CN100363484C - Hebei Amycolatopsis hebeiensis bacterial strain and preparation Norvancomycin fermented by the strain - Google Patents
Hebei Amycolatopsis hebeiensis bacterial strain and preparation Norvancomycin fermented by the strain Download PDFInfo
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- CN100363484C CN100363484C CNB2004100121464A CN200410012146A CN100363484C CN 100363484 C CN100363484 C CN 100363484C CN B2004100121464 A CNB2004100121464 A CN B2004100121464A CN 200410012146 A CN200410012146 A CN 200410012146A CN 100363484 C CN100363484 C CN 100363484C
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Abstract
The present invention discloses a new species of amycolatopsis-amycolatopsis hebeiensis and the typical strain thereof (CCTCC No. M203099). Demethylvancomycin can be conveniently prepared by using the strain through three steps of fermentation, extraction and purification.
Description
Technical field
The present invention relates to the novel species and the typical strain thereof of Amycolatopsis mediterranei and utilize this strain fermentation to prepare norvancomycin hydrochloride.
Background technology
Norvancomycin hydrochloride is a glycopeptide antibiotics, and structural formula is the hydrochloride of following molecular formula:
Disclose North China Pharmaceutical Factory's he incomparably in the scientific and technological achievement database [record number] 171764 and grasped female achievement, this achievement has selected based on the generation bacterium that produces norvancomycin hydrochloride (mutation of no mycolic acids bacterium is intended in east).
In recent years pharmacology and clinical study prove, the norvancomycin hydrochloride intravenous drip is applicable to endocarditis due to the Staphylococcus (comprising methicillin resistance bacterial strain and multiple antibiotic resistant strain), osteomyelitis, pneumonia, septicemia or soft tissue infection etc.Also be used for the faecalis endocarditis to penicillin anaphylaxis person, the drug of first choice of corynebacterium (diphtheroid genus) endocarditis treatment.The treatment that the artery and vein shunting is infected due to the Staphylococcus is taken place in penicillin anaphylaxis and penicillin hemodialysis person not hypersensitive.The oral treatment that is applicable to microbiotic dependency pseudomembranous colitis or multidrug-resistant staphylococcus enterocolitis.(seeing 688 pages of two clinical application notices of Pharmacopoeia of the People's Republic of China version in 2000)
Summary of the invention
Purpose of the present invention is exactly the novel species that a kind of Amycolatopsis mediterranei will be provided: no mycolic acids bacterium and typical strain thereof are intended in Hebei, utilize this strain fermentation to prepare norvancomycin hydrochloride simultaneously.
The object of the present invention is achieved like this:
Amycolatopsis mediterranei novel species that provides and typical strain thereof are that no mycolic acids bacterium (Amycolatopsis hebeiensis) NCPC 1023 bacterial strains, CCTCC NO:M203099 are intended in Hebei.
This bacterial strain is preserved in Chinese typical culture collection center on December 22nd, 2003, and preserving number is: CCTCC NO:M203099.
This bacterial strain separates by the following method and obtains: the soil sample of gathering from positive definite vegetable garden, Hebei province in 1996 is placed under the room temperature one week of natural air drying back grind into fine powder, 80 ℃ xeothermic 30 minutes, get xeothermic soil sample 1 gram, do 100 times of dilutions with sterilized water, get 0.2 milliliter and coat the starch/casein nutrient agar that is added with Rifampin, cultivated for 3 weeks for 28 ℃, picking list bacterium colony connects the inclined-plane and preserves.
Hebei is intended no mycolic acids bacterium NCPC 1023 and is had following Microbiological Characteristics:
Morphological specificity: the diameter that the dull and stereotyped single bacterium colony of no mycolic acids bacterium NCPC 1023 bacterial strains is intended in Hebei is about the 4-5 millimeter, and more than dry, the fold and edge is irregular, and there is circular depressed the centre.Aerial hyphae white, spore chain is shorter, and is straight or ripple is bent; Yellowish or the light brown of the living mycelia of base.No soluble pigment.
Cultural characteristic:
Hebei intend no mycolic acids bacterium NCPC 1023 on eight kinds of substratum in 28 ℃ of cultivations 14 days, well-grown, growth characteristics sees Table 1.
