Moore, B. S. Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic Taromycin A. Proc. Natl. Acad. Sci. USA 2014, 111, 1957-1962.
5. Medema, M. H.; Cimermancic, P.; Sali, A.; Takano, E.; Fischbach, M. A. A systematic computational analysis of biosynthetic gene cluster evolution: Lessons for engineering biosynthesis. PLoS Comput. Biol. 2014, 10, e1004016, doi:10.1371/journal.pcbi.1004016.
6. Berti, A. D.; Greve, N. J.; Christensen, Q. H.; Thomas, M. G. Identification of a biosynthetic gene cluster and the six associated lipopeptides involved in swarming motility of Pseudomonas syringae pv. Tomato DC3000. J. Bacteriol. 2007, 189, 6312-6323.
7. Nielsen, K. F.; Mansson, M.; Rank, C.; Frisvad, J. C.; Larsen, T. O. Dereplication of microbial natural products by LC-DAD-TOFMS. J. Nat. Prod. 2011, 74, 2338-2348.
8. Gaudêncio, S. P.; Pereiraa, F. Dereplication: Racing to speed up the natural products discovery process. Nat. Prod. Rep. 2015, 32, 779-810.
9. Patridge, E.; Gareiss, P.; Kinch, M. S.; Hoyer, D. An analysis of FDA-approved drugs: Natural products and their derivatives. Drug Discov. Today 2015, doi:10.1016/j.drudis.2015.01.009.
10. Baltz, R. H. Marcel faber roundtable: Is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration? J. Ind. Microbiol. Biotechnol. 2006, 33, 507-513.
11. Kralj, A.; Kehraus, S.; Krick, A.; Eguereva, E.; Kelter, G.; Maurer, M.; Wortmann, A.; Fiebig, H. H.; Konig, G. M. Arugosins G and H: Prenylated polyketides from the marine-derived fungus Emericella nidulans var. Acristata. J. Nat. Prod. 2006, 69, 995-1000.
12. Kusari, S.; Lamshoft, M.; Spiteller, M. Aspergillus fumigatus fresenius, an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro-drug deoxypodophyllotoxin. J. Appl. Microbiol. 2009, 107, 1019-1030.
13. Gram, L. Silent clusters-Speak up! Microb. Biotechnol. 2015, 8, 13-14.
14. Rutledge, P. J.; Challis, G. L. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat. Rev. Microbiol. 2015, 13, 509-523.
15. Brakhage, A. A.; Schuemann, J.; Bergmann, S.; Scherlach, K.; Schroeckh, V.; Hertweck, C. Activation of fungal silent gene clusters: A new avenue to drug discovery. Prog. Drug Res. 2008, 66, 3-12.
16. Netzker, T.; Fischer, J.; Weber, J.; Mattern, D. J.; Konig, C. C.; Valiante, V.; Schroeckh, V.; Brakhage, A. A. Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Front. Microbiol. 2015, 6, 299.
17. Fischbach, M. A.; Clardy, J. One pathway, many products. Nat. Chem. Biol. 2007, 3, 353-355.
18. Wasil, Z.; Pahirulzaman, K. A. K.; Butts, C.; Simpson, T. J.; Lazarus, C. M.; Cox, R. J. One pathway, many compounds: Heterologous expression of a fungal biosynthetic pathway reveals its intrinsic potential for diversity. Chem. Sci. 2013, 4, 3845-3856.
19. Egli, T. Microbial growth and physiology: A call for better craftsmanship. Front. Microbiol. 2015, 6, 287.
20. Bode, H. B.; Bethe, B.; Hofs, R.; Zeeck, A. Big effects from small changes: Possible ways to explore nature's chemical diversity. ChemBioChem 2002, 3, 619-627.
21. Martin, J. F. Phosphate control of the biosynthesis of antibiotics and other secondary metabolites is mediated by the PhoR-PhoP system: An unfinished story. J. Bacteriol. 2004, 186, 5197-5201.
22. Romano, S.; Dittmar, T.; Bondarev, V.; Weber, R. J.; Viant, M. R.; Schulz-Vogt, H. N. Exo-metabolome of Pseudovibrio sp. FO-BEG1 analyzed by ultra-high resolution mass spectrometry and the effect of phosphate limitation. PLoS ONE 2014, 9, e96038, doi:10.1371/journal.pone.0096038.
23. Lin, Z. J.; Zhu, T. J.; Wei, H. J.; Zhang, G. J.; Wang, H.; Gu, Q. Q. Spicochalasin A and new aspochalasins from the marine-derived fungus Spicaria elegans. Eur. J. Org. Chem. 2009, 2009, 3045-3051.
24. Wang, W. J.; Li, D. Y.; Li, Y. C.; Hua, H. M.; Ma, E. L.; Li, Z. L. Caryophyllene sesquiterpenes from the marine-derived fungus Ascotricha sp. ZJ-M-5 by the one strain-many compounds strategy. J. Nat. Prod. 2014, 77, 1367-1371.
