Bioprocess and Biosystems Engineering

, Volume 36, Issue 3, pp 259–272 | Cite as

Effects of bioreactor hydrodynamics on the physiology of Streptomyces

  • E. OlmosEmail author
  • N. Mehmood
  • L. Haj Husein
  • J.-L. Goergen
  • M. Fick
  • S. Delaunay
Mini Review


Streptomyces are filamentous bacteria which are widely used industrially for the production of therapeutic biomolecules, especially antibiotics. Bioreactor operating conditions may impact the physiological response of Streptomyces especially agitation and aeration as they influence hydromechanical stress, oxygen and nutrient transfer. The understanding of the coupling between physiological response and bioreactor hydrodynamics lies on a simultaneous description of the flow and transfers encountered by the bacteria and of the microbial response in terms of growth, consumption, morphology, production or intracellular signals. This article reviews the experimental and numerical works dedicated to the study of the coupling between bioreactor hydrodynamics and antibiotics producing Streptomyces. In a first part, the description of hydrodynamics used in these works is presented and then the main relations used. In a second part, the assumptions made in these works are discussed and put into emphasize. Lastly, the various Streptomyces physiological responses observed are detailed and compared.


Bioreactor Hydrodynamics Streptomyces Mass transfer Antibiotic production 


  1. 1.
    Rokem JS, Lantz AE, Nielsen J (2007) Systems biology of antibiotic production by microorganisms. Nat Prod Rep 24:1262–1287CrossRefGoogle Scholar
  2. 2.
    Ruiz B, Chevez A, Forero A, Garcia-Huante Y, Romero A, Sanchez M, Rocha D, Sanchez B, Rodriguez-Sanoja R, Sanchez S, Langley E (2010) Production of microbial secondary metabolites: regulation by the carbon source. Crit Rev Microbiol 36:146–167CrossRefGoogle Scholar
  3. 3.
    Sanchez S, Chavez A, Forero A, Garcia-Huante Y, Romero A, Sanchez M, Rocha D, Sanchez B, Valos M, Guzman-Trampe S et al (2010) Carbon source regulation of antibiotic production. J Antibiot 63:442–459CrossRefGoogle Scholar
  4. 4.
    Martín J (1977) Control of antibiotic synthesis by phosphate. In: Advances in biochemical engineering, vol 6. Springer, Heidelberg, pp 105–127Google Scholar
  5. 5.
    Deutscher J (2008) The mechanisms of carbon catabolite repression in bacteria. Curr Opin Microbiol 11:87–93CrossRefGoogle Scholar
  6. 6.
    Görke B, Stülke J (2008) Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nat Rev Microbiol 6:613–624CrossRefGoogle Scholar
  7. 7.
    Delafosse A, Morchain J, Guiraud P, Liné A (2009) Trailing vortices generated by a Rushton turbine: assessment of URANS and large Eddy simulations. Chem Eng Res Des 87:401–411CrossRefGoogle Scholar
  8. 8.
    Mehmood N, Olmos E, Marchal P, Goergen JL, Delaunay S (2010) Relation between pristinamycins production by Streptomyces pristinaespiralis, power dissipation and volumetric gas-liquid mass transfer coefficient, k L a. Process Biochem 45:1779–1786CrossRefGoogle Scholar
  9. 9.
    Huchet F, Line A, Morchain J (2009) Evaluation of local kinetic energy dissipation rate in the impeller stream of a Rushton turbine by time-resolved PIV. Chem Eng Res Des 87:369–376CrossRefGoogle Scholar
  10. 10.
    Hughmark GA (1980) Power requirements and interfacial area in gas-liquid turbine agitated systems. Ind Eng Chem Process Des Dev 19:638–641CrossRefGoogle Scholar
  11. 11.
    Cui YQ, Van Der Lans RGJM, Luyben KCAM (1996) Local power uptake in gas-liquid systems with single and multiple Rushton turbines. Chem Eng Sci 51:2631–2636CrossRefGoogle Scholar
  12. 12.
    Fujasová M, Linek V, Moucha T (2007) Mass transfer correlations for multiple-impeller gas-liquid contactors. Analysis of the effect of axial dispersion in gas and liquid phases on “local” k L a values measured by the dynamic pressure method in individual stages of the vessel. Chem Eng Sci 62:1650–1669CrossRefGoogle Scholar
  13. 13.
    Roubos JA, Krabben P, Luiten RGM, Verbruggen HB, Heijnen JJ (2001) A quantitative approach to characterizing cell lysis caused by mechanical agitation of Streptomyces clavuligerus. Biotechnol Prog 17:336–347CrossRefGoogle Scholar
  14. 14.
