CN101928330A - New compound and application thereof - Google Patents
New compound and application thereof Download PDFInfo
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- CN101928330A CN101928330A CN2009100539054A CN200910053905A CN101928330A CN 101928330 A CN101928330 A CN 101928330A CN 2009100539054 A CN2009100539054 A CN 2009100539054A CN 200910053905 A CN200910053905 A CN 200910053905A CN 101928330 A CN101928330 A CN 101928330A
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Abstract
The invention provides a new compound and an application thereof. The compound comprises the structure as shown in formula (I), four-bit hydroxyl of glycosyl on hydroxy benzyl of six-bit amino acid of a peptide framework of the compound is an axial bond, and the compound is obtained through fermentation of CGMCC No. 3053. The compound has good antibacterial activity, thereby having very important significance for developing new antibacterial drugs.
Description
Technical field
The invention belongs to biological technical field, specifically, relate to a kind of new compound and application thereof.
Background technology
Vancomycin is obtained by isolating east amycolatosis (Amycolatopsis orientalis) fermentation in Indonesia's soil in 1956, be clinical treatment methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MRSA) choice drug of Gan Raning.But continuous use along with vancomycin, streptococcus aureus descends to some extent to the susceptibility of vancomycin, this will produce serious threat to clinical anti-infective therapy, therefore, it is extremely urgent that searching can improve the s-generation glycopeptide antibiotics of vigor to Resistant strain, simultaneously, but the recombinant bacterial strain that the preparation fermentative production is improved the s-generation glycopeptide antibiotics of vigor to Resistant strain also becomes an important research project, also has same urgency.
Summary of the invention
The allos replacement operator of present inventor by glycosyltransferase gene among the Vancomycine producing fungus A.orientalis HCCB10007 is carried out, obtained the new east amycolatosis bacterial strain of a strain, and in the fermented liquid of this strain east amycolatosis, found a kind of new compound.
Therefore, primary and foremost purpose of the present invention is, a kind of new compound is provided.
Second purpose of the present invention is, the preparation method of the compound shown in the said structure formula (I) is provided.
The 3rd purpose of the present invention provides this application of compound.
New compound provided by the present invention has with the structure shown in the following formula (I):
Wherein: four hydroxyls of glycosyl on the benzyl hydroxyl of peptide backbone six amino acids (OH is as 1 sign in the structural formula) are axial bond.
According to one embodiment of present invention, the compound shown in the described formula (I) obtains by fermentation strain CGMCCNo.3053.
According to a preferred embodiment of the present invention, the preparation method of described compound also comprises the step of fermented liquid being carried out separation and purification; Particularly, described purification procedures is as follows:
With macropore low-pole resin filtrate is carried out dynamic adsorption, carry out gradient elution with the ethanol-water solution that contains 0.005% hydrochloric acid, and collection ethanol: water is 6: 4 elutriant, then with activated carbon decolorizing, carry out the medium pressure liquid chromatography chromatography after concentrating, again to contain 0.3%NaH
2PO
4The methanol-water solution gradient wash-out of buffering salt, collect main elutriant and concentrate, the wash-out concentrated solution that at last medium pressure liquid chromatography is prepared is with macropore low-pole resin absorption, with the methanol-water solution gradient wash-out that contains 0.001% hydrochloric acid, collect methyl alcohol: water is 6: 4 elutriant, desalination.
According to the present invention, fermented liquid carried out also comprising before the separation and purification fermented liquid carried out pretreated step that particularly, described pre-treatment step is as follows:
Fermented liquid is transferred pH3～4 with HCl, removes by filter mycelium.
Compound shown in the formula provided by the invention (I) has good antibacterial activity, thereby can be used for preparing antibacterials.
Compound provided by the invention all has good antibacterial activity for the various clinical pathogenic bacterium, and therefore the exploitation for new antibacterials has very important significance.
Description of drawings
Fig. 1 is the MS collection of illustrative plates of LYV07ww03.
Fig. 2 is LYV07ww03
1H NMR (Nuclear Magnetic Resonance) spectrum figure.
Fig. 3 is LYV07ww03
13C NMR (Nuclear Magnetic Resonance) spectrum figure.
Fig. 4 is the Cosy NMR (Nuclear Magnetic Resonance) spectrum figure of LYV07ww03.
Fig. 5 is the Noesy NMR (Nuclear Magnetic Resonance) spectrum figure of LYV07ww03.
Fig. 6 is the Tocsy NMR (Nuclear Magnetic Resonance) spectrum figure of LYV07ww03.
Fig. 7 is the Hsqc NMR (Nuclear Magnetic Resonance) spectrum figure of LYV07ww03.
Fig. 8 is the Hmbc NMR (Nuclear Magnetic Resonance) spectrum figure of LYV07ww03.
