CN102257154A - 用座坚壳属物种以及炭角菌科其他属的真菌菌株制备具有24个环原子的含乳酸或含苯基乳酸的光学活性环缩酚酸肽的方法 - Google Patents
用座坚壳属物种以及炭角菌科其他属的真菌菌株制备具有24个环原子的含乳酸或含苯基乳酸的光学活性环缩酚酸肽的方法 Download PDFInfo
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Abstract
本发明涉及用不仅座坚壳属和Coniolariella属(炭角菌科)的从在落叶树木和针叶树木死木和活木上的子实体生长的代表而且座坚壳属以及其他炭角菌的直接分离自落叶树木和针叶树木木质和根的真菌菌株，或者用分离自这些真菌菌株的酶制剂，制备具有24个环原子的光学活性含乳酸和含苯基乳酸的环缩酚酸肽的方法。具有通式(I)的PF1022A极好地适合于对抗内寄生虫，尤其是在人医学和兽医学领域内。
Description
本发明涉及制备用座坚壳属(Rosellinia)和炭角菌科(Xylariaceae)其他属的真菌菌株或用分离自这些真菌菌株的酶制剂制备具有24个环原子的光学活性的含乳酸或含苯基乳酸环缩酚酸肽(例如PF1022A)的方法。具有通式(I)的PF1022A极好地适合于对抗体内寄生虫，尤其是在人医学和兽医学领域内。
本发明涉及制备已知的具有24个环原子的含乳酸或含苯基乳酸环缩酚酸肽的新方法。这样的具有24个环原子的环缩酚酸肽(八缩酚酸肽)和其作为杀内寄生虫药的用途已经是一项先前专利申请(US005571793A)的目标。它给出了一系列制备具有24个环原子的环状含D-2-羟基-异戊酸的缩酚酸肽的化学和微生物方法(例如，通过合成，参见：Ohyama M.等人.，Biosci.Biotechnol.Biochem.58(1994)，第1193-1194页；Scherkenbeck J.等人.Tetrahedron 51(1995)，第8459-8470页；Kobayashi M.等人.Annu.Rep.Sankyo Res.Lab.46(1994)，第67-75页；Lee B.等人.Bioorg.Med.Chem.Lett.12(2002)，第353-356页；Dutton FE等人.J.Antibiot.47(1994)，第1322-1327页)。
用真菌菌株(其已知为“PF1022A菌株”)发酵含D-乳酸和含D-苯基乳酸的环八缩酚酸肽PF1022A，在一项日本专利中进行了描述(Sasaki T.等人.J.Antibiot.45(1992)，第692-697页；Yanai K等人.Nature Biotechnology 22(2004)，第848-855页)。该菌株PF1022A分离自在日本茨城(Ibaraki)县采集的山茶(Camellia japonica)的植物叶片。该菌株以登录号FERM BP-2671保藏于“工业科学与技术机构，生物科学与人类技术国家研究所”(“National Institute ofBioscience and Human Technology，Agency of Industrial Science and Technology”)(日本)和以编号IFO33096保藏于“发酵研究所(Institute for Fermentation)，大阪”。由Meiji Saika Kaisha有限公司描述的产生PF1022A的真菌菌株属于炭角菌科，其最近的亲属是褐座坚壳(Rosellinia necatrix)IFO 32537(Miyadoh S.等人.Nippon Kingakukai Kaiho 41(2000)，第183-188页)和多形炭角菌(Xylariapolymorpha)IFO 9780(Sasaki T.等人.J.Antibiot.45(1992)，第692-697页)。这两个菌株不产生PF1022A化合物。
本发明涉及发现新的真菌菌株，其分离自座坚壳属和Coniolariella属以及其他炭角菌在落叶树和针叶树的死木上生长的物种的子实体，以便制备PF1022A。
从在落叶树和针叶树的死木上生长的座坚壳属物种和其他炭角菌的子实体分离
真菌菌株作为PF1022A的潜在活性成分形成物的描述：
到处生长的座坚壳属被分类于炭角菌科，其属于广泛的炭角菌(Xylariales)目(子囊菌(Ascomycota)门)。该目的代表具有带有定义的小孔的特征性球状子实体(子囊壳)，其中形成具有孢子的子囊。
除了座坚壳属，其他属Coniolariella属、炭球菌属(Daldinia)、炭团菌属(Hypoxylon)、孔座壳属(Poronia)、焦菌属(Ustulina)和炭角菌属(Xylaria)也被分类于该科。这些属的每个具有一系列不同的物种，其中可能出现环缩酚酸肽的潜在产生者。
炭角菌科的属具有非常坚硬的脆的
子囊壳，其中存在各自具有8个深棕色至黑色孢子的子囊。座坚壳属包含一系列物种，其腐生或内寄生地生活，但也作为病原体出现。致病物种寄生于落叶树木和针叶树木的活木和根系统。该属的腐生代表首先生活在已经处在分解过程中的死木上。Coniolariella属只是最近才作为独立的属从座坚壳属分离出来(Checa，J.；Arenal，F.；Blanco，N.；Rogers，L.D.：“Coniolariella hispanica sp.nov.and other additions toConiolariella”Mycological Research 2008，112，7，795-801)。在自然界中，单一物种对温度状况、湿度状况和光状况具有相对高的要求。此外，其发生依赖于季节交替(特别是晚冬、早春)以及在高程度上依赖于优选群落生境的自然环境。可以在少耕作或未耕作的树林中发现座坚壳属物种。