    Büchs J, Maier U, Milbradt C, Zoels B (2000) Power consumption in shaking flasks on rotary shaking machines: II. Nondimensional description of specific power consumption and flow regimes in unbaffled flasks at elevated liquid viscosity. Biotechnol Bioeng 68:594–601CrossRefGoogle Scholar
  15. 15.
    Peter CP, Suzuki Y, Rachinskiy K, Lotter S, Büchs J (2006) Volumetric power consumption in baffled shake flasks. Chem Eng Sci 61:3771–3779CrossRefGoogle Scholar
  16. 16.
    Büchs J, Lotter S, Milbradt C (2001) Out-of-phase operating conditions, a hitherto unknown phenomenon in shaking bioreactors. Biochem Eng J 7:135–141CrossRefGoogle Scholar
  17. 17.
    Douaire M, Morchain J, Liné A (2009) Mini-review: relationship between hydrodynamic conditions and substrate influx toward cells. In: 13th European conference on mixing, 14–17th April 2009, London, UKGoogle Scholar
  18. 18.
    Hille A, Neu TR, Hempel DC, Horn H (2009) Effective diffusivities and mass fluxes in fungal biopellets. Biotechnol Bioeng 103:1202–1213CrossRefGoogle Scholar
  19. 19.
    Hille A, Neu TR, Hempel DC, Horn H (2005) Oxygen profiles and biomass distribution in biopellets of Aspergillus niger. Biotechnol Bioeng 92:614–623CrossRefGoogle Scholar
  20. 20.
    Makagiansar HY, Ayazi Shamlou P, Thomas CR, Lilly MD (1993) The influence of mechanical forces on the morphology and penicillin production of Penicillium chrysogenum. Bioprocess Eng 9:83–90CrossRefGoogle Scholar
  21. 21.
    Garcia-Ochoa F, Gomez E (2009) Bioreactor scale-up and oxygen transfer rate in microbial processes: an overview. Biotechnol Adv 27:153–176CrossRefGoogle Scholar
  22. 22.
    Maier U (2002) Gas–Flüssigkeits–Stofftransfer im Schüttelkolben. PhD thesis. RWTH Aachen University, AachenGoogle Scholar
  23. 23.
    Mehmood N, Olmos E, Goergen JL, Blanchard F, Ullisch D, Klöckner W, Büchs J, Delaunay S (2011) Oxygen supply controls the onset of pristinamycins production by Streptomyces pristinaespiralis in shaking flasks. Biotechnol Bioeng 108:2151–2161CrossRefGoogle Scholar
  24. 24.
    Paul GC, Thomas CR (1998) Characterisation of mycelial morphology using image analysis. Adv Biochem Eng Biotechnol 60:1–59CrossRefGoogle Scholar
  25. 25.
    Yin P, Wang YH, Zhang SL, Chu J, Zhuang YP, Chen N, Li XF, Wu YB (2008) Effect of mycelial morphology on bioreactor performance and avermectin production of Streptomyces avermitilis in submerged cultivations. J Chin Inst Chem Eng 39:609–615CrossRefGoogle Scholar
  26. 26.
    Kim JH, Hancock IC (2000) Pellet forming and fragmentation in liquid culture of Streptomyces griseus. Biotechnol Lett 22:189–192CrossRefGoogle Scholar
  27. 27.
    Papagianni M (2004) Fungal morphology and metabolite production in submerged mycelial processes. Biotechnol Adv 22:189–259CrossRefGoogle Scholar
  28. 28.
    Wucherpfennig T, Hestler T, Krull R (2011) Morphology engineering—osmolality and its effect on Aspergillus niger morphology and productivity. Microb Cell Fact 10:58CrossRefGoogle Scholar
  29. 29.
    Krull R, Cordes C, Horn H, Kampen I, Kwade A, Neu TR, Nörtemann B (2010) Morphology of filamentous fungi—linking cellular biology to process engineering using Aspergillus niger. Adv Biochem Eng/Biotechnol 121:1–21CrossRefGoogle Scholar
  30. 30.
    Coufort C, Bouyer D, Liné A (2005) Flocculation related to local hydrodynamics in a Taylor-Couette reactor and in a jar. Chem Eng Sci 60:2179–2192CrossRefGoogle Scholar
  31. 31.
    Bouyer D, Coufort C, Line A, Do-Quang Z (2005) Experimental analysis of floc size distributions in a 1-L jar under different hydrodynamics and physicochemical conditions. J Colloid Interface Sci 292:413–428CrossRefGoogle Scholar
  32. 32.
