Production of Antibiotics and other Commercially Valuable Secondary Metabolites

  • Javier Barrios-González
  • Armando Mejýa


Secondary metabolites are compounds produced mainly by actinomycetes and fungi, usually late in the growth cycle (idiophase). Although antibiotics are the best known secondary metabolites, there are others with an enormous range of other biological activities. Moreover, the last two decades have been a phase of rapid discovery of new activities and development of major compounds of use in different industrial fields, mainly: pharmaceutical and cosmetics, food, agriculture and farming. Some examples are: anti-inflammatory, hypotensive, antitumor, anticholestrolemic, but also insecticides, plant growth regulators and environmental friendly herbicides and pesticides. These compounds are usually produced by liquid submerged fermentation, but many of these metabolites could be advantageously produced by solid-state fermentation.


Wheat Bran Solid Substrate Initial Moisture Content Solid Culture Inert Support 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adinarayana K, Ellaiah P, Srinivasulu B, Bhavani Devi R, & Adinarayana G, 2003a, Response surface methodological approach to optimize the nutritional parameters for neomycin production by Streptomyces marinensis under solid-state fermentation, Process Biochemistry, 38(11), 1565–1572.CrossRefGoogle Scholar
  2. Adinarayana K, Prabhakar T, Srinivasulu V, Rao MA, Lakshmi PJ, & Ellaiah P, 2003b, Optimization of process parameters for cephalosporin C production under solid state fermentation from Acremonium chrysogenum, Process Biochemistry, 39(2), 171–177.CrossRefGoogle Scholar
  3. Agosin E, Maureira M, Biffani V & Pérez F, 1995, Production of gibberellins by solid-substrate cultivation of Gibberella fujikuroi, Proceedings of The 2nd International Workshop on Solid State Fermentation, February 27–28, Montpellier, France, p. 28.Google Scholar
  4. Asagbra AE, Sanni AI, & Oyewole OB, 2005, Solid-state fermentation production of tetracycline by Streptomyces strains using some agricultural wastes as substrate, World Journal of Microbiology and Biotechnology, 21, 107–114.CrossRefGoogle Scholar
  5. Balakrishnan K & Pandey A, 1996, Production of biologically active secondary metabolites in solid state fermentation, Journal of Science Industrial Research 55, 365–372Google Scholar
  6. Baños JG, Tomasini A, Szacaks G & Barrios-González J, 2006a, Lovastatin production by solid-state fermentation on artificial inert support. Unpublished results.Google Scholar
  7. Banos JG, Mejía A, & Barrios-González J, 2006b, Rational selection methods to obtain mutants that overproduce lovastatin in solid-state fermentation or in liquid submerged fermentation. Unpublished results.Google Scholar
  8. Barrios-González J, Tomasini A, Viniegra-González G, & Lopez L, 1988, Penicillin production by solid state fermentation, Biotechnology Letters, 10, 793–798.CrossRefGoogle Scholar
  9. Barrios-González J, Rodriguez GM, & Tomasini A, 1990, Environmental and nutritional factors controlling aflatoxin production in cassava solid state fermentation, Journal of Fermentation and Bioengineering, 70, 329–333.CrossRefGoogle Scholar
  10. Barrios-González J, Castillo TE, & Mejía A, 1993, Development of high penicillin producing strains for solid-state fermentation, Biotechnology Advances, 11, 539–547.CrossRefGoogle Scholar
  11. Barrios-González J & Mejia A, 1996, Production of secondary metabolites by solid-state fermentation, Biotechnology Annual Review, 2, 85–121.CrossRefGoogle Scholar
  12. Barrios-González J, Fernández FJ, & Tomasini A, 2003, Production of microbial secondary metabolites and strain improvement, Indian Journal of Biotechnology, Special Issue: Microbial Biotechnology, 2(3), 322–333.Google Scholar
