CN1657601A - 一种河北拟无枝菌酸菌菌株以及利用该菌株发酵制备盐酸去甲万古霉素 - Google Patents
一种河北拟无枝菌酸菌菌株以及利用该菌株发酵制备盐酸去甲万古霉素 Download PDFInfo
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- CN1657601A CN1657601A CN 200410012146 CN200410012146A CN1657601A CN 1657601 A CN1657601 A CN 1657601A CN 200410012146 CN200410012146 CN 200410012146 CN 200410012146 A CN200410012146 A CN 200410012146A CN 1657601 A CN1657601 A CN 1657601A
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- hebei
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- amycolatopsis
- hebeiensis
- norvancomycin
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明公开了一种拟无枝菌酸菌属的新种：河北拟无枝菌酸菌(Amycolatopsis hebeiensis)及其典型菌株：CCTCC NO：M203099，利用此菌株经过发酵、提炼、纯化三个步骤可以方便地制备盐酸去甲万古霉素。
Description
技术领域
本发明涉及拟无枝菌酸菌属的新种及其典型菌株以及利用该菌株发酵制备盐酸去甲万古霉素。
背景技术
盐酸去甲万古霉素为糖肽类抗生素，结构式为如下分子式的盐酸盐：
万方科技成果数据库【记录编号】171764中公开了华北制药厂贺秉坤的成果，此成果选育出了以产生盐酸去甲万古霉素为主的产生菌(东方拟无枝菌酸菌变种)。
近年来的药理和临床研究证明，盐酸去甲万古霉素静脉滴注适用于葡萄球菌属(包括甲氧西林耐药菌株和多重耐药菌株)所致心内膜炎、骨髓炎、肺炎、败血症或软组织感染等。也用于对青霉素过敏者的肠球菌心内膜炎、棒状杆菌属(类白喉杆菌属)心内膜炎治疗的首选药。对青霉素过敏与青霉素不过敏的血液透析者发生葡萄球菌属所致动、静脉分流感染的治疗。口服适用于抗生素相关性伪膜性结肠炎或多重耐药葡萄球菌小肠结肠炎的治疗。(见《中华人民共和国药典》2000年版 二部 临床用药须知 688页)
发明内容
本发明的目的就是要提供一种拟无枝菌酸菌属的新种：河北拟无枝菌酸菌及其典型菌株，同时利用该菌株发酵制备得到盐酸去甲万古霉素。
本发明的目的是这样实现的：
提供的拟无枝菌酸菌属新种及其典型菌株为河北拟无枝菌酸菌(Amycolatopsis hebeiensis)NCPC 1023菌株，CCTCC NO：M203099。
该菌株已于2003年12月22日保藏于中国典型培养物保藏中心，保藏号为：CCTCC NO：M203099。
该菌株通过以下方法分离得到：将1996年从河北省正定菜园采集的土样置于室温下自然风干一周后研成粉末状，80℃干热30分钟，取干热土样1克，用无菌水作100倍稀释，取0.2毫升涂布于加有利福平的淀粉/酪素琼脂培养基，28℃培养3周，挑取单菌落，接斜面保存。
河北拟无枝菌酸菌NCPC 1023具有以下微生物学特性：
形态特征：河北拟无枝菌酸菌NCPC 1023菌株平板单菌落的直径约为4-5毫米，干燥、皱折多且边缘不整齐，中间有圆形凹陷。气生菌丝白色，孢子链较短，直或波曲；基生菌丝淡黄或浅棕色。无可溶性色素。
培养特征：