    Pilz RD, Hempel DC (2005) Mechanical stress on suspended particles in two- and three-phase airlift loop reactors and bubble columns. Chem Eng Sci 60:6004–6012CrossRefGoogle Scholar
  33. 33.
    Pamboukian CRD, Facciotti MCR (2005) Rheological and morphological characterization of Streptomyces olindensis growing in batch and fed-batch fermentations. Braz J Chem Eng 22:31–40CrossRefGoogle Scholar
  34. 34.
    Tamura S, Park Y, Toriyama M, Okabe M (1997) Change of mycelial morphology in tylosin production by batch culture of Streptomyces fradiae under various shear conditions. J Ferment Bioeng 83:523–528CrossRefGoogle Scholar
  35. 35.
    Warren SJ, Keshavarz-Moore E, Shamlou PA, Lilly MD, Thomas CR, Dixon K (1995) Rheological measurements of three actinomycetes in submerged cultures. Bioprocess Eng 13:45–48CrossRefGoogle Scholar
  36. 36.
    Ohta N, Yong Soo P, Yahiro K, Okabe M (1995) Comparison of neomycin production from Streptomyces fradiae cultivation using soybean oil as the sole carbon source in an air-lift bioreactor and a stirred-tank reactor. J Ferment Bioeng 79:443–448CrossRefGoogle Scholar
  37. 37.
    Pinto LS, Vieira LM, Pons MN, Fonseca MMR, Menezes JC (2004) Morphology and viability analysis of Streptomyces clavuligerus in industrial cultivation systems. Bioprocess Biosyst Eng 26:177–184CrossRefGoogle Scholar
  38. 38.
    Wucherpfennig T, Kiep KA, Driouch H, Wittmann C, Krull R (2010) Morphology and rheology in filamentous cultivations. Adv Appl Microbiol 72:89–133CrossRefGoogle Scholar
  39. 39.
    Campesi A, Cerri MO, Hokka CO, Badino AC (2009) Determination of the average shear rate in a stirred and aerated tank bioreactor. Bioprocess Biosyst Eng 32:241–248CrossRefGoogle Scholar
  40. 40.
    Gabelle JC, Augier F, Caravalho A, Rousset R, Morchain J (2011) Effect of tank size on k L a and mixing time in aerated stirred reactors with non-Newtonian fluids. Can J Chem Eng 89:1139–1153CrossRefGoogle Scholar
  41. 41.
    Hristov H, Mann R, Lossev V, Vlaev SD, Seichter P (2001) A 3-D analysis of gas-liquid mixing, mass transfer and bioreaction in a stirred bio-reactor. Food Bioprod Proc 79:232–241CrossRefGoogle Scholar
  42. 42.
    Large KP, Ison AP, Williams DJ (1998) The effect of agitation rate on lipid utilisation and clavulanic acid production in Streptomyces clavuligerus. J Biotechnol 63:111–119CrossRefGoogle Scholar
  43. 43.
    Mollet M, Ma N, Zhao Y, Brodkey R, Taticek R, Chalmers JJ (2004) Bioprocess equipment: characterization of energy dissipation rate and its potential to damage cells. Biotechnol Progr 20:1437–1448CrossRefGoogle Scholar
  44. 44.
    Olmos E, Gentric C, Midoux N (2003) Numerical description of flow regime transitions in bubble column reactors by a multiple gas phase model. Chem Eng Sci 58:2113–2121CrossRefGoogle Scholar
  45. 45.
    Olmos E, Gentric C, Vial C, Wild G, Midoux N (2001) Numerical simulation of multiphase flow in bubble column reactors. Influence of bubble coalescence and break-up. Chem Eng Sci 56:6359–6365CrossRefGoogle Scholar
  46. 46.
    Simonnet M, Gentric C, Olmos E, Midoux N (2008) CFD simulation of the flow field in a bubble column reactor: importance of the drag force formulation to describe regime transitions. Chem Eng Process 47:1726–1737CrossRefGoogle Scholar
  47. 47.
    Moilanen P, Laakkonen M, Aittamaa J (2006) Modeling aerated fermenters with computational fluid dynamics. Ind Eng Chem Res 45:8656–8663CrossRefGoogle Scholar
  48. 48.
    Peter CP, Suzuki Y, Büchs J (2006) Hydromechanical stress in shake flasks: correlation for the maximum local energy dissipation rate. Biotechnol Bioeng 93:1164–1176CrossRefGoogle Scholar
  49. 49.