25. Martin, J. F.; Sola-Landa, A.; Santos-Beneit, F.; Fernandez-Martinez, L. T.; Prieto, C.; Rodriguez-Garcia, A. Cross-talk of global nutritional regulators in the control of primary and secondary metabolism in Streptomyces. Microb. Biotechnol. 2011, 4, 165-174.
26. Sanchez, S.; Chavez, A.; Forero, A.; Garcia-Huante, Y.; Romero, A.; Sanchez, M.; Rocha, D.; Sanchez, B.; Avalos, M.; Guzman-Trampe, S.; et al. Carbon source regulation of antibiotic production. J. Antibiot. 2010, 63, 442-459.
27. Rateb, M. E.; Houssen, W. E.; Harrison, W. T. A.; Deng, H.; Okoro, C. K.; Asenjo, J. A.; Andrews, B. A.; Bull, A. T.; Goodfellow, M.; Ebel, R.; et al. Diverse metabolic profiles of a Streptomyces strain isolated from a hyper-arid environment. J. Nat. Prod. 2011, 74, 1965-1971.
28. Paranagama, P. A.; Wijeratne, E. M. K.; Gunatilaka, A. A. L. Uncovering biosynthetic potential of plant-associated fungi: Effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii. J. Nat. Prod. 2007, 70, 1939-1945.
29. Imhoff, J. F.; Labes, A.; Wiese, J. Bio-mining the microbial treasures of the ocean: New natural products. Biotechnol. Adv. 2011, 29, 468-482.
30. Romano, S.; Schulz-Vogt, H. N.; Gonzalez, J. M.; Bondarev, V. Phosphate limitation induces drastic physiological changes, virulence-related gene expression, and secondary metabolite production in Pseudovibrio sp. Strain FO-BEG1. Appl. Environ. Microbiol. 2015, 81, 3518-3528.
31. Shang, Z.; Li, X. M.; Li, C. S.; Wang, B. G. Diverse secondary metabolites produced by marine-derived fungus Nigrospora sp. MA75 on various culture media. Chem. Biodivers. 2012, 9, 1338-1348.
32. Williams, R. B.; Henrikson, J. C.; Hoover, A. R.; Lee, A. E.; Cichewicz, R. H. Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem. 2008, 6, 1895-1897.
33. Christian, O. E.; Compton, J.; Christian, K. R.; Mooberry, S. L.; Valeriote, F. A.; Crews, P. Using jasplakinolide to turn on pathways that enable the isolation of new chaetoglobosins from Phomospis asparagi. J. Nat. Prod. 2005, 68, 1592-1597.
34. Doull, J. L.; Singh, A. K.; Hoare, M.; Ayer, S. W. Conditions for the production of jadomycin B by Streptomyces venezuelae ISP5230: Effects of heat shock, ethanol treatment and phage infection. J. Ind. Microbiol. 1994, 13, 120-125.
35. Wei, Z. H.; Wu, H.; Bai, L. Q.; Deng, Z. X.; Zhong, J. J. Temperature shift-induced reactive oxygen species enhanced validamycin A production in fermentation of Streptomyces hygroscopicus 5008. Bioproc. Biosyst. Eng. 2012, 35, 1309-1316.
36. Zhou, W. W.; Ma, B.; Tang, Y. J.; Zhong, J. J.; Zheng, X. D. Enhancement of validamycin A production by addition of ethanol in fermentation of Streptomyces hygroscopicus 5008. Bioresour. Technol. 2012, 114, 616-621.
37. Seyedsayamdost, M. R. High-throughput platform for the discovery of elicitors of silent bacterial gene clusters. Proc. Natl. Acad. Sci. USA 2014, 111, 7266-7271.
38. Craney, A.; Ozimok, C.; Pimentel-Elardo, S. M.; Capretta, A.; Nodwell, J. R. Chemical perturbation of secondary metabolism demonstrates important links to primary metabolism. Chem. Biol. 2012, 19, 1020-1027.
39. Yoon, V.; Nodwell, J. R. Activating secondary metabolism with stress and chemicals. J. Ind. Microbiol. Biotechnol. 2014, 41, 415-424.
40. Pettit, R. K. Small-molecule elicitation of microbial secondary metabolites. Microb. Biotechnol. 2011, 4, 471-478.
41. Cueto, M.; Jensen, P. R.; Kauffman, C.; Fenical, W.; Lobkovsky, E.; Clardy, J. Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. J. Nat. Prod. 2001, 64, 1444-1446.
42. Marmann, A.; Aly, A. H.; Lin, W.; Wang, B.; Proksch, P. Co-cultivation-A powerful emerging tool for enhancing the chemical diversity of microorganisms. Mar. Drugs 2014, 12, 1043-1065.
43. Onaka, H.; Mori, Y.; Igarashi, Y.; Furumai, T. Mycolic acid-containing bacteria induce natural-product biosynthesis in Streptomyces species. Appl. Environ. Microbiol. 2011, 77, 400-406.