Fig. 9 is the chemical structural formula of LYV07ww03.
The engineering bacteria that the present invention obtained has been submitted on May 6th, 2009 and has been positioned at Pekinese China Committee for Culture Collection of Microorganisms common micro-organisms center (CGMCC) preservation, and preserving number is CGMCC No.3053.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
The allos replacement operator of contriver by glycosyltransferase gene among the Vancomycine producing fungus A.orientalis HCCB10007 is carried out, promptly from Amycolatopsis balhimyceticus NRRL B-24207, angle and get its glycosyltransferase gene and replaced the glycosyltransferase gene of vancomycin, thereby obtained the new bacterial strain of a strain by the method for conjugal transfer.
This bacterial strain has been submitted on May 6th, 2009 and has been positioned at Pekinese China Committee for Culture Collection of Microorganisms common micro-organisms center (CGMCC) preservation, and preserving number is CGMCC No.3053.
CGMCC NO.3053 is inserted in the seed culture medium, and in 28 ℃, 220rpm cultivates 40-48h.Then, under aseptic condition, cultured seed liquid is changed in the fermentation shake flask with 8% inoculum size, in 28 ℃, 220rpm cultivates 115-120h, the results fermented liquid.
3.1, fermentation liquor pretreatment
Fermented liquid is transferred pH3～4 with HCl, removes by filter mycelium, collects filtrate.
3.2, separation and purification
The separation purification method that provides among the referenced patent US5843437, the separation and purification fermented liquid, concrete separation and purification condition is as follows:
HP-20 carries out dynamic adsorption to filtrate with macropore low-pole resin, carry out gradient elution with the ethanol-water solution that contains 0.005% hydrochloric acid, collect ethanol-water solution (6: 4) elutriant, then with activated carbon decolorizing, carry out the medium pressure liquid chromatography chromatography after concentrating, again to contain 0.3%NaH
2PO
4The methanol-water solution gradient wash-out of buffering salt is collected main elutriant and is concentrated, and the wash-out concentrated solution that at last medium pressure liquid chromatography is prepared adsorbs with HP-20, with the methanol-water solution gradient wash-out that contains 0.001% hydrochloric acid, collect methyl alcohol: water is 6: 4 elutriant, desalination, drying.
With the product called after LYV07ww03 that obtains.
LYV07ww03 is carried out mass spectrometric detection, the result as shown in Figure 1, according to MS collection of illustrative plates shown in Figure 1, the molecular weight of LYV07ww03 is 1285.
By LYV07ww03 one-dimensional nuclear magnetic resonance wave spectrum (Fig. 2～3) and two dimensional NMR wave spectrum (Fig. 4～8) are resolved, determine the chemistry ownership of each carbon atom and hydrogen atom signal, confirm that its structure is similar, only slightly variant on six glycosyl configurations to Chloroorienticin C (two products that glycosyl hydrolase is sloughed on the phenolic hydroxyl group of Chloroeremomycin four amino acids).Wherein, the chemical shift of four hydrogen atoms is 3.43ppm on six glycosyls, shows as unimodal, coupling constant is less than 4Hz, and because of adjacent five hydrogen atoms are axial bond, then four hydrogen atoms can only be equatorial bonds, four hydroxyls are axial bonds, and promptly six of LYV07ww03 glycosyls are osamine base through the ages.
According to analysis result, obtain the chemical structural formula of LYV07ww03, specifically as shown in Figure 9, wherein, four hydroxyls (OH is shown in the structural formula 1) of glycosyl are axial bond on the benzyl hydroxyl of peptide backbone six amino acids of LYV07ww03.
By retrieval, do not see the report that this compound is arranged in the prior art, promptly LYV07ww03 is a kind of new compound.
With reference to the method that provides in the Pharmacopoeia of the People's Republic of China (version in 2005), detect the anti-microbial activity of LYV07ww03, wherein, the bacterial strain of use and LYV07ww03 are as shown in table 1 to the antibiotic dosage of described bacterial strain.
Table 1, detect anti-microbial activity with bacterial strain and LYV07ww03
| # | Test bacterial strain character | LYV07ww03 (MIC value) |
| 1 | Vancomycin-resistant enterococcus | 128μg/ml |
| 2 | Vancomycin-resistant enterococcus | 64μg/ |
| 3 | Faecalis | 0.5μg/ |
| 4 | MRSA | 0.5μg/ |
| 5 | MRSA | 0.25μg/ml |
| 6 | MRSA | 0.5μg/ |
| 7 | MRSA | 1μg/ml |
| 8 | MRSA | 0.5μg/ |
| 9 | MRSA | 0.5μg/ml |
| 10 | MRSA | 0.5μg/ |
| 11 | MRSA | 0.5μg/ |
| 12 | MRSA | 0.5μg/ml |
| 13 | MRSA | 0.5μg/ml |
| 14 | MRSA | 0.5μg/ml |
According to the result of table 1, the compound (LYV07ww03) shown in the formula provided by the invention (I) all has good antibacterial activity for the various clinical pathogenic bacterium.