本发明中所感兴趣的得自座坚壳属的真菌菌株全部分离自死落叶木的样品(例如欧亚槭(Berg-Ahorn)、刺槐)。然而，由于不同的分解程度对各个死木样品的树种进行精确归类并非总是可能的。
再培养的获得从成熟的、未受损害的和尽可能是单独站立的子囊壳(其从死木提取)进行。将其用0.05％AgNO3溶液进行表面消毒并用灭菌水冲洗多次。将子囊壳在载片上小心地压碎并将所释放的子囊和孢子用灭菌水转移入小试管中。
通过显微检查可以评价所发生的孢子处于怎样的密度和具有怎样的成熟状况。在高孢子密度的情况下，将孢子悬浮液进一步稀释十倍并将各种稀释梯级100μl涂布在麦芽提取物-琼脂(MEA)上。将平板在18至20℃下维持，每天在显微镜下进行评估并在新鲜的马铃薯-葡糖糖-琼脂(PDA)上传播萌发的孢子。在该培养基上的所形成的菌丝长成近白色平整的和细嫩的，没有气生菌丝形成。
在培养物充分生长后，按标准将菌丝用甲醇进行提取。用LC-PDA-ESI-Q-TOF-MS和LC-PDA-ESI-Q-TOF-MS/MS进行菌丝提取物成分的鉴定和PF1022A含量的定量。发现座坚壳属或来自新的Coniolariella属的不同系，其证明是就PF1022A形成而言阳性的。
在5.8S rDNA的ITS1/4片段以及部分的18S-和28S-范围的测序之后，根据形态学特征以及分子数据，将八个PF1022A产生者归入下述物种：
XR-9：落叶木的Rosellinia corticum或座坚壳属物种(Rosetlinia sp.)(不是新近确定的座坚壳属物种)
XR-15：欧亚槭的Coniolariella hispanica Checa，Arenal或J.D.Rogers，新种
XR-16：落叶木的Coniolariella hispanica Checa，Arenal或J.D.Rogers，新种
XR-19：刺槐或欧亚槭的座坚壳属物种或R.corticum
XR-21：落叶木的座坚壳属物种或R.corticum
XR-26：落叶木的座坚壳属物种或R.corticum
XR-55：落叶木的座坚壳属物种或R.corticum
XR-56：落叶木的座坚壳属物种或R.corticum
进行培养实验。与“野生型”无孢菌群(Mycelia sterilia)T38-18和菌株Rosellinia abscondita CBS 448.89和CBS 450.89相比，在新分离的真菌菌株的情况下，在培养基MEA、mPDA、CMA以及种子-琼脂(Seed-Agar)上发现明显更快的生长。
Rosellinia corticum或座坚壳属物种XR-9、Coniolariella hispanica XR-15和C.hispanica XR-16培养物在21至22℃下生长10至12天直至培养盘(9cm)的边缘，与此不同，对照培养物“野生型”无孢菌群T38-18、Rosellinia abscondita CBS448.89和R abscondita CBS 450.89具有明显更小的直径。这意味着，新的座坚壳属或Coniolariella菌株具有非常更快的生长。同样，座坚壳属物种或R.corticum XR-19、XR-21、XR-26、XR-55、XR-56也生长快速。
在MEA和mPDA上形成细嫩的菌丝，而在富营养物质的CMA和种子-琼脂培养基上形成浓密的、部分地似毡的菌丝。在培养基M1上菌株(Isolate)XR-19和XR-26形成部分地羽状的菌丝形态。
所使用的培养基的组成：
CMA：玉米面50g/l，琼脂15g/l
M1：麦芽提取物10g/l，酵母提取物4g/l，葡萄糖4g/l，琼脂15g/l
种子-琼脂：药用培养基(Pharmamedia)20g/l，大豆蛋白胨2g/l，麦芽糖40g/l，MgSO4·7H2O 2g/l，NaCl 2g/l，CaCO3 3g/l，琼脂15g/l
MEA：麦芽提取物17g/l，琼脂15g/l
mPDA：葡萄糖5g/l，马铃薯淀粉20g/l，酵母提取物1.5g/l，琼脂15g/l
因为在当前培养物的情况下涉及直接自自然生态系统转移进人工条件的菌株，因此可能出现这样的培养物形状，其产生不同的菌丝形状以及在活性物质形成强度
方面的变异。
用LC-PDA-ESI-Q-TOF-MS和LC-PDA-ESI-Q-TOF-MS/MS鉴定与无孢菌群 T38-18(WT)相比而言新分离菌株的麦芽提取物中成分(特别是PF1022A)的描 述：
为了鉴定成分，特别是PF1022化合物，用具有两个检测器光二极管阵列(PDA)和质谱仪(MS)的高效液相色谱(HPLC)研究无孢菌群T38-18(WT：野生型)和新菌株XR-9、XR-15、XR-16、XR-19、XR-21、XR-26、XR-55和XR-56的菌丝-甲醇提取物。
该研究允许在具有PDA和MS检测器进行检测的情况下根据HPLC色谱比较无孢菌群T38-18(WT)与新菌株XR-21的菌丝(在种子琼脂培养基上)的甲醇提取物中的成分。这里如下可以看出在成分的产生方面上述菌株的显著不同：