44. Schroeckh, V.; Scherlach, K.; Nutzmann, H. W.; Shelest, E.; Schmidt-Heck, W.; Schuemann, J.; Martin, K.; Hertweck, C.; Brakhage, A. A. Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA 2009, 106, 14558-14563.
45. Traxler, M. F.; Watrous, J. D.; Alexandrov, T.; Dorrestein, P. C.; Kolter, R. Interspecies interactions stimulate diversification of the Streptomyces coelicolor secreted metabolome. mBio 2013, 4, e00459-13, doi:10.1128/mBio.00459-13.
46. Oh, D. C.; Jensen, P. R.; Kauffman, C. A.; Fenical, W. Libertellenones A-D: Induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorg. Med. Chem. 2005, 13, 5267-5273.
47. Zhu, F.; Lin, Y. C. Marinamide, a novel alkaloid and its methyl ester produced by the application of mixed fermentation technique to two mangrove endophytic fungi from the South China Sea. Chin. Sci. Bull. 2006, 51, 1426-1430.
48. Angell, S.; Bench, B. J.; Williams, H.; Watanabe, C. M. H. Pyocyanin isolated from a marine microbial population: Synergistic production between two distinct bacterial species and mode of action. Chem. Biol. 2006, 13, 1349-1359.
49. Moree, W. J.; Yang, J. Y.; Zhao, X.; Liu, W. T.; Aparicio, M.; Atencio, L.; Ballesteros, J.; Sanchez, J.; Gavilan, R. G.; Gutierrez, M.; et al. Imaging mass spectrometry of a coral microbe interaction with fungi. J. Chem. Ecol. 2013, 39, 1045-1054.
50. Fuchser, J.; Zeeck, A. Secondary metabolites by chemical screening, 34. Aspinolides and aspinonene/aspyrone co-metabolites, new pentaketides produced by Aspergillus ochraceus. Liebigs Ann. 1997, 1997, 87-95.
51. Williamson, N. R.; Commander, P. M.; Salmond, G. P. Quorum sensing-controlled evr regulates a conserved cryptic pigment biosynthetic cluster and a novel phenomycin-like locus in the plant pathogen, Pectobacterium carotovorum. Environ. Microbiol. 2010, 12, 1811-1827.
52. Mahenthiralingam, E.; Song, L.; Sass, A.; White, J.; Wilmot, C.; Marchbank, A.; Boaisha, O.; Paine, J.; Knight, D.; Challis, G. L. Enacyloxins are products of an unusual hybrid modular polyketide synthase encoded by a cryptic Burkholderia ambifaria genomic island. Chem. Biol. 2011, 18, 665-677.
53. Biggins, J. B.; Gleber, C. D.; Brady, S. F. Acyldepsipeptide hdac inhibitor production induced in Burkholderia thailandensis. Org. Lett. 2011, 13, 1536-1539.
54. Ishida, K.; Lincke, T.; Behnken, S.; Hertweck, C. Induced biosynthesis of cryptic polyketide metabolites in a Burkholderia thailandensis quorum sensing mutant. J. Am. Chem. Soc. 2010, 132, 13966-13968.
55. Bunet, R.; Song, L.; Mendes, M. V.; Corre, C.; Hotel, L.; Rouhier, N.; Framboisier, X.; Leblond, P.; Challis, G. L.; Aigle, B. Characterization and manipulation of the pathway-specific late regulator AlpW reveals Streptomyces ambofaciens as a new producer of kinamycins. J. Bacteriol. 2011, 193, 1142-1153.
56. Metsa-Ketela, M.; Ylihonko, K.; Mantsala, P. Partial activation of a silent angucycline-type gene cluster from a rubromycin beta producing Streptomyces sp. PGA64. J. Antibiot. 2004, 57, 502-510.
57. Gottelt, M.; Kol, S.; Gomez-Escribano, J. P.; Bibb, M.; Takano, E. Deletion of a regulatory gene within the cpk gene cluster reveals novel antibacterial activity in Streptomyces coelicolor A3 (2). Microbiology 2010, 156, 2343-2353.
58. Shao, Z.; Rao, G.; Li, C.; Abil, Z.; Luo, Y.; Zhao, H. Refactoring the silent spectinabilin gene cluster using a plug-and-play scaffold. ACS Synth. Biol. 2013, 2, 662-669.
59. Bok, J. W.; Chiang, Y. M.; Szewczyk, E.; Reyes-Dominguez, Y.; Davidson, A. D.; Sanchez, J. F.; Lo, H. C.; Watanabe, K.; Strauss, J.; Oakley, B. R.; et al. Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol. 2009, 5, 462-464.
60. Ochi, K.; Hosaka, T. New strategies for drug discovery: Activation of silent or weakly expressed microbial gene clusters. Appl. Microbiol. Biotechnol. 2013, 97, 87-98.