  13. Barrios-González J, Tomasini A, Fernández FJ & Mejía A, 2004, “Production of antibiotics”, In: Encyclopedia on Bioresource Technology, Ed. by A Pandey, The Haworth Press, Inc. NY, USA, 423–431.Google Scholar
  14. Barrios-González J, Baños JG, Covarrubias A & Garay A, 2006, Comparative study of gene expression during lovastatin solid-state fermentation and liquid submerged fermentation. Unpublished results.Google Scholar
  15. Biesebeke R te, Ruijter G, Rahardjo YSP, Hoogschagen MJ, Heerikhuisen M, Levin A, van Driel KGA, Schutyser MAI, Dijksterhuis J, Zhu Y, Weber FJ, de Vos WM, van den Hondel KAMJJ, Rinzema A, Punt PJ, 2002, Aspergillus oryzae in solid state fermentation. FEMS Yeast Research, 2, 245–248CrossRefGoogle Scholar
  16. Biesebeke R te, Levin A, Sagt C, Bartels J, Goosen T, Ram A, Punt PJ, Van den Hondel C, & Punt P, 2005 Identification of growth phenotype-related genes in Aspergillus oryzae by heterologous macroarray and suppression subtractive hybridization In Solid State and Submerged Cultivated Aspergillus oryzae, Molecular Genetics and Genomics, 273, 33–42.CrossRefGoogle Scholar
  17. Carvalho JC, Pandey A, Oishi BO, Brand D, Rodríguez-León JA, & Soccol CR, 2006, Relation between growth, respirometric analysis and biopigments production from Monascus by solid-state fermentation, Biochemical Engineering Journal, 29, 262–269.Google Scholar
  18. Corona A, Sáez D, & Agosin E, 2005, Effect of water activity on gibberellic acid production by Gibberella fujikuroi under solid-state fermentation conditions, Process Biochemistry, 40, 2655–2658.CrossRefGoogle Scholar
  19. Cuadra T, Tomasini A, Fernandez FJ & Barrios-González J, 2006, pH effect on cephalosporin production by solid-state and liquid-submerged fermentation. Unpublished results.Google Scholar
  20. Domínguez M, Mejía A, & Barrios-González J, (2000), Respiration studies of penicillin solid state fermentation, Journal of Bioscience Bioengineering, 89(5), 409–413.CrossRefGoogle Scholar
  21. Domínguez M, Mejía A, Revah S, & Barrios-González J, 2001, Optimization of bagasse, nutrients and initial moisture ratios on the yield penicillin in solid-state fermentation, World Journal of Microbiology and Biotechnology, 17, 751–756.CrossRefGoogle Scholar
  22. Elibol M, 1997, Characteristics of antibiotic proa in a multyphase sistem, Process Biochemistry, 35, 85–90.Google Scholar
  23. Ellaiah P, Premkumar J, Kanthachari PV, & Adinarayana K, 2002, Production and optimization studies of cephalosporin C by solid state fermentation, Hindustan Antibiotic Bulletin, 44(1–4), 1–7.Google Scholar
  24. Ellaiah P, Srinivasulu B, & Adinarayana K, 2004, Optimization studies on neomycin production by a mutant strain of Streptomyces marinensis in solid-state fermentation, Process Biochemistry, 39, 529–534.CrossRefGoogle Scholar
  25. Farzana K, Shah SN, Butt FB, & Awan SB, 2005, Biosynthesis of bacitracin in solid-state fermentation by Bacillus licheniformis using defatted oil seed cakes as substrate, Pakistan Journal of Pharmaceutical Sciences, 18(1), 55–7.Google Scholar
  26. García BE, Barrios-González J, & Mejía A, 1993, Regulation of penicillin biosynthesis by glucose and ammonium in solid-state fermentation, Proceedings of The 9th International Biotechnology Symposium, August 18–20, Crystal City, VA, USA.Google Scholar
  27. Gutiérrez-Rojas M, Amar AHS, Auria R, Revah S & Favela-Torres E, 1996, Heat transfer in citric acid production by solid-state fermentation, Process Biochemistry, 31, 363–369.CrossRefGoogle Scholar
  28. Han JR & Yuan JM, 2003, Influence of inocula and grains on sclerotia biomasa and carotenoid yield of Penicillium sp. PT95 during solid-state fermentation, Journal of Industrial Microbiology and Biotechnology, 30, 589–592.CrossRefGoogle Scholar
