Process for producing aromatic polyene antibiotic through fermentation

A technology for aromatic polyenes and antibiotics, applied in the field of fermentation, can solve the problems of restricting the clinical trials and industrialization of aromatic polyene antibiotics, low yield of aromatic polyene antibiotics, etc.

Inactive Publication Date: 2013-07-10
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, the yield of these aromatic polyene antibiotics produced by genetic engineering is very low, usually only about 10 mg / L fermentation broth, thus restricting the clinical trials and industrialization of these aromatic polyene antibiotics

Method used

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  • Process for producing aromatic polyene antibiotic through fermentation
  • Process for producing aromatic polyene antibiotic through fermentation
  • Process for producing aromatic polyene antibiotic through fermentation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] In order to determine the time to regulate the pH, the concentration of the aromatic polyene antibiotics in the fermentation broth can be measured regularly (such as every 5 minutes or every 10 minutes) or in real time during the fermentation process, so as to judge whether the engineering bacteria start to produce aroma. polyene antibiotics. Once the engineered bacteria start or are about to start producing aromatic polyene antibiotics, the pH can be adjusted to 6.4-7.4.

[0065] Taking FR-008 decarboxylation-derived polyketide antibiotic CS103 as an example, the following methods were used to detect the initial stage of fermentation: high performance liquid chromatography (Agenlent 1100), the chromatographic column is SB-C8 (4.6mm*250mm), and the mobile phase is 20mM, pH4. 6 Ammonium acetate buffer solution-acetonitrile (60:40), the flow rate is 1mL / min, the column temperature is 25°C, the detection wavelength is 380nm, and the regression equation is obtained under th...

Embodiment 2

[0071] Fermentation of Polyketide Antibiotic CS103 Derivatized by Decarboxylation of FR-008

[0072] Same as Example 1, the difference lies in: maintain pH6.9 with hydrochloric acid and sodium hydroxide after inoculation, cultivate for 120 until the end of fermentation.

[0073] The result is as figure 2 shown. When the fermentation process maintains a pH of 6.9, due to the relatively stable pH of the fermentation process, the growth ability of the bacteria is also improved, and the final dry cell weight reaches 9.4g / L. Substrate consumption rate is quickened, and glucose is consumed to 10g / L in 48-72h, and 120h is almost exhausted, and does not control the batch fermentation of pH in embodiment 1, just consumes to about 10g / L until 120h. The consumption of amino nitrogen is also significantly accelerated. It can be seen that the metabolic rate of the bacteria is accelerated, which can also be clearly reflected from the dissolved oxygen and RQ values. The minimum value of...

Embodiment 3

[0075] Fermentation of Polyketide Antibiotic CS103 Derivatized by Decarboxylation of FR-008

[0076] Same as Example 1, the difference lies in: after inoculation, the pH was maintained at 8.0 with hydrochloric acid and sodium hydroxide. After 24 hours, the pH was quickly adjusted to 6.9, and maintained until the end of fermentation.

[0077] The result is as image 3 shown. After adopting the strategy of controlling the pH in stages, cultivated for 120h, put the fermentation level of FR-008 decarboxylated polyketide antibiotic CS103 into the bottle to further increase to 111 μg / mL, which was 141% higher than that in the batch fermentation without pH control in Example 1. Controlled pH6.9 batch fermentation also improved 26% among the example 2.

[0078] In addition, the highest bacterial dry weight DCW Max It was 9.5g / L, and there was no significant change from batch fermentation with controlled pH6.9. This indicated that the increase in antibiotic production was not due t...

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Abstract

The invention provides a process for producing aromatic polyene antibiotic through fermentation. The method comprises the following steps: in the initial process of growing engineering bacteria, cultivating the engineering bacteria under the condition from neutrality to alkalescence so as to promote the synthesis of an aromatic side chain precursor of the antibiotic, namely p-aminobenzoic acid; and continuously fermenting under the condition from alkalescence to neutrality, and converting the p-aminobenzoic acid into the aromatic polyene antibiotic. The method can effectively improve the yield of the aromatic polyene antibiotic and reduce byproducts.

Description

technical field [0001] The invention relates to the field of fermentation, in particular to a fermentation production method of aromatic polyene antibiotics. Background technique [0002] Aromatic polyene antibiotics are a class of antibiotics, which mainly interact with sterols in eukaryotic cell membranes to form channels, causing the loss of small molecules and leading to cell death. [0003] The application of aromatic polyene macrolide antifungal antibiotics such as amphotericin is limited mainly because of its strong toxicity, especially nephrotoxicity. [0004] In the pharmacological studies of aromatic polyene macrolide antifungal antibiotics such as amphotericin, it was found that chemically synthesized amphotericin derivatives with a methyl side chain at the C-16 position were more effective than amphotericin (its C-16 position The toxicity of carboxyl side chain) is greatly reduced. [0005] Liang Rongfang and others discovered a new Streptomyces strain capable ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P19/62C12R1/465
Inventor 沈亚领魏东芝毛相朝邓子新陈实
Owner EAST CHINA UNIV OF SCI & TECH
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