Monday, August 11, 2008
P120
Process Development for Pilot Scale Production of Nargenicin A1
High throughput screening of approximately 208,000 natural product samples from AMRI’s own natural product collection revealed, among several hundred additional compounds, Nargenicin A1 as a compound of interest in a targeted antibacterial screening initiative. To produce sufficient material for further studies with this compound as well as for lead optimization and SAR studies, AMRI fermentation scientists collaborated with their medicinal chemistry and high throughput screening colleagues. A variety of statistically designed experiments based on available literature and our experience with related natural products and biosynthetic pathways were conducted. In this case, the addition of 3% HP20 resin to the production medium at the start of fermentation was of critical importance, increasing titers from 20 mg/L to 300 mg/L. The increase in titer also greatly aided the isolation by allowing the product to be precipitated out of solution (which was unsuccessful at the lower titers) thereby eliminating the need for large scale chromatography and preparatory HPLC. This process was successfully and repeatedly scaled-up to 500L in our pilot fermentation facility resulting in the production of over 50 grams of Nargenicin A1. The following panels illustrate both the starting point for this development program as well as some of the critical data that resulted in significant process improvements.
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