Abstract
Natural products continue to play a major role in drug discovery and development. However, chemical redundancy is an ongoing problem. Genomic studies indicate that certain groups of bacteria and fungi have dozens of secondary metabolite pathways that are not expressed under standard laboratory growth conditions. One approach to more fully access the metabolic potential of cultivatable microbes is mixed fermentation, where the presence of neighboring microbes may induce secondary metabolite synthesis. Research to date indicates that mixed fermentation can result in increased antibiotic activity in crude extracts, increased yields of previously described metabolites, increased yields of previously undetected metabolites, analogues of known metabolites resulting from combined pathways and, importantly, induction of previously unexpressed pathways for bioactive constituents.
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References
Banerjee S, Wang Z, Mohammad M, Sarkar FH, Mohammad RM (2008) Efficacy of selected natural products as therapeutic agents against cancer. J Nat Prod 71:492–496
Bode HB, Bethe B, Höfs R, Zeeck A (2002) Big effects from small changes: possible ways to explore nature’s chemical diversity. ChemBioChem 3:619–627
Burgess JG, Jordan EM, Bregu M, Mearns-Spragg A, Boyd KG (1999) Microbial antagonism: a neglected avenue of natural products research. J Biotechnol 70:27–32
Cueto M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J (2001) Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. J Nat Prod 64:1444–1446
Degenkolb T, Heinze S, Schlegel B, Strobel G, Gräfe U (2002) Formation of new lipoaminopeptides, acremostatins A, B, and C, by co-cultivation of Acremonium sp. Tbp-5 and Mycogone rosea DSM 12973. Biosci Biotechnol Biochem 66:883–886
Knight V, Sanglier JJ, DiTullio D, Braccili S, Bonner P, Waters J, Hughes D, Zhang L (2003) Diversifying microbial natural products for drug discovery. Appl Microbiol Biotechnol 62:446–458
Kurosawa K, Ghiviriga I, Sambandan TG, Lessard PA, Barbara JE, Rha C, Sinskey AJ (2008) Rhodostreptomycins, antibiotics biosynthesized following horizontal gene transfer from Streptomyces padanus to Rhodococcus fascians. J Am Chem Soc 130:1126–1127
Long RA, Azam F (2001) Antagonistic interactions among marine pelagic bacteria. Appl Environ Microbiol 67:4975–4983
Mearns-Spragg A, Bregu M, Boyd KG, Burgess JG (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 27:142–146
Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477
Oh DC, Jensen PR, Kauffman CA, Fenical W (2005) Libertellenones A-D: induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorg Med Chem 13:5267–5273
Oh DC, Kauffman CA, Jensen PR, Fenical W (2007) Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing co-culture. J Nat Prod 70:515–520
Ōmura S, Ikeda H, Ishikawa J, Hanamoto A, Takahashi C, Shinose M, Takahashi Y, Horikawa H, Nakazawa H, Osonoe T, Kikuchi H, Shiba T, Sakaki Y, Hattori M (2001) Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci U S A 98:12215–12220
Payne GA, Nierman WC, Wortman JR, Pritchard BL, Brown D, Dean RA, Bhatnagar D, Cleveland TE, Machida M, Yu J (2006) Whole genome comparison of Aspergillus flavus and A. oryzae. Med Mycol 44:S9–S11
Pel HJ et al (2007) Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88. Nat Biotech 25:221–231
Salmon I, Bull AT (1984) Mixed-culture fermentations in industrial microbiology. Curr Perspect Microb Ecol; Proc of the Third Intl Symp on Microb Ecol (Michigan State University, 7–12 Aug., 1983):656–662
Schneider P, Misiek M, Hoffmeister D (2008) In vivo and in vitro production options for fungal secondary metabolites. Mol Pharmcol 5:234–242
Shin CS, Kim HJ, Kim MJ, Ju JY (1998) Morphological change and enhanced pigment production of Monascus when co-cultured with Saccharomyces cerevisiae or Aspergillus oryzae. Biotechnol Bioeng 59:576–581
Slattery M, Rajbhandari I, Wesson K (2001) Competition-mediated antibiotic induction in the marine bacterium Streptomyces tenjimariensis. Microb Ecol 41:90–96
Sonnenbichler J, Dietrich J, Peipp H (1994) Secondary fungal metabolites and their biological activities, V. Investigations concerning the induction of biosynthesis of toxic secondary metabolites in basidiomycetes. Biol Chem 375:71–79
Suh JH, Shin CS (2000a) Analysis of the morphologic changes of Monascus sp. J101 cells cocultured with Saccharomyces cerevisiae. FEMS Microbiol Lett 193:143–147
Suh JH, Shin CS (2000b) Physiological analysis on novel coculture of Monascus sp. J101 with Saccharomyces cerevisiae. FEMS Microbiol Lett 190:241–245
Udwary DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W, Jensen PR, Moore BS (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc Natl Acad Sci U S A 104:10376–10381
Ueda K, Kawai S, Ogawa HO, Kiyama A, Kubota T, Kawanobe H, Beppu T (2000) Wide distribution of interspecific stimulatory events on antibiotic production and sporulation among Streptomyces species. J Antibiot 53:979–982
Wiener P (1996) Experimental studies on the ecological role of antibiotic production in bacteria. Evol Ecol 10:405–421
Yakovleva EP, Sokolova EN (1978) Dissociation of a Candida tropicalis culture and its capacity to stimulate levorin synthesis when cultured together with Actinomyces levoris. Antibiotiki 23:199–203
Zhang L (2005) Integrated approaches for discovering novel drugs from microbial natural products. In: Zhang L, Demain AL (eds) Natural products: drug discovery and therapeutic medicine. Humana, Totowa NJ, pp 33–55
Zhu F, Lin Y (2006) 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 51:1426–1430
Zhu F, Lin Y, Ding J, Wang X, Huang L (2007) Secondary metabolites of two marine-derived mangrove endophytic fungi (strain nos. 1924# and 3893#) by mixed fermentation. Chem Ind Forest Prod 27:8–10
Acknowledgments
Financial support was provided by grants R01 CA90441-01-05, 2R56 CA090441-06A1, and 5R01 CA090441-07 from the Division of Cancer Treatment, Diagnosis and Centers, National Cancer Institute, DHHS, and the Arizona Biomedical Research Commission. Many thanks to Dr. F. Hogan for preparing Fig. 1.
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Pettit, R.K. Mixed fermentation for natural product drug discovery. Appl Microbiol Biotechnol 83, 19–25 (2009). https://doi.org/10.1007/s00253-009-1916-9
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DOI: https://doi.org/10.1007/s00253-009-1916-9