61. Miller, M. B.; Bassler, B. L. Quorum sensing in bacteria. Annu. Rev. Microbiol. 2001, 55, 165-199.
62. Purohit, A. A.; Johansen, J. A.; Hansen, H.; Leiros, H. K.; Kashulin, A.; Karlsen, C.; Smalas, A.; Haugen, P.; Willassen, N. P. Presence of acyl-homoserine lactones in 57 members of the vibrionaceae family. J. Appl. Microbiol. 2013, 115, 835-847.
63. Rasch, M.; Kastbjerg, V. G.; Bruhn, J. B.; Dalsgaard, I.; Givskov, M.; Gram, L. Quorum sensing signals are produced by Aeromonas salmonicida and quorum sensing inhibitors can reduce production of a potential virulence factor. Dis. Aquat. Org. 2007, 78, 105-113.
64. Rasmussen, B. B.; Nielsen, K. F.; Machado, H.; Melchiorsen, J.; Gram, L.; Sonnenschein, E. C. Global and phylogenetic distribution of quorum sensing signals, acyl homoserine lactones, in the family of vibrionaceae. Mar. Drugs 2014, 12, 5527-5546.
65. Yang, Q.; Han, Y.; Zhang, X. H. Detection of quorum sensing signal molecules in the family vibrionaceae. J. Appl. Microbiol. 2011, 110, 1438-1445.
66. Liu, X. G.; Bimerew, M.; Ma, Y. X.; Mueller, H.; Ovadis, M.; Eberl, L.; Berg, G.; Chernin, L. Quorum-sensing signaling is required for production of the antibiotic pyrrolnitrin in a rhizospheric biocontrol strain of Serratia plymuthica. FEMS Microbiol. Lett. 2007, 270, 299-305.
67. Duerkop, B. A.; Varga, J.; Chandler, J. R.; Peterson, S. B.; Herman, J. P.; Churchill, M. E. A.; Parsek, M. R.; Nierman, W. C.; Greenberg, E. P. Quorum-sensing control of antibiotic synthesis in Burkholderia thailandensis. J. Bacteriol. 2009, 191, 3909-3918.
68. Vynne, N. G. Bioactivity and Phylogeny of the Marine Bacterial Genus Pseudoalteromonas. Ph. D. Thesis, Technical University of Denmark, Copenhagen, Denmark, 2011.
69. Machado, H.; Sonnenschein, E. C.; Melchiorsen, J.; Gram, L. Genome mining reveals unlocked bioactive potential of marine Gram-negative bacteria. BMC Genomics 2015, 16, 158.
70. Thomson, N. R.; Crow, M. A.; McGowan, S. J.; Cox, A.; Salmond, G. P. C. Biosynthesis of carbapenem antibiotic and prodigiosin pigment in Serratia is under quorum sensing control. Mol. Microbiol. 2000, 36, 539-556.
71. Recinos, D. A.; Sekedat, M. D.; Hernandez, A.; Cohen, T. S.; Sakhtah, H.; Prince, A. S.; Price-Whelan, A.; Dietrich, L. E. P. Redundant phenazine operons in Pseudomonas aeruginosa exhibit environment-dependent expression and differential roles in pathogenicity. Proc. Natl. Acad. Sci. USA 2012, 109, 19420-19425.
72. Kitani, S.; Miyamoto, K. T.; Takamatsu, S.; Herawati, E.; Iguchi, H.; Nishitomi, K.; Uchida, M.; Nagamitsu, T.; Omura, S.; Ikeda, H.; et al. Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis. Proc. Natl. Acad. Sci. USA 2011, 108, 16410-16415.
73. Dworkin, J. The medium is the message: Interspecies and interkingdom signaling by peptidoglycan and related bacterial glycans. Annu. Rev. Microbiol. 2014, 68, 137-154.
74. Lowery, C. A.; Dickerson, T. J.; Janda, K. D. Interspecies and interkingdom communication mediated by bacterial quorum sensing. Chem. Soc. Rev. 2008, 37, 1337-1346.
75. Reen, F. J.; Mooij, M. J.; Holcombe, L. J.; McSweeney, C. M.; McGlacken, G. P.; Morrissey, J. P.; O'Gara, F. The pseudomonas quinolone signal (PQS), and its precursor HHQ, modulate interspecies and interkingdom behaviour. FEMS Microbiol. Ecol. 2011, 77, 413-428.
76. Williams, P. Quorum sensing, communication and cross-kingdom signalling in the bacterial world. Microbiology 2007, 153, 3923-3938.
77. Stacy, A. R.; Diggle, S. P.; Whiteley, M. Rules of engagement: Defining bacterial communication. Curr. Opin. Microbiol. 2012, 15, 155-161.
78. Diggle, S. P. Microbial communication and virulence: Lessons from evolutionary theory. Microbiology 2010, 156, 3503-3512.
79. Linares, J. F.; Gustafsson, I.; Baquero, F.; Martinez, J. L. Antibiotics as intermicrobial signaling agents instead of weapons. Proc. Natl. Acad. Sci. USA 2006, 103, 19484-19489.
