Production of Tetracyclines
The biosynthesis of tetracyclines, antibiotics containing the four-membered naphthacene ring, requires a large number of enzymatic steps. In the biosynthesis of chlortetracycline. For example, there are more than 72 intermediates. Genetic
studies of Streptomyces aureofaciens, the producing organism in the chlortetracycline fermentation, have shown that a total of
more than 300 genes are involved! With such a large number of genes, regulation of biosynthesis of this antibiotic is obviously
quite complex. However, some key regulatory signals are known and are accounted for in the production scheme.
Chlortetracycline synthesis is repressed by both glucose and phosphate. Phosphate repression is especially significant, and so
the medium used in commercial production contains relatively low phosphate concentrations. Appendix 4 shows a tetracycline production scheme and the various stages in scale-up leading to
the commercial fermentor. (This would make a wonderful final exam question.) As in penicillin production, corn steep liquor is used, but sucrose rather than lactose is used as a carbon source. Glucose is avoided because glucose strongly represses antibiotic production through the transcriptional control mechanism known as catabolite repression.