Fermentation On Anti-tumor Chaetominine Produced By Marine Fungus Aspergillus Fumigatus CY018

Chaetominine (CHA) is a quinazoline alkaloid derivative isolated from marine-derived fungus Aspergillus fumigatus CY018. CHA has comparable cytotoxic activity with positive drug 5-Fu. However its wide application has been limited by the low chemical synthesis yield and fermentation production from original cultures. We tried to establish large-scale fermentation technology to provide drug source for activity research.By basic medium screening and optimization of carbon and nitrogen sources, we improved CHA production to 31.78 mg/L, which was 2.16 times compared to that in original medium. Owing to reference of alkaloids and CHA biosynthetic pathway, we explored the addation of D-trytophan. Statistical methodologies including response surface methodology were used to optimize the concentration of D-tryptophan, carbon and nitrogen sources. Under the proposed optimized conditions, the experimental CHA production reached 55.92 mg/L.We further realized reactor fermentation with metabolic regulation and high yield medium. Study about shear stress and dissolved oxygen tension in shaking flask cultures revealed that Aspergillus fumigatus CY018 had strong shear tolerance and high dissolved oxygen tension favoured CHA production. We found that the main limiting factor based on the analysis between the metabolic profiles. Therefore,5L bioreactor system was proposed to produce CHA by using shear speed optimization and ammonium acetate feeding strategy, the producation reached 57.85 mg/L. By combined use of the scale-up strategy and similar impeller linear velocity, the fermentation was successfully scaled up to 50 L and 500 L finally. The highest CHA production in 50 L and 500 L cultures reached up to 49.40 mg/L and 58.64 mg/L.