无孢菌群(WT)产生一系列PF1022化合物：PF1022-A(C52H76N4O12)、PF1022-B(C64H84N4O12)、PF1022-C(C58H80N4O12)、PF1022-D(C46H72N4O12)、PF1022-E(C52H76N4O13)和PF1022-F(C40H68N4O12)。其中主要成分是PF1022-A(在用PDA和MS检测器进行检测的情况下，在色谱中，保留时间Rt：25.1-25.6分钟)和PF1022-D(Rt：19.5-20分钟)，而新菌株例如菌株XR-21，除了作为主要成分的PF1022-A(用LC-PDA-MS根据UV/可见光数据和MS数据以及Rt进行表征，与来自无孢菌群的PF1022A相比，在HPLC色谱中在相同保留时间下具有相同的分子质量)和其他化合物(Rt：12-24分钟)(其不属于PF1022化合物)以外，还有作为次要化合物的PF1022-B和PF1022-C，然而，几乎不产生PF1022-D，同样，这里也没有发现化合物PF1022-E和PF1022-F。
类似地，也可以看到在无孢菌群(WT)的TIC-MS色谱与新菌株XR-15和XR-19的TIC-MS色谱之间进行比较的情况下的结果。用LC-ESI-Q-TOF-MS/MS进行鉴定PF1022A化合物的进一步研究。
也进行无孢菌群(WT)与新菌株XR-15和XR-19的菌丝提取物的LC-MS/MS色谱中PF1022A化合物选中峰的比较。这些峰具有相同的保留时间。来自无孢菌群(WT)与新菌株XR-15和XR-19菌丝提取物PF1022A化合物加合质子的质量949.6的在MS/MS谱中检测的MS/MS碎片是彼此相同的。
上述LC-PDA-ESI-Q-TOF-MS研究和LC-PDA-ESI-Q-TOF-MS/MS研究的结果证实，新菌株如XR-9、XR-15、XR-16、XR-19、XR-21、XR-26、XR-55和XR-56不是无孢菌群(WT)，然而也产生PF1022A化合物。
因为新的座坚壳属和炭角菌属菌株不产生次要产物PF1022-D、PF1022-E、PF1022-F，因此与无孢菌群(WT)相比，PF1022A的提取和分离方法是非常强烈简化了。
Claims (2)
1.用座坚壳属物种和炭角菌科其他属的真菌菌株或用分离自这些真菌菌株的酶制剂制备式
的PF1022A，具有24个环原子的环八缩酚酸肽的方法。
2.根据权利要求1制备PF1022A的方法，用座坚壳属物种和其他炭角菌，特别是附孢(Rosellinia aquila)或Rosellinia corticum的真菌菌株来进行。
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| EP08021792 | 2008-12-16 | ||
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| PCT/EP2009/008740 WO2010072323A1 (de) | 2008-12-16 | 2009-12-08 | Verfahren zur herstellung milchsäure- und phenylmilchsäurehaltiger optisch aktiver, cyclischer depsipeptide mit 24 ringatomen mit hilfe von pilzstämmen der art rosellinia sowie weiteren gattungen xylariaceen |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570016A (zh) * | 2017-03-10 | 2018-09-25 | 上海医药工业研究院 | 一种pf1022a分离纯化的方法 |
| CN109880746A (zh) * | 2017-12-06 | 2019-06-14 | 海正药业(杭州)有限公司 | 一种座坚壳属真菌菌株及其应用 |
| CN110964646A (zh) * | 2019-11-15 | 2020-04-07 | 中国医药集团总公司四川抗菌素工业研究所 | 一种座坚壳菌、应用、发酵培养基及pf1022a的制备方法 |
| CN114875093A (zh) * | 2022-05-20 | 2022-08-09 | 浙江海正药业股份有限公司 | 一种提高pf1022a发酵产量的方法 |
| CN115247132A (zh) * | 2021-04-26 | 2022-10-28 | 中国科学院微生物研究所 | 一种组合型人工生物结皮治理荒漠的方法 |
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| US20120302496A1 (en) * | 2009-12-11 | 2012-11-29 | Bayer Intellectual Property Gmbh | Novel 24-membered cyclooctadepsipeptides from fungal strains and their use as anthelmintics or endoparasiticides |
