Monday, July 27, 2009
P68
Production of fungal natural products by mixed phase fermentation with milled cereal grains dispersed on polyester-cellulose
Ramunas Bigelis, Hui Y. Yang, and Haiyin He. Natural Products Discovery Research, Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965
New approaches to solid phase fermentation (SPF) that influence fungal secondary metabolism help identify new bioactive natural products for screening programs. Mixed phase fermentation (MPF), one such approach that uses inert polymeric supports in abundant liquid for mycelial attachment and growth, facilitated the discovery of acremonidins from Acremonium sp. LL-Cyan416, as reported earlier. The acremonidins are of interest because they structurally resemble a portion of balanol, a known inhibitor of serine/threonine protein kinases that are important targets for designing therapeutic drugs. Liquid phase fermentation (LPF) generated sufficient acremonidin E for semisynthesis of balanol analogs, but did not produce other desired compounds of the acremonidin family. Conventional SPF with moistened whole rice generated few members of the acremonidin family. MPF using solid substrates, such as milled cereal grains, was important to produce sufficient quantities of new acremonidins for semisynthesis. The yield and diversity of acremonidins was much higher after MPF than SPF. Successful MPF employed coarsely milled rice dispersed on a stationary polyester-cellulose support bearing abundant liquid. MPF with the absorbent support increased accessible surface area and water availability, and influenced growth patterns and differentiation. After MPF with many diverse fungi, yields of other metabolites were also enhanced, residual unused solid substrate reduced, and extraction of unwanted substrate components diminished, benefiting HPLC analysis and purification of natural products. The MPF approach with milled cereal grains dispersed on a polymeric support facilitates natural product discovery, and is routinely used together with traditional SPF and LPF in the Natural Products Group at Wyeth.
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