Enhanced production of heterologous macrolide aglycones by fed-batch cultivation of Streptomyces coelicolor

A media development program for the enhanced production of macrolide aglycones by Streptomyces coelicolor is described. Shake flask studies utilizing a yeast extract and a bakers' yeast increased production by 200% and 80%, respectively. However, ammonia generation and high pH were identified as potential problems in these enriched media. Studies in pH-controlled fermentors revealed that production stage pH significantly affects macrolide titers, with low pH (5.5) being more productive than high pH (6.5). Implementation of glucose feeding in shake flask cultures reduced ammonia generation and controlled production stage pH, resulting in significantly enhanced productivities. The combined effects of media supplementation and glucose feeding resulted in a three to five-fold overall improvement in total macrolide aglycone titers, and is the first reported high-level (>1 g/l) production of recombinant polyketides in a heterologous host.