  29. Hesseltine CW, 1972, Biotechnology report: solid-state fermentations, Biotechnology and Bioengineering, 14, 517–532.CrossRefGoogle Scholar
  30. Ishida H, hata Y, Kawato A, Abe Y, Suginami K & Imayasu S, 2000, Identification of the functional elements that regulate the glucoamylase-encoding gene (glaB) expressed in solid-state culture of Aspergillus oryzae, Current Genetics, 37, 373–379.CrossRefGoogle Scholar
  31. Keller NP, Turner G & Bennett JW, 2005, Fungal secondary metabolism-from biochemistry to genomics, Nature Reviews/Microbiology, 3, 937–947.CrossRefGoogle Scholar
  32. Khetan A, Malmberg LH, Kyung YS, Sherman DH & Hu WS, 1999, Precursor and cofactor as a check valve for cephamycin biosynthesis in Streptomyces clavuligerus, Biotechnology Progress, 15, 1020–1027.CrossRefGoogle Scholar
  33. Kota KP & Sridhar P, 1999, Solid state cultivation of Streptomyces clavuligerus for cephamycin C production, Process Biochemistry, 34, 325–328.CrossRefGoogle Scholar
  34. Krishna PK & Padma S, 1999, Solid state cultivation of Streptomyces clavuligerus for cephamycin C production, Process Biochemistry, 34(4), 325–328.CrossRefGoogle Scholar
  35. Krishna PSM, Venkateswarlu G, Pandey A, & Rao LV, 2003, Biosynthesis of rifamycin SV by Amycolatopsis mediterranei MTCC17 in solid cultures, Biotechnology Applied Biochemistry, 37, 311–315.CrossRefGoogle Scholar
  36. Kumar PKR & Lonsane BK, 1987, Gibberellic acid by solid state fermentation: consistent and improved yields, Biotechnology and Bioengineering, 30, 267–271.CrossRefGoogle Scholar
  37. Larroche C & Gros JB, 1992, Characterization of the behavior of Penicillium roquefortii in solid-state cultivation on support by material balances, Journal of Fermentation and Bioengineering, 74, 305–311.CrossRefGoogle Scholar
  38. Litzka O, Papagiannopolous P, Davis MA, Hynes MJ & Brakhage AA, 1998, The penicillin regulator PENR1 of Aspergillus nidulans is a HAP-like transcriptional complex, European Journal of Biochemistry, 251, 758–767.CrossRefGoogle Scholar
  39. Liu BL & Tzeng YM, 1999, Water content and water activity for the producciön of cyclodepsipeptides in solid-state fermentation by Metarhizium anisopliae, Biotechnology Letters, 21(8), 657–661.CrossRefGoogle Scholar
  40. Manzoni M & Rollin M, 2002, Biosynthesis and biotechnological producciön of statins by filamentous fungi and application of these cholesterol-lowering drugs, Applied Microbiology and Biotechnology, 58, 555–564.CrossRefGoogle Scholar
  41. Mejia A, Viniegra-González G, & Barrios-González J, 2003, Biochemical Mechanism of the Effect of Barbital on Rifamycin B Biosynthesis by Amycolatopsis mediterranei (Ml 8 Strain), Journal of Biosciences and Bioengineering, 95(3), 288–292.Google Scholar
  42. Miranda LO, Tomasini A, Mejía A, & Barrios-González J, 2003, Efecto del mezclado y la adición de agua y lactosa en la producciön de penicilina por Penicillium chrysogenum, en fermentatión en estado sólido usando un biorreactor dinámico, Revista Internacional Información Tecnológica, 14(1), 125–130.Google Scholar
  43. Mudgett RE, 1986, Solid state fermentation, In: Manual of Industrial Microbiology and Biotechnology, Eds. Demain AL & Solomon NA, Washington, American Society for Microbiology, 66–84.Google Scholar
  44. Murthy MVR, Mohan EVS, & Sadhukhan AK, 1999, Cyclosporin-A production by Tolypocladium inflatum using solid state fermentation, Process Biochemistry, 34, 269–280CrossRefGoogle Scholar
  45. Nakayama S, Takahashi S, Hirai M, & Shoda M, 1997, Isolation of new variants of surfactin by a recombinant Bacillus subtilis, Applied Microbiology and Biotechnology, 48(1), 80–82.CrossRefGoogle Scholar