80. Chiang, Y. M.; Chang, S. L.; Oakley, B. R.; Wang, C. C. Recent advances in awakening silent biosynthetic gene clusters and linking orphan clusters to natural products in microorganisms. Curr. Opin. Chem. Biol. 2011, 15, 137-143.
81. Shima, J.; Hesketh, A.; Okamoto, S.; Kawamoto, S.; Ochi, K. Induction of actinorhodin production by RpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3 (2). J. Bacteriol. 1996, 178, 7276-7284.
82. Hosaka, T.; Ohnishi-Kameyama, M.; Muramatsu, H.; Murakami, K.; Tsurumi, Y.; Kodani, S.; Yoshida, M.; Fujie, A.; Ochi, K. Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12. Nat. Biotechnol. 2009, 27, 462-464.
83. Inaoka, T.; Takahashi, K.; Yada, H.; Yoshida, M.; Ochi, K. RNA polymerase mutation activates the production of a dormant antibiotic 3, 3'-neotrehalosadiamine via an autoinduction mechanism in Bacillus subtilis. J. Biol. Chem. 2004, 279, 3885-3892.
84. Vigliotta, G.; Tredici, S. M.; Damiano, F.; Montinaro, M. R.; Pulimeno, R.; Di Summa, R.; Massardo, D. R.; Gnoni, G. V.; Alifano, P. Natural merodiploidy involving duplicated rpoB alleles affects secondary metabolism in a producer actinomycete. Mol. Microbiol. 2005, 55, 396-412.
85. Tala, A.; Wang, G.; Zemanova, M.; Okamoto, S.; Ochi, K.; Alifano, P. Activation of dormant bacterial genes by Nonomuraea sp. Strain ATCC 39727 mutant-type RNA polymerase. J. Bacteriol. 2009, 191, 805-814.
86. Colombo, V.; Fernandez-de-Heredia, M.; Malpartida, F. A polyketide biosynthetic gene cluster from Streptomyces antibioticus includes a LysR-type transcriptional regulator. Microbiology 2001, 147, 3083-3092.
87. Rodriguez, M.; Nunez, L. E.; Brana, A. F.; Mendez, C.; Salas, J. A.; Blanco, G. Identification of transcriptional activators for thienamycin and cephamycin c biosynthetic genes within the thienamycin gene cluster from Streptomyces cattleya. Mol. Microbiol. 2008, 69, 633-645.
88. Waldron, C.; Matsushima, P.; Rosteck, P. R., Jr.; Broughton, M. C.; Turner, J.; Madduri, K.; Crawford, K. P.; Merlo, D. J.; Baltz, R. H. Cloning and analysis of the spinosad biosynthetic gene cluster of Saccharopolyspora spinosa. Chem. Biol. 2001, 8, 487-499.
89. Maddocks, S. E.; Oyston, P. C. F. Structure and function of the LysR-type transcriptional regulator (LTTR) family proteins. Microbiology 2008, 154, 3609-3623.
90. Zhao, C.; Coughlin, J. M.; Ju, J.; Zhu, D.; Wendt-Pienkowski, E.; Zhou, X.; Wang, Z.; Shen, B.; Deng, Z. Oxazolomycin biosynthesis in Streptomyces albus JA3453 featuring an "acyltransferase-less" Type I polyketide synthase that incorporates two distinct extender units. J. Biol. Chem. 2010, 285, 20097-20108.
91. Cimermancic, P.; Medema, M. H.; Claesen, J.; Kurita, K.; Brown, L. C. W.; Mavrommatis, K.; Pati, A.; Godfrey, P. A.; Koehrsen, M.; Clardy, J.; et al. Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell 2014, 158, 412-421.
92. Reen, F. J.; Barret, M.; Fargier, E.; O'Muinneachain, M.; O'Gara, F. Molecular evolution of LysR-type transcriptional regulation in Pseudomonas aeruginosa. Mol. Phylogenet. Evol. 2013, 66, 1041-1049.
93. Novakova, R.; Rehakova, A.; Kutas, P.; Feckova, L.; Kormanec, J. The role of two SARP family transcriptional regulators in regulation of the auricin gene cluster in Streptomyces aureofaciens CCM 3239. Microbiology 2011, 157, 1629-1639.
94. Aigle, B.; Pang, X.; Decaris, B.; Leblond, P. Involvement of AlpV, a new member of the Streptomyces antibiotic regulatory protein family, in regulation of the duplicated Type II polyketide synthase alp gene cluster in Streptomyces ambofaciens. J. Bacteriol. 2005, 187, 2491-2500.
95. Arias, P.; Fernandez-Moreno, M. A.; Malpartida, F. Characterization of the pathway-specific positive transcriptional regulator for actinorhodin biosynthesis in Streptomyces coelicolor A3 (2) as a DNA-binding protein. J. Bacteriol. 1999, 181, 6958-6968.
