Development of a defined medium fermentation process for physostigmine production by Streptomyces griseofuscus.
Physostigmine is a plant alkaloid of great interest as a therapeutic candidate for the treatment of Alzheimer's disease. Fortunately, this compound is also produced by Streptomyces griseofuscus NRRL 5324 during submerged cultivation. A fermentation process that used chemically defined medium was therefore developed for its production. By means of statistical experimentation, the physostigmine titer was quickly increased from 20 mg/l to 520 mg/l with a culture growth of 19 gl dry cell weight on the shake-flask scale. Further medium optimization resulted in a yield of 790 mg/l in a 23-1 bioreactor using a batch process. A titer of 880 mg/l was attained during scale-up in a 800-1 fermentor by employing a nutrient-feeding strategy. This production represents a 44-fold increase over the yield from the initial process in shake-flasks. The defined-medium fermentation broth was very amenable to downstream processing.
Zhang
J
J
Department of Bioprocess R&D, Merck Research Laboratories, New Jersey 07065, USA.
Marcin
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Shifflet
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Salmon
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Brix
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Greasham
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Buckland
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B
Chartrain
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D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D003470:Culture Media; D005285:Fermentation; D010830:Physostigmine / Q000378:metabolism*; D013302:Streptomyces / Q000378:metabolism*
D002800:Cholinesterase Inhibitors; D003470:Culture Media; D010830:Physostigmine