Fermentation and Mutational Development of the Tetracyclines

Abstract

The first of the tetracycline family of antibiotics, chlortetracycline (CTC), was introduced over 3 decades ago (Duggar 1948) and in the following years, with the introduction of new members of the family, the tetracyclines have retained their importance in both human therapy and animal feed use. According to reports of the US Tariff Commission, annual production is in the order of 11,000–13,000 tonnes. Numerous reviews dealing with the pathways of biosynthesis and the genetics and biochemistry of the producing organisms have appeared and these will be cited in the appropriate sections. The production aspects of the fermentation and the factors leading to higher yields have been dealt with less frequently and this is understandable in view of the proprietary nature of much of the information. An excellent review by Di Marco and Pennella appeared in 1959 (Di Marco and Pennella 1959) and the most recent general review is by Hostalek et al. (1979). A great deal of the pertinent information is to be found in the patent literature, where, again for obvious reasons, only minimal disclosures are often made. A compendium giving excerpts from the United States patent literature appeared in 1968 (Evans 1968). This review will attempt to deal with the fermentation and mutational development of the tetracyclines from the practical perspective of increasing fermentation potencies. The large number of enzymes and individual steps involved in biosynthesis and the large number of possible compounds on the pathway to the final products (see Hostalek et al. 1974 for a review) can all have a potential effect on ultimate yield.