96. Hindra; Pak, P.; Elliot, M. A. Regulation of a novel gene cluster involved in secondary metabolite production in Streptomyces coelicolor. J. Bacteriol. 2010, 192, 4973-4982.
97. Rehakova, A.; Novakova, R.; Feckova, L.; Mingyar, E.; Kormanec, J. A gene determining a new member of the SARP family contributes to transcription of genes for the synthesis of the angucycline polyketide auricin in Streptomyces aureofaciens CCM 3239. FEMS Microbiol. Lett. 2013, 346, 45-55.
98. Novakova, R.; Kutas, P.; Feckova, L.; Kormanec, J. The role of the TetR-family transcriptional regulator Aur1R in negative regulation of the auricin gene cluster in Streptomyces aureofaciens CCM 3239. Microbiology 2010, 156, 2374-2383.
99. Gao, C.; Hindra; Mulder, D.; Yin, C.; Elliot, M. A. Crp is a global regulator of antibiotic production in Streptomyces. mBio 2012, 3, e00407-12, doi:10.1128/mBio.00407-12.
100. Bergmann, S.; Schumann, J.; Scherlach, K.; Lange, C.; Brakhage, A. A.; Hertweck, C. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 2007, 3, 213-217.
101. Chiang, Y. M.; Szewczyk, E.; Davidson, A. D.; Keller, N.; Oakley, B. R.; Wang, C. C. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J. Am. Chem. Soc. 2009, 131, 2965-2970.
102. Kontnik, R.; Crawford, J. M.; Clardy, J. Exploiting a global regulator for small molecule discovery in Photorhabdus luminescens. ACS Chem. Biol. 2010, 5, 659-665.
103. Nguyen, T.; Ishida, K.; Jenke-Kodama, H.; Dittmann, E.; Gurgui, C.; Hochmuth, T.; Taudien, S.; Platzer, M.; Hertweck, C.; Piel, J. Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection. Nat. Biotechnol. 2008, 26, 225-233.
104. Bok, J. W.; Soukup, A. A.; Chadwick, E.; Chiang, Y. M.; Wang, C. C.; Keller, N. P. VeA and MvlA repression of the cryptic orsellinic acid gene cluster in Aspergillus nidulans involves histone 3 acetylation. Mol. Microbiol. 2013, 89, 963-974.
105. Gerke, J.; Bayram, O.; Feussner, K.; Landesfeind, M.; Shelest, E.; Feussner, I.; Braus, G. H. Breaking the silence: Protein stabilization uncovers silenced biosynthetic gene clusters in the fungus Aspergillus nidulans. Appl. Environ. Microbiol. 2012, 78, 8234-8244.
106. Luo, Y.; Huang, H.; Liang, J.; Wang, M.; Lu, L.; Shao, Z.; Cobb, R. E.; Zhao, H. Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster. Nat. Commun. 2013, 4, 2894.
107. Li, Y.; Li, Z.; Yamanaka, K.; Xu, Y.; Zhang, W.; Vlamakis, H.; Kolter, R.; Moore, B. S.; Qian, P. Y. Directed natural product biosynthesis gene cluster capture and expression in the model bacterium Bacillus subtilis. Sci. Rep. 2015, 5, 9383.
108. Ross, A. C.; Gulland, L. E.; Dorrestein, P. C.; Moore, B. S. Targeted capture and heterologous expression of the Pseudoalteromonas alterochromide gene cluster in Escherichia coli represents a promising natural product exploratory platform. ACS Synth. Biol. 2015, 4, 414-420.
109. Baltz, R. H. Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J. Ind. Microbiol. Biotechnol. 2010, 37, 759-772.
110. Spohn, M.; Kirchner, N.; Kulik, A.; Jochim, A.; Wolf, F.; Muenzer, P.; Borst, O.; Gross, H.; Wohlleben, W.; Stegmann, E. Overproduction of ristomycin A by activation of a silent gene cluster in Amycolatopsis japonicum MG417-CF17. Antimicrob. Agents Chemother. 2014, 58, 6185-6196.
111. Gressler, M.; Hortschansky, P.; Geib, E.; Brock, M. A new high-performance heterologous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front. Microbiol. 2015, 6, doi:10.3389/fmicb.
112. Cichewicz, R. H. Epigenetic regulation of secondary metabolite biosynthetic genes in fungi. In Biocommunication of Fungi; Springer: Berlin, Germany, 2012; pp. 57-69.
113. Perrin, R. M.; Fedorova, N. D.; Bok, J. W.; Cramer, R. A.; Wortman, J. R.; Kim, H. S.; Nierman, W. C.; Keller, N. P. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 2007, 3, e50, doi:10.1371/journal.ppat.0030050.
114. Shwab, E. K.; Bok, J. W.; Tribus, M.; Galehr, J.; Graessle, S.; Keller, N. P. Histone deacetylase activity regulates chemical diversity in aspergillus. Eukaryot. Cell 2007, 6, 1656-1664.
