The effect of cycling dissolved oxygen tension on the synthesis of the antibiotic difficidin by bacillus subtilis

Suphantharika, Manop; Ison, A. P.; Lilly, M. D.

doi:10.1007/bf01767464

Cited by 2 publications

(2 citation statements)

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“…Oxygen derepression of key pathway enzymes upon maintaining saturation dissolved oxygen levels was also demonstrated. The diering eect of dissolved oxygen on the production of pneumocandins was comparable to the eects on the production of dicidin and its hydroxylated derivative oxydicidin by Bacillus subtilis (Suphantharika et al, 1994). The rate of dicidin synthesis was aected by dissolved oxygen below 40%, whereas oxydicidin production was independent of dissolved oxygen.…”

Section: Separation Of the Impact Of Agitation And Dissolved Oxygenmentioning

confidence: 69%

“…The interrelationship between fermentation parameters (such as agitation and dissolved oxygen) has made it historically dicult to separate eects on productivity for industrial fermentation processes. The sensitivity of secondary metabolite production to dissolved oxygen has been shown by a number of studies: cephamycin C (Yegneswaran et al, 1991), tylosin (Chen and Wilde, 1991), capreomycin (Feren et al, 1969), candicidin (Martin et al, 1975), dicidin (Suphantharika et al, 1994), erythromycin (Pollard et al, 1998), moranoline, (Kojima et al, 1995), and cephalosporin C (Hilgendorf et al, 1987;Rollins et al, 1991). Most examples are at laboratory scale and few have truly separated the impact of dissolved oxygen from agitation.…”

Section: Introductionmentioning

confidence: 96%

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Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

Pollard

Kirschner²,

Hernandez³

et al. 2002

Biotech & Bioengineering

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The filamentous fungus Glarea lozoyensis produces a novel, pharmaceutically important pneumocandin (B(0)) that is used to synthesize a lipopeptide which demonstrates cidal activity against clinically relevant pathogens. A range of unwanted pneumocandin analogs are also produced by the organism. To maintain the unwanted impurities to acceptable levels upon scaleup, a good understanding of the impact of chemical and physical environment on the cell physiology is required, which benefits downstream processing. Pilot-scale studies were performed to determine the impact of dissolved oxygen, temperature, pH, and carbon dioxide on the process. Experiments included multiple fermenters (up to seven) at 0.07 and 0.8 m(3) scale using single source medium sterilization and inoculum. Gas blending was used to separate effects of dissolved oxygen from agitation. The process was significantly influenced by dissolved oxygen level. The critical dissolved oxygen tension (C(crit)) for growth was below 2% air saturation. The C(crit) for production of pneumocandin B(0) was 20% air saturation, with a significant reduction of the specific production rate below this value. In contrast, low dissolved oxygen levels produced a substantial increase of pneumocandins B(1), B(5), and E(0), while high dissolved oxygen levels produced a disproportionate increase of D(5). This sensivity to dissolved oxygen was independent of agitation within a power range of 2-15 kW/m(3). Broth viscosity was impacted below 10% dissolved oxygen, suggesting an effect on morphology. The process was shown to be sensitive to temperature but relatively insensitive to pH and carbon dioxide (in the exhaust gas) within the ranges studied. This scaledown analysis explained phenomena seen at pilot scale and helped define operating boundary conditions for successful scale up to 19 m(3).

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Section: Separation Of the Impact Of Agitation And Dissolved Oxygenmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 96%

Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

Pollard

Kirschner²,

Hernandez³

et al. 2002

Biotech & Bioengineering

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The response of GS‐NS0 myeloma cells to single and multiple pH perturbations

Osman

Birch

Varley

2002

Biotech & Bioengineering

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Animal cells are cultured in several types of vessels at laboratory and industrial scale the most common being the stirred tank and the air-lift. Economically, it is preferable to culture animal cells at the largest possible scale but the perceived sensitivity of animal cells to hydrodynamic shear has, until now, limited the aeration and agitation rates used. This has been reported to cause inhomogeneities in operational parameters such as dissolved oxygen concentration, temperature and pH. pH is of special interest during the latter stages of many animal cell fermentation because alkali additions, used for pH control, can cause large local pH perturbations of varying size and duration. The effect of single and multiple pH perturbations on the cell growth of a widely used GS-NS0 mouse myeloma cell line grown in batch culture was investigated. The effect of perturbation amplitude and duration was investigated using a single stirred tank reactor (STR). In the single STR system cells were subjected to one pH 8.0 or 9.0 perturbation ranging in duration from 0-90 minutes. No measurable decrease in viable cell number was seen for pH 8.0 perturbations of any duration whereas pH 9.0 perturbations lasting for 10 minutes caused a 15% decrease in viable cell number. The proportion of viable cells decreased with increasing perturbation time and a 90-minute exposure killed all of the cells. The effect of multiple pH perturbations on GS-NS0 cells was investigated using two connected STR's. More specifically the number of perturbations and the perturbation frequency were investigated. Cells were subjected to between 0 and 100 perturbations at pH 8.0; the time between each perturbation (frequency) was 6 minutes and each perturbation lasted for 200 seconds. Viable cell number decreased with increasing perturbation number, with 100 perturbations causing death of 27.5% of cells. Cells were also exposed to 10 perturbations at pH 9.0, each of 200 second duration at frequencies of either 6, 18 or 60 minutes. Approximately 8 times more cells were killed with perturbations at a 6-minute frequency (28.3% cell death) than at a 60-minute frequency (3.4% cell death).

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The effect of cycling dissolved oxygen tension on the synthesis of the antibiotic difficidin by bacillus subtilis

Cited by 2 publications

References 20 publications

Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

The response of GS‐NS0 myeloma cells to single and multiple pH perturbations

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