title: Development of a defined medium fermentation process for physostigmine production by Streptomyces griseofuscus.
abstract: 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.
authors.affiliation: Department of Bioprocess R&D, Merck Research Laboratories, New Jersey 07065, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Marcin
authors.forename: M A
authors.initials: MA
authors.lastname: Shifflet
authors.forename: P
authors.initials: P
authors.lastname: Salmon
authors.forename: T
authors.initials: T
authors.lastname: Brix
authors.forename: R
authors.initials: R
authors.lastname: Greasham
authors.forename: B
authors.initials: B
authors.lastname: Buckland
authors.forename: M
authors.initials: M
authors.lastname: Chartrain
mesh_terms: D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D003470:Culture Media; D005285:Fermentation; D010830:Physostigmine / Q000378:metabolism*; D013302:Streptomyces / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D003470:Culture Media; D010830:Physostigmine