115. Dorman, C. J.; Ni Bhriain, N.; Higgins, C. F. DNA supercoiling and environmental regulation of virulence gene expression in Shigella flexneri. Nature 1990, 344, 789-792.
116. Szewczyk, E.; Chiang, Y. M.; Oakley, C. E.; Davidson, A. D.; Wang, C. C.; Oakley, B. R. Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 2008, 74, 7607-7612.
117. Strahl, B. D.; Allis, C. D. The language of covalent histone modifications. Nature 2000, 403, 41-45.
118. Nutzmann, H. W.; Reyes-Dominguez, Y.; Scherlach, K.; Schroeckh, V.; Horn, F.; Gacek, A.; Schumann, J.; Hertweck, C.; Strauss, J.; Brakhage, A. A. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires SAGA/ADA-mediated histone acetylation. Proc. Natl. Acad. Sci. USA 2011, 108, 14282-14287.
119. Cabrita, M. T.; Vale, C.; Rauter, A. P. Halogenated compounds from marine algae. Mar. Drugs 2010, 8, 2301-2317.
120. Gribble, G. W. Natural organohalogens: A new frontier for medicinal agents? J. Chem. Educ. 2004, 81, 1441-1449.
121. Van Pee, K. H. Biosynthesis of halogenated metabolites by bacteria. Annu. Rev. Microbiol. 1996, 50, 375-399.
122. Winterton, N. Chlorine: The only green element-Towards a wider acceptance of its role in natural cycles. Green Chem. 2000, 2, 173-225.
123. MaCuMBA-Marine Microorganisms: Cultivation Methods for Improving their Biotechnological Applications Home Page.. Availablie online: http://www.macumbaproject.eu/(accessed on 29 July 2015).
124. Medema, M. H.; Breitling, R.; Bovenberg, R.; Takano, E. Exploiting plug-and-play synthetic biology for drug discovery and production in microorganisms. Nat. Rev. Microbiol. 2011, 9, 131-137.
125. Medema, M. H.; Breitling, R.; Takano, E. Synthetic biology in Streptomyces bacteria. Methods Enzymol. 2011, 497, 485-502.
126. Wright, G. Perspective: Synthetic biology revives antibiotics. Nature 2014, 509, S13.
127. Breitling, R.; Takano, E. Synthetic biology advances for pharmaceutical production. Curr. Opin. Biotechnol. 2015, 35, 46-51.
128. Helfrich, E. J. N.; Reiter, S.; Piel, J. Recent advances in genome-based polyketide discovery. Curr. Opin. Biotechnol. 2014, 29, 107-115.
129. Bentley, S. D.; Chater, K. F.; Cerdeno-Tarraga, A. M.; Challis, G. L.; Thomson, N. R.; James, K. D.; Harris, D. E.; Quail, M. A.; Kieser, H.; Harper, D.; et al. Complete genome sequence of the model actinomycete Sreptomyces coelicolor A3 (2). Nature 2002, 417, 141-147.
130. Medema, M. H.; Trefzer, A.; Kovalchuk, A.; Van Den Berg, M.; Muller, U.; Heijne, W.; Wu, L. A.; Alam, M. T.; Ronning, C. M.; Nierman, W. C.; et al. The sequence of a 1.8-Mb bacterial linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biol. Evol. 2010, 2, 212-224.
131. Piel, J. Approaches to capturing and designing biologically active small molecules produced by uncultured microbes. Annu. Rev. Microbiol. 2011, 65, 431-453.
132. Fischbach, M.; Voigt, C. A. Prokaryotic gene clusters: A rich toolbox for synthetic biology. Biotechnol. J. 2010, 5, 1277-1296.
133. Dietrich, J. A.; Yoshikuni, Y.; Fisher, K. J.; Woolard, F. X.; Ockey, D.; McPhee, D. J.; Renninger, N. S.; Chang, M. C. Y.; Baker, D.; Keasling, J. D. A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450 (BM3). ACS Chem. Biol. 2009, 4, 261-267.
134. Martin, V. J. J.; Pitera, D. J.; Withers, S. T.; Newman, J. D.; Keasling, J. D. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotechnol. 2003, 21, 796-802.
135. Newman, J. D.; Marshall, J.; Chang, M.; Nowroozi, F.; Paradise, E.; Pitera, D.; Newman, K. L.; Keasling, J. D. High-level production of amorpha-4, 11-diene in a two-phase partitioning bioreactor of metabolically engineered Escherichia coli. Biotechnol. Bioeng. 2006, 95, 684-691.
136. Ro, D. K.; Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K. L.; Ndungu, J. M.; Ho, K. A.; Eachus, R. A.; Ham, T. S.; Kirby, J.; et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 2006, 440, 940-943.
137. Klein, J.; Heal, J. R.; Hamilton, W. D. O.; Boussemghoune, T.; Tange, T. O.; Delegrange, F.; Jaeschke, G.; Hatsch, A.; Heim, J. Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery. ACS Synth. Biol. 2014, 3, 314-323.