河北拟无枝菌酸菌NCPC 1023在八种培养基上于28℃培养14天，生长良好，生长特征见表1。
表1.河北拟无枝菌酸菌NCPC 1023的培养特征
| 培养基 | 气生菌丝 | 基生菌丝 | 可溶性色素 |
| 胰胨酵母膏琼脂 | 白色 | 淡萤黄 | 无 |
| 酵母膏-麦芽膏琼脂 | 白色 | 榴萼黄 | 无 |
| 燕麦片琼脂 | 白色 | 白色 | 无 |
| 无机盐淀粉琼脂 | 白色 | 白色 | 无 |
| 甘油天门冬酰胺琼脂 | 白色 | 榴萼黄 | 无 |
| 蛋白胨酵母膏铁琼脂 | 白色 | 肉色 | 无 |
| 酪氨酸琼脂 | 白色 | 浅芒果棕 | 无 |
| 营养琼脂 | 白色 | 橙皮黄 | 无 |
生理生化特征：河北拟无枝菌酸菌NCPC 1023生理生化特征见表2。
表2 河北拟无枝菌酸菌NCPC 1023的生理生化特征
| 生理生化指标 | 结果 | 生理生化指标 | 结果 |
| 可溶性色素 | - | 底物利用 | |
| 黑色素产生 | - | 鼠李糖 | + |
| 明胶液化 | + | 蔗糖 | - |
| 牛奶凝固、胨化 | v | 棉子糖 | + |
| 生长温度 | 葡萄糖 | + | |
| 10℃ | - | 阿拉伯糖 | + |
| 27℃ | + | 木糖 | + |
| 30℃ | + | 甘露醇 | + |
| 37℃ | + | 果糖 | + |
| 45℃ | - | 纤维素 | - |
| 耐受性 | 木聚糖 | + | |
| 0.1％苯酚 | + | 肌醇 | + |
| 0.2％苯酚 | - | 淀粉 | + |
| 0.5％苯酚 | - | 果胶 | + |
| 1％苯酚 | - | 腺嘌呤 | - |
| 4％氯化钠 | + | 黄嘌呤 | + |
| 7％氯化钠 | + | 酪素 | + |
| 10％氯化钠 | v | L-组氨酸 | + |
| 13％氯化钠 | - | L-羟脯氨酸 | v |
河北拟无枝菌酸菌NCPC 1023菌株的16S rDNA序列分析：
河北拟无枝菌酸菌NCPC 1023菌株的16S rDNA全序列长度为1508bp。以该序列与Genbank数据库中其它放线菌菌株的16S rDNA序列进行BLAST分析，发现该菌与拟无枝菌酸菌属菌株近源，并且该菌株与拟无枝菌酸菌属其它有效发表种的典型菌株间序列差异率在1.3％以上，与东方拟无枝菌酸菌东方亚种16SrDNA序列差异率在2％，即有27个碱基不同。以Saccharomonospora.viridis为外群，以近源的16S rDNA全序列进行系统进化分析得到系统进化树，见附图1。从所得的系统进化树表明河北拟无枝菌酸菌NCPC 1023菌株形成一个明显的单独分枝。河北拟无枝菌酸菌NCPC 1023菌株的16S rDNA全序列，见说明书。
另外从培养特征和生理生化特征方面来看，河北拟无枝菌酸菌NCPC 1023菌株与拟无枝菌酸菌属的其它有效发表的典型菌株间有较大的差异。根据现代微生物的分类标准确定该菌株为拟无枝菌酸菌属的一个新种，并将其命名为河北拟无枝菌酸菌(Amycolatopsis hebeiensis)，典型菌株为NCPC 1023(CCTCCNo：M203099)。
利用河北拟无枝菌酸菌NCPC 1023菌株发酵制备盐酸去甲万古霉素的方法是：包括在含有碳源、氮源、无机盐和其它营养物的培养基中培养河北拟无枝菌酸菌的步骤和从发酵液中提取去甲万古霉素的步骤，最终得到盐酸去甲万古霉素。
在本发明的河北拟无枝菌酸菌NCPC 1023菌株发酵培养基中所使用的碳源可包括但不限于淀粉、葡萄糖。在本发明发酵培养基中所使用的氮源可包括但不限于酵母粉、玉米浆。在本发明发酵培养基中所使用的无机盐可包括但不限于磷酸氢二钾、氯化钾、氯化锰等。
