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Didemethylated actinomycin derivative and application thereof in preparation of drugs for resisting drug-resistant bacteria infection

A technology of actinomycin and double demethylation, applied in the field of natural products, can solve problems such as high toxicity and restricted use

Inactive Publication Date: 2020-01-10
SOUTH CHINA SEA INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although actinomycin has shown good advantages in antibacterial, antiviral and antitumor aspects, its toxicity is relatively large, thus limiting its further clinical use

Method used

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  • Didemethylated actinomycin derivative and application thereof in preparation of drugs for resisting drug-resistant bacteria infection
  • Didemethylated actinomycin derivative and application thereof in preparation of drugs for resisting drug-resistant bacteria infection
  • Didemethylated actinomycin derivative and application thereof in preparation of drugs for resisting drug-resistant bacteria infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Knockout of methyltransferase genes in the actinomycin D biosynthetic gene cluster of marine-derived Streptomyces S. costaricanus SCSIO ZS0073

[0024] The Streptomyces S. costaricanus SCSIO ZS0073 involved in the present invention is isolated from the soil of the South China Sea mangrove forest. The methyltransferase in the gene cluster was knocked out by insertional inactivation to construct the mutant strain ZS0073 / ΔacnM. ZS0073 / ΔacnM strains grown on ISP2 medium were inoculated into 250mL Erlenmeyer flasks containing 50mL ISP2 medium, and fermented and cultured at 28°C and 200rpm for seven days. The fermented medium was extracted with butanone and analyzed by HPLC. It was found that ZS0073 / ΔacnM could produce Didemactinomycins ( figure 1 ).

[0025] Among them, the composition of ISP2 medium is as follows: 4.0g / L glucose, 4.0g / L yeast extract powder, 10g / L malt extract powder, 30g / L sea salt, 20g / L agar powder, the solvent is water, and the pH value is ...

Embodiment 2D

[0026] Isolation and structural identification of embodiment 2Didemactinomycins

[0027] 1. Preparation of fermentation culture of marine Streptomyces S. costaricanus SCSIO ZS0073 methyltransferase inactivated mutant strain ZS0073 / ΔacnM

[0028] (1) Preparation of seed medium and fermentation medium:

[0029] Both the seed medium and the fermentation medium are liquid ISP2 medium containing sea salt, the composition of which is as follows: 4.0g / L glucose, 4.0g / L yeast extract powder, 10g / L malt extract powder, 30g / L sea salt, 20g / L Agar powder, the solvent is water, adjust the pH value to 7.3, the preparation method is to mix the ingredients evenly, adjust the pH value, and sterilize; divide the seed culture medium into 250mL conical flasks, 50mL per bottle, 115°C Sterilize for 30min and set aside. The amplified fermentation medium was divided into 1L Erlenmeyer flasks, 200mL per bottle, and sterilized at 115°C for 30min for later use.

[0030] (2) Cultivation of seeds:

[0...

Embodiment 3

[0049] Example 3 Compounds Didemactinomycin D and Didemactinomycin X 2 Test and analysis of antibacterial activity against a series of Staphylococcus aureus

[0050] Testing Compounds Didemactinomycin D and Didemactinomycin X by Microwell Method 2 Inhibitory activity against a series of Staphylococcus aureus. A series of Staphylococcus aureus was cultured in Mueller-Hinton (MH) broth medium. And prepare the sample solution before the experimental bacteria grow well. Concentrations of samples and positive controls were configured, and ampicillin, kanamycin or vancomycin were selected as positive controls. Both the sample and the sample were configured to 3200μg / mL, and both were dissolved in DMSO. Add 92 μL of sterile MH broth to the first column of the 96-well plate with a row gun, add 50 μL of MH broth to the remaining columns, and add 50 μL of sterile MH broth to the 11th and 12th columns, respectively as positive control and For the negative control, mark it and cover ...

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Abstract

The invention discloses a didemethylated actinomycin derivative and an application thereof in preparation of drugs for resisting drug-resistant bacteria infection. The structural formula of the actinomycin double-demethylation derivative Didemactinomycin D is as shown in a formula (I), and the structural formula of the Didemactinomycin X2 is as shown in a formula (II). The actinomycin demethylation derivatives Didemactinomycin D and Didemactinomycin X2 having drug-resistant staphylococcus aureus resistance are separated from a transmethylase inactivated mutant strain ZS0073 / delta acnM of a marine-derived actinomycin D production strain S.costaricaus SCSIO ZS0073. The test results show that the Didemactinomycin D has good inhibitory activity (MIC is 4-32 [mu] g / mL) on 14 strains of staphylococcus aureus, compared with actinomycin D, the toxicity to normal human cells is greatly weakened, and the Didemactinomycin D has important value in development of anti-infective drugs.

Description

technical field [0001] The invention belongs to the technical field of natural products, and in particular relates to demethylated actinomycin derivatives-Didemactinomycins and its preparation method and application. Background technique [0002] Actinomycin D is a pigment peptide lactone antibiotic, which was first isolated in actinomycetes by Waskman and Wooddruff in 1940. Its structure consists of a chromophore (actinocin, 2-amino-4,6-dimethylphenoxazine-3-one-1,9-dicarbo xylic acid) and two cyclic pentapeptide lactones (α ring and β ring ) composition, if the amino acid types of the α ring and β ring are the same, it is called iso-actinomycins, and if the amino acid composition of the α ring and β ring is different, it is called aniso-actinomycins. Due to the presence of chromophores, actinomycin compounds generally appear in a prominent orange or red color. Actinomycin has significant antibacterial, antitumor and antiviral biological activities. Its main mechanism of...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/14C07K1/16C12P21/02A61K38/08A61P31/04A61P35/00C12R1/01
CPCA61K38/00A61P31/04A61P35/00C07K7/06C12P21/02
Inventor 鞠建华刘梦婵孙长利马俊英李青连
Owner SOUTH CHINA SEA INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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