138. Cai, X.; Teta, R.; Kohlhaas, C.; Crusemann, M.; Ueoka, R.; Mangoni, A.; Freeman, M. F.; Piel, J. Manipulation of regulatory genes reveals complexity and fidelity in hormaomycin biosynthesis. Chem. Biol. 2013, 20, 839-846.
139. Bachmann, B. O.; Van Lanen, S. G.; Baltz, R. H. Microbial genome mining for accelerated atural products discovery: Is a renaissance in the making? J. Ind. Microbiol. Biotechnol. 2014, 41, 175-184.
140. Luo, Y.; Lee, J. K.; Zhao, H. Challenges and opportunities in synthetic biology for chemical engineers. Chem. Eng. Sci. 2013, 103, doi:10.1016/j.ces.2012.06.013.
141. Walsh, C. T. Polyketide and nonribosomal peptide antibiotics: Modularity and versatility. Science 2004, 303, 1805-1810.
142. Liu, T.; Chiang, Y. M.; Somoza, A. D.; Oakley, B. R.; Wang, C. C. Engineering of an "unnatural" natural product by swapping polyketide synthase domains in Aspergillus nidulans. J. Am. Chem. Soc. 2011, 133, 13314-13316.
143. Ortholand, J. Y.; Ganesan, A. Natural products and combinatorial chemistry: Back to the future. Curr. Opin. Chem. Biol. 2004, 8, 271-280.
144. Drews, J. Drug discovery: A historical perspective. Science 2000, 287, 1960-1964.
145. Breitling, R.; Ceniceros, A.; Jankevics, A.; Takano, E. Metabolomics for secondary metabolite research. Metabolites 2013, 3, 1076-1083.
146. Peric-Concha, N.; Long, P. F. Mining the microbial metabolome: A new frontier for natural product lead discovery. Drug Discov. Today 2003, 8, 1078-1084.
147. Goulitquer, S.; Potin, P.; Tonon, T. Mass spectrometry-based metabolomics to elucidate functions in marine organisms and ecosystems. Mar. Drugs 2012, 10, 849-880.
148. Sarkar, A.; Funk, A. N.; Scherlach, K.; Horn, F.; Schroeckh, V.; Chankhamjon, P.; Westermann, M.; Roth, M.; Brakhage, A. A.; Hertweck, C.; et al. Differential expression of silent polyketide biosynthesis gene clusters in chemostat cultures of Aspergillus nidulans. J. Biotechnol. 2012, 160, 64-71.
149. Forseth, R. R.; Fox, E. M.; Chung, D.; Howlett, B. J.; Keller, N. P.; Schroeder, F. C. Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. J. Am. Chem. Soc. 2011, 133, 9678-9681.
150. Hou, Y.; Braun, D. R.; Michel, C. R.; Klassen, J. L.; Adnani, N.; Wyche, T. P.; Bugni, T. S. Microbial strain prioritization using metabolomics tools for the discovery of natural products. Anal. Chem. 2012, 84, 4277-4283.
151. Wilson, M. C.; Mori, T.; Ruckert, C.; Uria, A. R.; Helf, M. J.; Takada, K.; Gernert, C.; Steffens, U. A.; Heycke, N.; Schmitt, S.; et al. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 2014, 506, 58-62.
152. Owen, J. G.; Reddy, B. V. B.; Ternei, M. A.; Charlop-Powers, Z.; Calle, P. Y.; Kim, J. H.; Brady, S. F. Mapping gene clusters within arrayed metagenomic libraries to expand the structural diversity of biomedically relevant natural products. Proc. Natl. Acad. Sci. USA 2013, 110, 11797-11802.
153. Khaldi, N.; Seifuddin, F. T.; Turner, G.; Haft, D.; Nierman, W. C.; Wolfe, K. H.; Fedorova, N. D. Smurf: Genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 2010, 47, 736-741.
154. Li, M. H.; Ung, P. M.; Zajkowski, J.; Garneau-Tsodikova, S.; Sherman, D. H. Automated genome mining for natural products. BMC Bioinform. 2009, 10, 185.
155. Van Heel, A. J.; De Jong, A.; Montalban-Lopez, M.; Kok, J.; Kuipers, O. P. BAGEL3: Automated identification of genes encoding bacteriocins and (non-) bactericidal posttranslationally modified peptides. Nucleic Acids Res. 2013, 41, W448-W453.
156. Weber, T.; Blin, K.; Duddela, S.; Krug, D.; Kim, H. U.; Bruccoleri, R.; Lee, S. Y.; Fischbach, M. A.; Muller, R.; Wohlleben, W.; et al. AntiSMASH 3.0-A comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Res. 2015, 43, W237-W243.
157. Ziemert, N.; Podell, S.; Penn, K.; Badger, J. H.; Allen, E.; Jensen, P. R. The natural product domain seeker NaPDoS: A phylogeny based bioinformatic tool to classify secondary metabolite gene diversity. PLoS ONE 2012, 7, e34064, doi:10.1371/journal.pone.0034064. © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).