    Douaire M, Mercade M, Morchain J, Loubière P (2010) A unique phenotypic modification of Lactococcus lactis cultivated in a Couette bioreactor. Biotechnol Bioeng 108:559–571CrossRefGoogle Scholar
  50. 50.
    Lin PJ, Scholz A, Krull R (2010) Effect of volumetric power input by aeration and agitation on pellet morphology and product formation of Aspergillus niger. Biochem Eng J 49:213–220CrossRefGoogle Scholar
  51. 51.
    Yegneswaran PK, Gray MR, Thompson BG (1991) Experimental simulation of dissolved oxygen fluctuations in large fermentors: effect on Streptomyces clavuligerus. Biotechnol Bioeng 38:1203–1209CrossRefGoogle Scholar
  52. 52.
    Shioya S, Morikawa M, Kajihara Y, Shimizu H (1999) Optimization of agitation and aeration conditions for maximum virginiamycin production. Appl Microbiol Biotechnol 51:164–169CrossRefGoogle Scholar
  53. 53.
    Tough AJ, Prosser JI (1996) Experimental verification of a mathematical model for pelleted growth of Streptomyces coelicolor A3 (2) in submerged batch culture. Microbiology 142:639–648CrossRefGoogle Scholar
  54. 54.
    El-Enshasy HA, Farid MA, El-Sayed ESA (2000) Influence of inoculum type and cultivation conditions on natamycin production by Streptomyces natalensis. J Basic Microbiol 40:333–342CrossRefGoogle Scholar
  55. 55.
    Okabe M, Kuwajima T, Satoh M, Kimura K, Okamura K, Okamoto R (1992) Preferential and high-yield production of a cephamycin C by dissolved oxygen controlled fermentation. J Ferment Bioeng 73:292–296CrossRefGoogle Scholar
  56. 56.
    Rosa JC, Neto AB, Hokka CO, Badino AC (2005) Influence of dissolved oxygen and shear conditions on clavulanic acid production by Streptomyces clavuligerus. Bioprocess Biosystems Eng 27:99–104CrossRefGoogle Scholar
  57. 57.
    Belmar-Beiny MT, Thomas CR (1991) Morphology and clavulanic acid production of Streptomyces clavuligerus: effect of stirrer speed in batch fermentations. Biotechnol Bioeng 37:456–462CrossRefGoogle Scholar
  58. 58.
    Rikmanis M, Berzinš A, Viesturs U (2007) Excess turbulence as a cause of turbohypobiosis in cultivation of microorganisms. Cent Eur J Biol 2:481–501CrossRefGoogle Scholar
  59. 59.
    Toma MK, Ruklisha MP, Vanags JJ, Zeltina MO, Leite MP, Galinina NI, Viesturs UE, Tengerdy RP (1991) Inhibition of microbial growth and metabolism by excess turbulence. Biotechnol Bioeng 38:552–556CrossRefGoogle Scholar
  60. 60.
    Ayazi Shamlou P, Makagiansar HY, Ison AP, Lilly MD, Thomas CR (1994) Turbulent breakage of filamentous microorganisms in submerged culture in mechanically stirred bioreactors. Chem Eng Sci 49:2621–2631CrossRefGoogle Scholar
  61. 61.
    Amanullah A, Justen P, Davies A, Paul GC, Nienow AW, Thomas CR (2000) Agitation induced mycelial fragmentation of Aspergillus oryzae and Penicillium chrysogenum. Biochem Eng J 5:109–114CrossRefGoogle Scholar
  62. 62.
    Bellgardt KH (1998) Process models for production of beta-lactam antibiotics. Adv Biochem Eng Biotechnol 60:153–194Google Scholar
  63. 63.
    Whitaker A (1992) Actinomycetes in submerged culture. Appl Biochem Biotechnol 32:23–35CrossRefGoogle Scholar
  64. 64.
    Kahar P, Kobayashi K, Iwata T, Hiraki J, Kojima M, Okabe M (2002) Production of alph-polylysine in an airlift bioreactor (ABR). J Biosci Bioeng 93:274–280Google Scholar
  65. 65.
    Liu TJ, Xu WL, Sun WB, Zhang YZ (2000) Effect of dissolved oxygen on mutanolysin fermentation. Chin J Biotechnol 16:229–231Google Scholar
  66. 66.
    Kaiser D, Onken U, Sattler I, Zeeck A (1994) Influence of increased dissolved oxygen concentration on the formation of secondary metabolites by manumycin-producing. Appl Microbiol Biotechnol 41:309–312CrossRefGoogle Scholar
  67. 67.