本发明的发酵培养可在26-28℃和pH6.0-7.0下，在需氧条件下进行6-7天。
本发明产生的去甲万古霉素主要存在于发酵液中。最常采用的制备方法包括有发酵、过滤、脱色、树脂吸附、解析、脱色、喷雾干燥工序，即将所得去甲万古霉素发酵液加入硅藻土，搅拌，过滤得到滤液，滤液再经活性炭脱色，脱色液浓缩后经DK-80树脂吸附，氢氧化钠溶液解析，解析液经树脂脱盐，活性炭脱色，脱色液喷雾干燥得到盐酸去甲万古霉素，HPLC分析方法详见2000版《中华人民共和国药典》第二部553-554页。
本发明为公众提供了一种新菌株，该菌株可以用于制各盐酸去甲万古霉素。
附图说明：
图1是河北拟无枝菌酸菌NCPC 1023菌株的系统进化树图。
具体实施方式
下面结合实施例进一步详细说明本发明，但它们并非理解成为对本发明范围的任何限制。
实施例1：河北拟无枝菌酸菌NCPC 1023菌株的分离
将1996年从河北省正定菜园采集的土样置于室温下自然风干一周后研成粉末状，80℃干热30分钟，取干热土样1克，用无菌水作100倍稀释，取0.2毫升涂布于加有利福平(Sigma公司0.5μg/ml)的淀粉/酪素琼脂培养基，28℃培养3周，挑取单菌落，接斜面保存。
实施例2：河北拟无枝菌酸菌NCPC 1023菌株发酵培养制备盐酸去甲万古霉素
培养基(含量均为w/v百分比)为：
1号：斜面培养基：可溶性淀粉1％，K2HPO4 0.1％，MgSO4·7H2O 0.1％，NaCl0.1％，(NH4)2SO4 0.2％，CaCO3 0.2％，pH7.2。
2号：种子培养基：葡萄糖1％，淀粉2％，酵母粉1％，K2HPO4 0.1％，MgSO4·7H2O0.1％，NaCl 0.1％，CaCO3 0.2％，pH7.0。
3号：发酵培养基：葡萄糖4％，脱脂大豆粉2％，玉米浆1％，K2HPO4 0.1％，MgSO4·7H2O 0.1％，NaCl 0.1％，MnCl2 0.005％，CaCO3 0.2％，pH6.5。
用一铂环将河北拟无枝菌酸菌NCPC 1023给斜面培养基(1号)接种。在28℃下培养7天。将所得斜面培养物接种于750ml的三角瓶内的140ml的种子培养基(2号)中，在旋转式摇床200转/分，28℃下培养2天。以2％接种量接种于750ml的三角瓶内的140ml的发酵培养基(3号)中，在旋转式摇床200转/分，28℃下培养6天，共得到发酵液5000ml，摇瓶单位7000μ/ml。
将河北拟无枝菌酸菌发酵培养液5000ml以5％(w/v)的比例加入硅藻土，搅拌，过滤得到滤液，滤液再经6％活性炭脱色，脱色液浓缩后经DK-80树脂吸附，0.5N氢氧化钠溶液解析，6％活性炭脱色，脱色液喷雾干燥可得到14.2克盐酸去甲万古霉素，经HPLC分析和盐酸去甲万古霉素标准品(购自国家药品生物制品检定所)相比保留时间一致。
序列表
<110>华北制药集团有限责任公司
<120>一种河北拟无枝菌酸菌菌株以及利用该菌株发酵制备盐酸去甲万古霉
素
<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)
1.一种河北拟无枝菌酸菌菌株Amycolatopsis hebeiensis：CCTCC NO：M203099。
2.一种利用权利要求1的菌株制备盐酸去甲万古霉素的方法：包括发酵、提炼、纯化三个步骤。
3.权利要求2所述的方法，其中发酵步骤中培养基所使用碳源优选淀粉或葡萄糖，氮源优选酵母粉或玉米浆，无机盐优选磷酸氢二钾或氯化锰。
4.权利要求2所述的方法，其中发酵步骤中培养条件为26-28℃、pH6.0-7.0、在有氧下进行6-7天。
5.权利要求2所述的方法，其中提炼、纯化步骤为：过滤、脱色、树脂吸附、解析、脱色、喷雾干燥。
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