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Decarboxylated FR-008 derivative polyketone antibiotic and use thereof

A technology of FR-008 and antibiotics, applied in the field of biomedicine, can solve problems such as high cost, unbearable for patients, and high price

Inactive Publication Date: 2010-05-19
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the compound FR-008 complex and polyketide antibiotics such as Candicidin and amphotericin reported in the patent "Heptacene macrolide polyketide antibiotic FR-008 complex" (application number: CN200310108746.6) can pass through the liposome form of application to reduce the side effects of such antibiotics, however, its high price makes it unaffordable for patients
After the modification of the dosage form, the price (imported product) has become the biggest obstacle to drug promotion, that is, the biggest disadvantage of liposomal antibiotics is high cost, high price, and cumbersome production process
These small molecule secondary metabolites obtained from microbial secondary metabolites are often difficult to synthesize by chemical methods, even if they can be synthesized in the laboratory, it is often difficult to achieve industrialization

Method used

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  • Decarboxylated FR-008 derivative polyketone antibiotic and use thereof
  • Decarboxylated FR-008 derivative polyketone antibiotic and use thereof
  • Decarboxylated FR-008 derivative polyketone antibiotic and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Construction of gene replacement plasmid for cytochrome P450 monooxygenase gene fscP

[0045] Based on the sequence information obtained from the FR-008 gene cluster, a gene replacement plasmid for the cytochrome P450 monooxygenase gene fscP was constructed. pJTU28 is a derivative clone of pIJ2925 carrying the 2.3 kb Pst I-Kpn I fragment containing the fscP gene. pJTU28 was obtained by self-ligating pJTU26 after digestion with PstI. pJTU26 is a clone in which the 6.6 kb Kpn I fragment from pHZ145 was inserted at the pIJ2925 Kpn I cloning site. There are two BssH II restriction sites 165 and 561 bases downstream of the start codon of fscP in the cytochrome P450 monooxygenase gene. After pJTU28BssH II digestion, the 396bp sequence inside the fscP gene was deleted, and the 1.4kb fragment containing the apramycin resistance gene excised from pJTU33 was inserted to obtain pJTU37. pJTU33 is a derivative plasmid from the BamH I fragment containing the apramycin r...

Embodiment 2

[0046] Example 2: Screening of deletion mutants of fscP gene

[0047] The gene replacement plasmid pJTU50 was introduced into Streptomyces FR-008 by conjugative transfer of two parents, and after two rounds of relaxation culture without antibiotics, a mutant strain CS103 resistant to apramycin and sensitive to thiostrepton was obtained by counter selection .

Embodiment 3

[0048] Example 3: Fermentation of the deletion mutant strain CS103 of the fscP gene

[0049] Medium (m / v): glucose 2%, starch 1%, glycerol 1.389%, yeast powder 0.3%, industrial amino acid powder 0.5%, peptone 0.101%, NaCl 1%, FeSO 4 ·7H 2 O 0.05%, CuSO 4 0.00428%. Before sterilization, the pH was adjusted to 6.90 with 5 mol / l NaOH solution, the inoculation time was 30 hours, the inoculum size (v / v) was 10%, and the culture was carried out at 28 degrees and 200 rpm for 4 days on a shaking table.

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Abstract

The invention relates to decarboxylation FR-008 derivation polyketone antibiotic. It uses gene engineering to delete gene fscP to gain mutant CS103 which has the product of decarboxylation FR-008 hepa-olefin macrolide polyketone antibiotic. Compared with the FR-008 / Candicidin compound, it has lower toxicity, higher anti fungi activity, potential clinical application value, can be used in medical industry by further development.

Description

technical field [0001] The invention relates to a heptacene macrolide polyketide antibiotic obtained through genetic engineering, in particular to a decarboxylated FR-008 derived polyketide antibiotic, which belongs to the technical field of biomedicine. Background technique [0002] Combinatorial biosynthesis involves reciprocal exchange of secondary metabolic genes or heterozygous exchange within a single gene in antibiotic-producing bacteria. Through the role of newly added enzymes in the metabolic pathway or the new enzyme activity of the hybrid protein, new metabolites can be obtained in both pathways. [0003] In particular, combinatorial biochemistry has been successful in the case of polyketide synthase genes, through which hybrid type I polyketide synthase genes have produced pharmaceutically important macrolide antibiotics. A series of erythromycin-derived polyketide antibiotics have been obtained through combinatorial biosynthesis techniques, and these erythromyc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08A61K31/7048A61P31/10A61P31/04A01N43/04A01N43/90A01P7/04
Inventor 沈亚领魏东芝毛相朝杨亮周文瑜邓子新陈实周秀芬
Owner EAST CHINA UNIV OF SCI & TECH
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