    Dick O, Onken U, Sattler I, Zeeck A (1994) Influence of increased dissolved oxygen concentration on productivity and selectivity in cultures of a colabomycin-producing strain of Streptomyces griseoflavus. Appl Microbiol Biotechnol 41:373–377Google Scholar
  68. 68.
    Chen HC, Wilde F (1991) The effect of dissolved oxygen and aeration rate on antibiotic production of Streptomyces fradiae. Biotechnol Bioeng 37:591–595CrossRefGoogle Scholar
  69. 69.
    Rollins MJ, Jensen SE, Westlake DWS (1988) Effect of aeration on antibiotic production by Streptomyces clavuligerus. J Ind Microbiol 3:357–364CrossRefGoogle Scholar
  70. 70.
    Vecht-Lifshitz SE, Magdassi S, Braun S (1990) Pellet formation and cellular aggregation in Streptomyces tendae. Biotechnol Bioeng 35:890–896CrossRefGoogle Scholar
  71. 71.
    Braun S, Vecht-Lifshitz SE (1991) Mycelial morphology and metabolite production. Trends Biotechnol 9:63–68Google Scholar
  72. 72.
    Rollins MJ, Jensen SE, Westlake DWS (1991) Effect of dissolved oxygen level on ACV synthetase synthesis and activity during growth of Streptomyces clavuligerus. Appl Microbiol Biotechnol 35:83–88CrossRefGoogle Scholar
  73. 73.
    Zhang J, Demain AL (1991) Regulation of ACV synthetase in penicillin- and cephalosporin-producing microorganisms. Biotechnol Adv 9:623–641CrossRefGoogle Scholar
  74. 74.
    Clark GJ, Langley D, Bushell ME (1995) Oxygen limitation can induce microbial secondary metabolite formation: investigations with miniature electrodes in shaker and bioreactor culture. Microbiology 141:663–669CrossRefGoogle Scholar
  75. 75.
    Dunstan GH, Avignone-Rossa C, Langley D, Bushell ME (2000) The Vancomycin biosynthetic pathway is induced in oxygen-limited Amycolatopsis orientalis (ATCC 19795) cultures that do not produce antibiotic. Enzyme Microb Technol 27:502–510CrossRefGoogle Scholar
  76. 76.
    Elibol M, Mavituna F (1998) A remedy to oxygen limitation problem in antibiotic production: addition of perfluorocarbon. Biochem Eng J 3:1–7CrossRefGoogle Scholar
  77. 77.
    Elibol M, Ulgen K, Kamaruddin K, Mavituna F (1995) Effect of inoculum type on actinorhodin production by Streptomyces coelicolor A3(2). Biotechnol Lett 17:579–582CrossRefGoogle Scholar
  78. 78.
    Martins RA, Guimares LM, Pamboukian CR, Tonso A, Facciotti MCR, Schmidell W (2004) The effect of dissolved oxygen concentration control on cell growth and antibiotic retamycin production in Streptomyces olindensis So20 fermentations. Braz J Chem Eng 21:185–192CrossRefGoogle Scholar
  79. 79.
    Yegneswaran PK, Gray MR (1991) Effect of dissolved oxygen control on growth and antibiotic production in Streptomyces clavuligerus fermentations. Biotechnol Prog 7:246–250CrossRefGoogle Scholar
  80. 80.
    Jensen AL, Schultz JS, Shu P (1966) Scale-up of antibiotic fermentations by control of oxygen utilization. Biotechnol Bioeng 8:525–537CrossRefGoogle Scholar
  81. 81.
    Yegneswaran PK, Gray MR, Westlake DWS (1988) Effects of reduced oxygen on growth and antibiotic production in Streptomyces clavuligerus. Biotechnol Lett 10:479–484CrossRefGoogle Scholar
  82. 82.
    Feren CJ, Squires RW (1969) The relationship between critical oxygen level and antibiotic synthesis of capreomycin and cephalosporin C. Biotechnol Bioeng 11:583–592CrossRefGoogle Scholar
  83. 83.
    Chen C, Si S, He Q, Xu H, Lu M, Xie Y, Wang Y, Chen R (2008) Isolation and characterization of antibiotic NC0604, a new analogue of bleomycin. J Antibiot 61:747–751CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • E. Olmos
    • 1
    • 2
    Email author
  • N. Mehmood
    • 1
    • 2
  • L. Haj Husein
    • 1
    • 2
  • J.-L. Goergen
    • 1
    • 2
  • M. Fick
    • 1
    • 2
  • S. Delaunay
    • 1
    • 2
  1. 1.CNRSVandoeuvre-lès-NancyFrance
  2. 2.CNRSUniversité de LorraineVandoeuvre-lès-NancyFrance

Personalised recommendations