  46. Ohno A, Ano T, & Shoda M, 1992, Production of antifungal antibiotic, iturin in a solid state fermentation by Bacillus subtilis NB22 using wheat bran as a substrate, Biotechnology Letters, 14, 817–822.CrossRefGoogle Scholar
  47. Ohno A, Takashi A, & Shoda M, 1995, Production of a lipopeptide antibiotic, surfactin, by recombinant Bacillus subtilis in solid state fermentation, Biotechnology and Bioengineering, 47, 209–213.CrossRefGoogle Scholar
  48. Ooijkaas LP, Weber FJ, Buitelaar RM, Tramper J & Rinzema A, 2000, Defined media and inert supports: their potential as solid-state fermentation production systems, Trends in Biotechnology, 18, 356–360.CrossRefGoogle Scholar
  49. Oriol E, Schettino B, Viniegra-Gonzalez G & Raimbault M, 1988a, Solid state culture of Aspergillus niger on support, Journal of Fermentation Technology, 66, 57–62.CrossRefGoogle Scholar
  50. Oriol E, Raimbault M, Roussos S, & Viniegra-González G, 1988b, Water and water activity in the solid state fermentation of cassava starch by Aspergillus niger, Applied Microbiology and Biotechnology, 27, 498–503.Google Scholar
  51. Parekh S, Vinci VA & Strobel RJ, 2000, Improvement of microbial strains and fermentation processes, Applied Microbiology and Biotechnology, 54(3), 287–301.CrossRefGoogle Scholar
  52. Peberdy JF, 1985, Biology of Penicillium, pp. 407–431, In: Biology of Industrial Microorganisms, Demain AL & Solomon NA, Eds. The Benjamin/Cummings Pub. Co., Inc. London.Google Scholar
  53. Rahardjo YSP, Korona D, Haemers S, Weber FJ, Tramper J & Rinzema A, 2004, Limitations of membrane cultures as a model solid-state fermentation system, Letters in Applied Microbiology, 39, 504–508.CrossRefGoogle Scholar
  54. Ramunas B, He H, Yang H, Chang LP, & Greenstein M, 2006, Production of fungal antibiotics using polymeric solid supports in solid-state and liquid fermentation, Journal of Industrial Microbiology and Biotechnology, 101, 275–83.Google Scholar
  55. Rao KCS, Karanth NG & Sattur AP, 2005, Production of nigerloxin, an enzyme inhibitor and a free radical scavenger, by Aspergillus niger using solid state fermentation, Process Biochemistry, 40(7), 2517–2522.CrossRefGoogle Scholar
  56. Robinson T, Singh D, & Nigam P, 2001, Solid state fermentation: a promising microbial technology for secondary metabolite production, Applied Microbiology and Biotechnology, 55, 284–289.CrossRefGoogle Scholar
  57. Ruijter GJ, Visser J & Rinzema A, 2004, Polyol accumulation by Aspergillus oryzae at low water activity in slid-state fermentation, Microbiology, 150, 1095–1101.CrossRefGoogle Scholar
  58. Sadhukhan AK, Ramana MMV, Kumar RA, Mohan EVS, Vandana G, Bhar C & Venkateswara RK, 1999, Optimization of mycophenolic acid production in solid state fermentation using response surface methodology, Journal of Industrial Microbiology and Biotechnology, 22, 33–38.CrossRefGoogle Scholar
  59. Sadhukhan AK, Murthy MVR, Kumar RA, Mohan EVS, Vandana G, Bhar C & Rao KV, 1999, Optimization of mycophenolic acid production in solid-state fermentation using response surface methodology, Journal of Industrial Microbiology and Biotechnology, 22(1), 33–38.CrossRefGoogle Scholar
  60. Sarhy-Bagnon V, Lozano P, Saucedo-Castaneda G, & Roussos S, 2000, Production of 6-pentyl-a-pyrone by Trichoderma harzianum in liquid and solid state cultures, Process Biochemistry, 36, 103–109.CrossRefGoogle Scholar
  61. Saykhedkar SS & Singhai RS, 2004, Solid-state fermentation for production of griseofulvin on rice bran using Penicillium griseofulvum, Biotechnology Progress, 20(4), 1280–1284.CrossRefGoogle Scholar
  62. Segreth MP, Bonnefoy A, Bronstrup M, Knauf M, Schummer D, & Toti L, 2003, Conisetin a noavel from Coniochaeta ellipsoidea, Journal of Antibiotics, 56, 114–122.Google Scholar
