Method for lowering down proportion of by-product produced in fermentation of demethylchlortetracycline

Abstract

The invention discloses a method for lowering down the proportion of a by-product produced in fermentation of demethylchlortetracycline. The method comprises the following steps: inoculating the spore of a mutant strain of streptomyces aureus NRRL3203 to a seed medium for culture; and then inoculating a product of seed culture to a fermentation medium for fermentation culture, wherein 150 to 300 ppm of cupric chloride is added into the fermentation medium, and a PH value is controlled in the process of fermentation to allow the PH value to be 6.2 to 6.4 in the period from 0 h to 50 h, 6.0 to 6.2 in the period from 51 h to 100 h and 5.8 to 6.0 in the period from 101 h to time for releasing of fermentation broth from a tank. According to the invention, the spore of the mutant strain of streptomyces aureus NRRL3203 is inoculated into the seed medium for culture and then inoculated into the fermentation medium including cupric chloride for culture, the PH value is regulated and controlled according to the fermentation culture time, so the concentration of the by-product demethyltetracycline in a product is substantially decreased.

Description

technical field [0001] The invention relates to the field of antibiotic fermentation technology, in particular to a method for reducing the proportion of by-products in the fermentation of demethylaureomycin. Background technique [0002] Demethylchlortetracycline (I) (Demeclocycline, Demethylchlortetracycline, DMCTC), also known as 6-demethyl-7-chlorotetracycline, demeclocycline, etc., belongs to tetracyclic antibiotics, and its molecular structure is as follows: [0003] [0004] DMCTC has strong antibacterial property, its antibacterial spectrum is similar to that of aureomycin, its effect is stronger than that of tetracycline and oxytetracycline, and it is more stable than aureomycin. , Treatment of brucellosis and scarlet fever in children. In addition to clinical applications, it also synthesizes its downstream products Minocycline (II) (Minocycline, also known as Minocycline, Minocycline) and Tigecycline (III) (Tigecycline) (Chinese patent CN 200710171556.7), etc....

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Problems solved by technology

[0014] Although the above reports have improved the DMCTC fermentation titer to a certain extent, they have not paid attention to the main by-product DMTC in the fermentation process

At present, in the industrial fermentation process of DMCTC, the proportion of DMTC generally accounts for 8-12% of the total. Due to the similar structure and physical and chemical properties of DMCTC and DMTC (Acta Microbiology, 1974, 14 (2): 172-175) (Table 1), The current industrial solvent extraction process is difficult to completely remove DMTC, so that the concentration of DMTC in the finished DMCTC product reaches 5-6%; in addition, DMCTC will also react with 4-epimerization during the extraction process to generate antibacterial The low activity and high toxicity of 4-epimer and other problems make the purity of the current DMCTC product generally between 91-92%

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