The cultural characteristic of no mycolic acids bacterium NCPC 1023 is intended in table 1. Hebei
| Substratum | Aerial hyphae | The living mycelia of base | Soluble pigment |
| Tryptone yeast extract paste agar | White | Light firefly Huang | Do not have |
| Yeast extract paste-malt extract agar | White | Pomegranate calyx Huang | Do not have |
| Rolled oats agar | White | White | Do not have |
| The inorganic salt Starch Agar | White | White | Do not have |
| Glycerine asparagine agar | White | Pomegranate calyx Huang | Do not have |
| Peptone yeast extract paste iron agar | White | Yellowish pink | Do not have |
| Tyrosine agar | White | Shallow mango palm fibre | Do not have |
| Nutrient agar medium | White | The orange peel Huang | Do not have |
Physiological and biochemical property: Hebei is intended no mycolic acids bacterium NCPC 1023 physiological and biochemical properties and is seen Table 2.
The physiological and biochemical property of no mycolic acids bacterium NCPC 1023 is intended in table 2 Hebei
| Physiological and biochemical index | The result | Physiological and biochemical index | The result |
| Soluble pigment | - | Substrate utilization | |
| Melanochrome produces | - | Rhamnosyl | + |
| Gelatine liquefication | + | Sucrose | - |
| Milk solidifies, peptonizes | v | Raffinose | + |
| Growth temperature | Glucose | + | |
| 10℃ | - | Pectinose | + |
| 27℃ | + | Wood sugar | + |
| 30℃ | + | N.F,USP MANNITOL | + |
| 37℃ | + | Fructose | + |
| 45℃ | - | Mierocrystalline cellulose | - |
| Tolerance | Xylan | + | |
| 0.1% phenol | + | Inositol | + |
| 0.2% phenol | - | Starch | + |
| 0.5% phenol | - | Pectin | + |
| 1% phenol | - | VITAMIN B4 | - |
| 4% sodium-chlor | + | Xanthine | + |
| 7% sodium-chlor | + | Casein | + |
| 10% sodium-chlor | v | The L-Histidine | + |
| 13% sodium-chlor | - | The L-oxyproline | v |
The 16S rDNA sequential analysis of no mycolic acids bacterium NCPC 1023 bacterial strains is intended in Hebei:
The 16S rDNA complete sequence length that no mycolic acids bacterium NCPC 1023 bacterial strains are intended in Hebei is 1508bp.Carrying out BLAST with the 16S rDNA sequence of other actinomycetes strain in this sequence and the Genbank database analyzes, find this bacterium and the nearly source of Amycolatopsis mediterranei bacterial strain, and the sequence difference rate is more than 1.3% between the typical strain of other effective publication kind of this bacterial strain and Amycolatopsis mediterranei, intend no mycolic acids bacterium east subspecies 16SrDNA sequence difference rate 2% with east, 27 base differences are promptly arranged.Is outer group with Saccharomonospora.viridis, carries out phylogenetic analysis with the 16S rDNA complete sequence in nearly source and obtain systematic evolution tree, see accompanying drawing 1.Show that from the systematic evolution tree of gained Hebei no mycolic acids bacterium NCPC 1023 bacterial strains of plan form a significantly independent branch.The 16S rDNA complete sequence of no mycolic acids bacterium NCPC 1023 bacterial strains is intended in Hebei, sees specification sheets.
From cultural characteristic and physiological and biochemical property aspect, between the typical strain of other effective publication of Hebei no mycolic acids bacterium NCPC 1023 bacterial strains of plan and Amycolatopsis mediterranei bigger difference is arranged in addition.Determine that according to the criteria for classification of modern microorganism this bacterial strain is a novel species of Amycolatopsis mediterranei, and no mycolic acids bacterium (Amycolatopsis hebeiensis) is intended in its called after Hebei, typical strain is NCPC 1023 (CCTCCNo:M203099).
The method of utilizing Hebei no mycolic acids bacterium NCPC 1023 strain fermentations of plan to prepare norvancomycin hydrochloride is: be included in to contain and cultivate the step that Hebei is intended the step of no mycolic acids bacterium and extract Norvancomycin from fermented liquid in carbon source, nitrogenous source, inorganic salt and other the nutraceutical substratum, finally obtain norvancomycin hydrochloride.
Employed carbon source can include but not limited to starch, glucose in the no mycolic acids bacterium NCPC 1023 strain fermentation substratum of Hebei plan of the present invention.Employed nitrogenous source can include but not limited to yeast powder, corn steep liquor in fermention medium of the present invention.Employed inorganic salt can include but not limited to dipotassium hydrogen phosphate, Repone K, Manganous chloride tetrahydrate etc. in fermention medium of the present invention.