  63. Rao KCS, Karanth NG, & Sattur AP, 2005, Production of nigerlosin, an enzyme inhibitor and a free radical scavenger, by Aspergillus niger using solid state fermentation, Process Biochemistry, 40, 2517–2522.CrossRefGoogle Scholar
  64. Sekar C, Rajasekar VW, & Balaram K, 1997, Production of cyclosporin A by solid state fermentation, Bioprocess Engineering, 17, 257–259.CrossRefGoogle Scholar
  65. Sekar C & Balaram K, 1998, Optimization studies on the production of cyclosporin A by solid state fermentation, Bioprocess Engineering, 18, 293–296.CrossRefGoogle Scholar
  66. Sekar C & Balaraman K, 1999, Cyclosporin A production by Tolypocladium inflatum using solid state fermentation, Process Biochemistry, 18, 293–296.Google Scholar
  67. Shankarananda VS, Ramesh MV, & Lonsane BK, 1992, Idiosyncrasies of solid-state fermentation system in the biosynthesis of metabolites by some bacterial and fungal cultures, Process Biochemistry, 27, 33–36.CrossRefGoogle Scholar
  68. Suryanarayan S, 2003, Current industrial practice in solid state fermentations for secondary metabolite production: the Biocon India experience, Biochemical Engineering Journal, 13, 189–195CrossRefGoogle Scholar
  69. Szakács G, Morovján G & Tengerdy RP, 1998, Production of lovastatin by a wild strain of Aspergillus terreus Biotechnology Letters, 20(4), 411–415.CrossRefGoogle Scholar
  70. Taylor AP, 2004, Quantification of the contribution of surface outgrowth to biocatalysis in sol-gels: oxytetracycline production by Streptomyces rimosus, Biotechnology Letters, 26(22), 1707–1711.CrossRefGoogle Scholar
  71. Trejo MR, (1992) These de Doctorat Biologie Cellulaire-Microbiologie, Université de Provence, Aix-Marseille I, FranceGoogle Scholar
  72. Trejo HMR, Lonsane BK, Raimbault M & Roussos S, 1993, Spectra of ergot alkaloids produced by Claviceps purpurea 1029c in solid-state fermentation system: influence of the composition of liquid medium used for impregnating sugar-cane pith bagasse, Process Biochemistry, 28(1), 23–27.CrossRefGoogle Scholar
  73. Valera HR, Gomes J, Lakshmi S, Gururaja R, Suryanarayan S, & Kumar D, 2005, Lovastatin production by solid state fermentation using Aspergillus flavipes, Enzyme and Microbial Technology, 37, 521–526.CrossRefGoogle Scholar
  74. Weber FJ, Tramper J & Rinzema A, 1999, A simplified material and energy balance approach for process development and scale-up of Coniothyrium minitans conidia production by solid-state cultivation in a packed-bed reactor, Biotechnology and Bioengineering, 65, 447–458.CrossRefGoogle Scholar
  75. Woloshuk CP, Foutz KR, Brewer JF, Bhatnagar D, Cleveland TE & Payne GA, 1994, Molecular characterization of aflR, a regulatory locus for aflatoxin biosynthesis, Applied Environmental Microbiology, 60(7), 2408–2414.Google Scholar
  76. Xu G, Chen Y, Chen Y, Ling X, & Li X, 2004, Production of monacolin K in solid-state fermentation of Monascus sp. 9901 that does not produce citrinin, Proceedings of The First International Symposium on Insight into the world of indigenous fermented foods for Technol Development and Food Safety, Food and Fermentation Industries, 30(10), 59–63.Google Scholar
  77. Yang SS & Swei WJ, 1996, Oxytetracycline production by Streptomyces rimosus in solid-state fermentation of corncob, World Journal of Microbiology and Biotechnology, 12(1), 43–46.CrossRefGoogle Scholar
  78. Yang SS & Wang JY, 1996, Morphogenesis, ATP content and oxytetracycline production by Streptomyces rimosus in solid substrate cultivation, Journal of Applied Bacteriology, 80, 545–550.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Javier Barrios-González
    • 1
  • Armando Mejýa
    • 2
  1. 1.Departamento de BiotecnologíUniversidad Autó Metropolitane IztapalapaMäxico D. F.Mäxico
  2. 2.Depariamento de BiotecnologíaUniversidad Autönoma MetropolitanaMexico D. F.Mexico

Personalised recommendations