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Illicicolin was cultivated at the 600-L pilot scale for purposes of material generation and process development. The initial medium containing oat flour was difficult operationally as a result of excessive foaming during sterilization, so a new defined medium process (with either glucose or sucrose as the carbon source), developed at the 23-L scale, was scaled up and improved for pilot scale needs. Pilot scale media development efforts focused on exploring the highest concentration of media (1.0 x to 3.0 x) that could be cultivated at the pilot scale and not be limited by mixing or oxygen mass transfer. The process was scaled up successfully and peak titers improved 7.5-fold, from about 200 mg/L in the initial complex medium to 1500 mg/L in the final defined medium.

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RESUMEN

The fermentation of desmethyl-asterriquinone B-1, a diabetes target, by a Pseudomonasarias species was conducted at the 600-l scale using a revised complex medium containing yeast extract and soy hydrolysate. Oat flour and tomato paste were removed from this medium due to difficulties in sterilization. An initial cerelose charge of 40 g/l improved titer and reduced product degradation in the broth at cultivation conditions. An initial mannitol concentration of 65 g/l effectively avoided mid-cycle mannitol additions necessary for the 40 g/l mannitol concentration without the reduction in productivity seen at 90 g/l mannitol. These additions diluted the broth because of the low aqueous solubility of mannitol. Titers reached 3.0 g/l after 158 h with an optimized process, increasing two-fold from the original medium and operating conditions. Reproducible foaming occurred at the point of glucose exhaustion when the culture switched to mannitol consumption. Use of alternative carbon sources (glycerol, soybean oil, sorbitol in conjunction with cerelose) was not effective in attaining similar productivity and did not reduce the extent of foaming. In the case of fructose, the extent of foaming was markedly reduced but product formation was negligible.

RESUMEN

We extended prior studies on the influence of impeller type on fermentation performance to include a novel low-power-number, high-efficiency radial flow impeller, the CD-6, possessing six curved blades on a disk turbine. Dual impeller combinations of CD-6/CD-6, CD-6/Maxflo T, and CD-6/HE-3 were compared with Rushton/Rushton and Maxflo T/Maxflo T base cases. Qualitative comparisons of unaerated and aerated power draw in both water and glycerol were conducted. These suggested minimal power drops with aeration for dual CD-6 impellers and hybrids containing the CD-6 impeller design. We also examined fermentation performance for Streptomyces and Glarea secondary metabolite fermentations. A qualitative comparison of the data suggested that dual CD-6 impellers and hybrids containing the CD-6 impeller design resulted in reasonable power draws, improved mass transfer rates with airflow increases, and acceptable peak titers. These arrangements may warrant further study under a wider range of production conditions.

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A valine-overproducing mutant (MA7040, Streptomyces hygroscopicus) was found to produce 1.5 to 2.0 g/L of the immunoregulant, L-683,590, at the 0.6 m3 fermentation scale in a simple batch process using soybean oil and ammonium sulfate-based GYG5 medium. Levels of both lower (L-683,795) and higher (HH1 and HH2) undesirable homolog levels were controlled adequately. This batch process was utilized to produce broth economically at the 19 m3 fermentation scale. Material of acceptable purity was obtained without the multiple pure crystallizations previously required for an earlier culture, MA6678, requiring valine supplementation for impurity control. Investigations at the 0.6 m3 fermentation scale were conducted, varying agitation, pH, initial soybean oil/ammonium sulfate charges, and initial aeration rate to further improve growth and productivity. Mid-cycle ammonia levels and lipase activity appeared to have an important role. Using mid-cycle soybean oil additions, a titer of 2.3 g/L of L-683,590 was obtained, while titers reached 2.7 g/L using mid-cycle soybean oil and ammonium sulfate additions. Both higher and lower homolog levels remained acceptable during this fed-batch process. Optimal timing of mid-cycle oil and ammonium sulfate additions was considered a critical factor to further titer improvements.

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