Fermentation culture of the present invention can under aerobic conditions be carried out 6-7 days under 26-28 ℃ and pH6.0-7.0.
The Norvancomycin that the present invention produces mainly is present in the fermented liquid.The preparation method of normal employing includes fermentation, filtration, decolouring, resin absorption, parsing, decolouring, spraying drying operation, be about to gained Norvancomycin fermented liquid and add diatomite, stir, filtration obtains filtrate, filtrate is again through activated carbon decolorizing, destainer concentrates after the DK-80 resin absorption, sodium hydroxide solution is resolved, desorbed solution is through the resin desalination, activated carbon decolorizing, the destainer spraying drying obtains norvancomycin hydrochloride, and the HPLC analytical procedure sees second 553-554 page or leaf of 2000 editions Pharmacopoeias of the People's Republic of China for details.
The present invention provides a kind of new bacterial strain for the public, and this bacterial strain can be used to prepare norvancomycin hydrochloride.
Description of drawings:
Fig. 1 is the phyletic evolution tree graph that no mycolic acids bacterium NCPC 1023 bacterial strains are intended in Hebei.
Embodiment
Further describe the present invention below in conjunction with embodiment, but they are not to understand any restriction that becomes the scope of the invention.
Embodiment 1: the separation of no mycolic acids bacterium NCPC 1023 bacterial strains is intended in Hebei
Soil sample from the collection of positive definite vegetable garden, Hebei province in 1996 is placed natural air drying one all backs grind into fine powder under the room temperature, 80 ℃ xeothermic 30 minutes, get xeothermic soil sample 1 gram, do 100 times of dilutions with sterilized water, get 0.2 milliliter and coat the starch/casein nutrient agar that is added with Rifampin (the 0.5 μ g/ml of Sigma company), cultivated for 3 weeks for 28 ℃, picking list bacterium colony connects the inclined-plane and preserves.
Embodiment 2: Hebei is intended no mycolic acids bacterium NCPC 1023 strain fermentations and is cultivated the preparation norvancomycin hydrochloride
Substratum (content is w/v per-cent) is:
No. 1: slant medium: Zulkovsky starch 1%, K
2HPO
40.1%, MgSO
47H
2O 0.1%, NaCl0.1%, (NH
4)
2SO
40.2%, CaCO
30.2%, pH7.2.
No. 2: seed culture medium: glucose 1%, starch 2%, yeast powder 1%, K
2HPO
40.1%, MgSO
47H
2O0.1%, NaCl 0.1%, CaCO
30.2%, pH7.0.
No. 3: fermention medium: glucose 4%, defatted soyflour 2%, corn steep liquor 1%, K
2HPO
40.1%, MgSO
47H
2O 0.1%, and NaCl 0.1%, MnCl
20.005%, CaCO
30.2%, pH6.5.
With a platinum loop no mycolic acids bacterium NCPC 1023 is intended in Hebei and give slant medium (No. 1) inoculation.Cultivated 7 days down at 28 ℃.The gained slant culture is inoculated in the seed culture medium (No. 2) of the 140ml in the triangular flask of 750ml,, cultivated 2 days down for 28 ℃ 200 rev/mins of rotary shaking tables.Be inoculated in 2% inoculum size in the fermention medium (No. 3) of the 140ml in the triangular flask of 750ml,, cultivated 6 days down for 28 ℃, obtain fermented liquid 5000ml altogether, shake bottle 7000 μ of a unit/ml 200 rev/mins of rotary shaking tables.
The ratio adding diatomite of no mycolic acids bacterium fermentation culture 5000ml with 5% (w/v) is intended in Hebei, stir, filtration obtains filtrate, filtrate is again through 6% activated carbon decolorizing, destainer concentrates after the DK-80 resin absorption, and the 0.5N sodium hydroxide solution is resolved, 6% activated carbon decolorizing, the destainer spraying drying can obtain 14.2 gram norvancomycin hydrochlorides, analyzes through HPLC and compares the retention time unanimity with norvancomycin hydrochloride standard substance (available from the national drug biological products assay institute).