| SMT202100417T1 (it) | 2015-05-20 | 2021-09-14 | Boehringer Ingelheim Animal Health Usa Inc | Composti depsipeptidici antielmintici |
| AU2016380868B2 (en) | 2015-12-28 | 2019-11-28 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
| WO2018166899A1 (en) | 2017-03-14 | 2018-09-20 | Acidophil Ltd | Methods for production of pf1022a derivatives |
| WO2020018888A1 (en) | 2018-07-20 | 2020-01-23 | The Board Of Regents Of The University Of Oklahoma | Antimicrobial peptides and methods of use |
| CN114084497B (zh) * | 2021-10-25 | 2023-05-05 | 中国热带农业科学院海口实验站 | 一种果蔬保鲜袋及其制备方法与应用 |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570016A (zh) * | 2017-03-10 | 2018-09-25 | 上海医药工业研究院 | 一种pf1022a分离纯化的方法 |
| CN108570016B (zh) * | 2017-03-10 | 2021-11-26 | 上海医药工业研究院 | 一种pf1022a分离纯化的方法 |
| CN109880746A (zh) * | 2017-12-06 | 2019-06-14 | 海正药业(杭州)有限公司 | 一种座坚壳属真菌菌株及其应用 |
| CN109880746B (zh) * | 2017-12-06 | 2023-10-20 | 海正药业(杭州)有限公司 | 一种座坚壳属真菌菌株及其应用 |
| CN110964646A (zh) * | 2019-11-15 | 2020-04-07 | 中国医药集团总公司四川抗菌素工业研究所 | 一种座坚壳菌、应用、发酵培养基及pf1022a的制备方法 |
| CN110964646B (zh) * | 2019-11-15 | 2021-07-27 | 成都大学 | 一种座坚壳菌、应用、发酵培养基及pf1022a的制备方法 |
| CN115247132A (zh) * | 2021-04-26 | 2022-10-28 | 中国科学院微生物研究所 | 一种组合型人工生物结皮治理荒漠的方法 |
| CN115247132B (zh) * | 2021-04-26 | 2024-04-16 | 中国科学院微生物研究所 | 一种组合型人工生物结皮治理荒漠的方法 |
| CN114875093A (zh) * | 2022-05-20 | 2022-08-09 | 浙江海正药业股份有限公司 | 一种提高pf1022a发酵产量的方法 |
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| Publication number | Publication date |
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| UY32322A (es) | 2010-07-30 |
| AR074673A1 (es) | 2011-02-02 |
| CA2746733A1 (en) | 2010-07-01 |
| BRPI0922388A2 (pt) | 2019-09-24 |
| MX2011006140A (es) | 2011-08-03 |
| CR20110325A (es) | 2011-09-29 |
| ZA201104410B (en) | 2012-09-26 |
| ECSP11011117A (es) | 2011-07-29 |
| DOP2011000182A (es) | 2011-07-15 |
| TW201034681A (en) | 2010-10-01 |
| WO2010072323A1 (de) | 2010-07-01 |
| AU2009331930A1 (en) | 2011-06-30 |
| RU2011129395A (ru) | 2013-01-27 |
| SV2011003943A (es) | 2011-11-08 |
| CO6362018A2 (es) | 2012-01-20 |
| IL213006A0 (en) | 2011-07-31 |
| EP2379731A1 (de) | 2011-10-26 |
| KR20110095350A (ko) | 2011-08-24 |
| US20110262969A1 (en) | 2011-10-27 |
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