In sum, the compound shown in the formula provided by the invention (I) all has good antibacterial activity for the various clinical pathogenic bacterium, therefore can be used for preparing antibacterials, has the wide development application prospect.
Claims (9)
1. a compound is characterized in that, described compound has the structure shown in the formula (I):
Wherein: four hydroxyls of glycosyl are axial bond on the benzyl hydroxyl of peptide backbone six amino acids of described compound.
2. the preparation method of compound as claimed in claim 1 is characterized in that, described compound obtains by CGMCC No.3053 fermentation.
3. preparation method as claimed in claim 2 is characterized in that described method also comprises the step of fermented liquid being carried out separation and purification.
4. preparation method as claimed in claim 3 is characterized in that, described purification procedures is as follows:
With macropore low-pole resin filtrate is carried out dynamic adsorption, carry out gradient elution with the ethanol-water solution that contains 0.005% hydrochloric acid, and collection ethanol: water is 6: 4 elutriant, then with activated carbon decolorizing, carry out the medium pressure liquid chromatography chromatography after concentrating, again to contain 0.3%NaH
2PO
4The methanol-water solution gradient wash-out of buffering salt, collect main elutriant and concentrate, the wash-out concentrated solution that at last medium pressure liquid chromatography is prepared is with macropore low-pole resin absorption, with the methanol-water solution gradient wash-out that contains 0.001% hydrochloric acid, collect methyl alcohol: water is 6: 4 elutriant, desalination.
5. preparation method as claimed in claim 4 is characterized in that, described macropore low-pole resin is HP-20.
6. preparation method as claimed in claim 4 is characterized in that, also comprises drying step after the described desalination step.
7. preparation method as claimed in claim 2 is characterized in that, also comprises before fermented liquid is carried out separation and purification fermented liquid is carried out pretreated step.
8. preparation method as claimed in claim 7 is characterized in that, described pre-treatment step is as follows:
Fermented liquid is transferred pH3～4 with HCl, removes by filter mycelium.
9. compound as claimed in claim 1 is used to prepare the application of antibacterials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910053905 CN101928330B (en) | 2009-06-26 | 2009-06-26 | New compound and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200910053905 CN101928330B (en) | 2009-06-26 | 2009-06-26 | New compound and application thereof |
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| Publication Number | Publication Date |
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| CN101928330A true CN101928330A (en) | 2010-12-29 |
| CN101928330B CN101928330B (en) | 2013-10-16 |
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| CN 200910053905 Active CN101928330B (en) | 2009-06-26 | 2009-06-26 | New compound and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690331A (en) * | 2011-03-23 | 2012-09-26 | 浙江医药股份有限公司新昌制药厂 | Monosaccharide glycopeptide derivative, pharmaceutical composition, preparation method and purpose thereof and preparation method of intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315961A (en) * | 1998-12-23 | 2001-10-03 | 先进医药公司 | Glycopeptide derivatives and pharmaceutical compositions containing same |
| CN101222933A (en) * | 2005-02-28 | 2008-07-16 | 诺瓦蒂斯疫苗和诊断公司 | Semi-synthetic glycopeptides with antibiotic activity |
-
2009
- 2009-06-26 CN CN 200910053905 patent/CN101928330B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315961A (en) * | 1998-12-23 | 2001-10-03 | 先进医药公司 | Glycopeptide derivatives and pharmaceutical compositions containing same |
| CN101222933A (en) * | 2005-02-28 | 2008-07-16 | 诺瓦蒂斯疫苗和诊断公司 | Semi-synthetic glycopeptides with antibiotic activity |
Non-Patent Citations (1)
| Title |
|---|
| NAOKI TSUJI等: "New glycopeptides antibiotics: II. The isolation and structures of chloroorienticins", 《THE JOURNAL OF ANTIBIOTICS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690331A (en) * | 2011-03-23 | 2012-09-26 | 浙江医药股份有限公司新昌制药厂 | Monosaccharide glycopeptide derivative, pharmaceutical composition, preparation method and purpose thereof and preparation method of intermediate |
| CN102690331B (en) * | 2011-03-23 | 2015-05-20 | 浙江医药股份有限公司新昌制药厂 | Monosaccharide glycopeptide derivative, pharmaceutical composition, preparation method and purpose thereof and preparation method of intermediate |
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| Publication number | Publication date |
|---|---|
| CN101928330B (en) | 2013-10-16 |
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