Sequence table
＜110〉North China Pharmaceutical Group Company Ltd
＜120〉a kind of Hebei is intended amycolatopsis hebeiensis bacterial strain and is utilized this strain fermentation to prepare norvancomycin hydrochloride
<130>3
<160>1
<170>PatentIn version 3.1
<210>1
<211>1508
<212>DNA
<213>Amycolatopsis hebeiensis
<400>1
tagagtttga tcctggctca ggacgaacgc tggcggcgtg cttaacacat gcaagtcgaa
cgatgaagcc ttcgggtgga ttagtggcga acgggtgagt aacacgtggg caatctgccc
tgtactttgg gataagcctg ggaaactggg tctaataccg gatatgactg ctgatcgcat
ggttggtggt ggaaagctcc ggcggtacag gatgagcccg cggcctatca gcttgttggt
ggggtaatgg cctaccaagg cgacgacggg tggccggcct gagagggtga ccggccacac
tgggactgag acacggccca gactcctacg ggaggcagca gtggggaata ttgcacaatg
ggcgcaagcc tgatgcagcg acgccgcgtg agggatgacg gcctcgggtt gtaaacctct
ttcgccaggg acgaagcgca agtgacggta cctggataag aagcaccggc taactacgtg
ccagcagccg cggtaatacg tagggtgcga gcgttgtccg gaattattgg gcgtaaagag
ctcgtaggcg gtttgtcgcg tcgttcgtga aaactccacg cttaacgtgg agcgtgcggg
cgatacgggc agacttgagt tcggtagggg agactggaat tcctggtgta gcggtgaaat
cctcctta
Claims (5)
1. amycolatopsis hebeiensis bacterial strain NCPC 1023 (Amycolatopsis hebeiensis) are intended in a Hebei, and its preserving number is CCTCC NO:M203099.
2. a bacterial strain that utilizes claim 1 prepares the method for norvancomycin hydrochloride: comprise fermentation, refinement, three steps of purifying.
3. the described method of claim 2, wherein the employed carbon source of substratum is starch or glucose in the fermentation step, and nitrogenous source is yeast powder or corn steep liquor, and inorganic salt are dipotassium hydrogen phosphate or Manganous chloride tetrahydrate.
4. the described method of claim 2, wherein culture condition is 26-28 ℃, pH6.0-7.0, carried out under aerobic 6-7 days in the fermentation step.
5. the described method of claim 2 is wherein refined, purification step is: filtration, decolouring, resin absorption, parsing, decolouring, spraying drying.
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| CN101245068A (en) | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | Crystallization type entecavir, method of producing the same, pharmaceutical composition and uses thereof |
| CN101284799B (en) | 2007-03-23 | 2013-04-03 | 浙江医药股份有限公司新昌制药厂 | Nitrogen-contained derivates of caffeoylquinic acid, method for preparing same, pharmaceutical compositions thereof and uses |
| CN101397333A (en) * | 2007-09-27 | 2009-04-01 | 浙江医药股份有限公司新昌制药厂 | De-hydroxyl vancomycin, preparation method thereof, medicament composition and use thereof |
| CN101828693B (en) | 2009-03-09 | 2013-01-02 | 浙江医药股份有限公司新昌制药厂 | Preparation method and application of low-viscosity high-fluidity carotenoid oil suspension |
| CN104404113B (en) * | 2014-11-26 | 2018-07-03 | 丽珠集团福州福兴医药有限公司 | A kind of feeding medium of vancomycin and the method for producing vancomycin |
| CN105886421B (en) * | 2015-07-16 | 2019-04-02 | 中山大学 | One plant is intended without mycolic acids bacterium and the method for preparing special penta Efrotomycin using the bacterium |
| CN105669789A (en) * | 2016-02-23 | 2016-06-15 | 华北制药集团新药研究开发有限责任公司 | Preparation method for norvancomycin |
| CN105506041A (en) * | 2016-02-23 | 2016-04-20 | 华北制药集团新药研究开发有限责任公司 | Method for producing norvancomycin by fermentation |
| CN108504594B (en) * | 2018-03-29 | 2021-03-19 | 云南大学 | Amycolatopsis and application thereof in preparation of pseudo-ginseng root rot resistant agent |
| CN115044501B (en) * | 2022-05-27 | 2023-08-25 | 湖南大学 | Endophytic rare actinomycetes for promoting plant growth and application thereof |
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| Title |
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| N-去甲万古霉素的开发研究. 贺秉坤.万方科技成果数据库. 1993 * |
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