MAXIMUM VIRGINIAMYCIN PRODUCTION BY OPTIMIZATION OF CULTIVATION CONDITIONS IN BATCH CULTURE WITH AUTOREGULATOR ADDITION

A strategy for optimization of non-growth-associated production in bat ch culture employing an empirical approach was developed through the s tudy of virginiamycin production. The strategy is formulated with two aims: attaining a high cell concentration at the beginning of the prod uction phase without decrease in production activity; and enhancing th e production activity during the production phase. As a practical exam ple, the goal of a maximum virginiamycin (M and S) production in the b atch culture of Streptomyces virginiae was set. To attain a high cell concentration in the production phase of the batch culture, that is, t o extend the growth phase for as long as possible, the optimum composi tion and concentration of the complex medium, especially the yeast ext ract (YE) concentration, were first investigated. Dissolved oxygen (DO ) concentration control was also a parameter considered in maintaining the production activity during the production phase. In addition, to enhance the production activity, an optimum addition strategy of an au toregulator, virginiae butanolide-C (VB-C), was investigated. Combinin g these measures, the optimum cultivation conditions were found to be an initial YE concentration in the complex medium of 45 g/L, the shot addition of 300 mu g/L of VB-C 11.5 h after the start of the batch cul ture, and a DO concentration maintained above 2 mg/L. The maximum conc entrations of virginiamycin M and S were about ninefold those obtained under nonoptimum cultivation conditions. Nonoptimum cultivation condi tions consisted of an initial YE concentration one sixth (7.5 g/L) tha t of the optimum cultivation conditions, and no VB-C addition. These c onditions were used as representative of the standard cultivation of v irginiamycin in this study. The strategy developed here will be applic able to the production of other antibiotics, especially to the cultiva tion of Streptomyces species, in which a hormonelike signal material ( an autoregulator) plays an important role in antibiotic production. (C ) 1996 John Wiley & Sons, Inc.