CN116836112A - 一种吡啶类生物碱及其应用 - Google Patents
一种吡啶类生物碱及其应用 Download PDFInfo
- Publication number
- CN116836112A CN116836112A CN202311068990.8A CN202311068990A CN116836112A CN 116836112 A CN116836112 A CN 116836112A CN 202311068990 A CN202311068990 A CN 202311068990A CN 116836112 A CN116836112 A CN 116836112A
- Authority
- CN
- China
- Prior art keywords
- pyridine alkaloid
- streptomyces
- kcb
- mic
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229930002371 pyridine alkaloid Natural products 0.000 title claims abstract description 23
- 150000003222 pyridines Chemical class 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 12
- 244000052769 pathogen Species 0.000 claims abstract description 8
- 230000003115 biocidal effect Effects 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 229930000044 secondary metabolite Natural products 0.000 claims abstract description 4
- 229940124350 antibacterial drug Drugs 0.000 claims abstract description 3
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 3
- 238000000855 fermentation Methods 0.000 claims description 15
- 230000004151 fermentation Effects 0.000 claims description 15
- 241000186361 Actinobacteria <class> Species 0.000 claims description 6
- 241000194031 Enterococcus faecium Species 0.000 claims description 6
- 101000610620 Homo sapiens Putative serine protease 29 Proteins 0.000 claims description 6
- 102100040345 Putative serine protease 29 Human genes 0.000 claims description 6
- 241000588724 Escherichia coli Species 0.000 claims description 5
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 5
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 230000001717 pathogenic effect Effects 0.000 claims description 5
- 239000013535 sea water Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000012258 culturing Methods 0.000 claims description 4
- 238000003306 harvesting Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 2
- 238000011097 chromatography purification Methods 0.000 claims description 2
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- 244000005700 microbiome Species 0.000 claims description 2
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 8
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- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
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- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 1
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- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
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- 239000004098 Tetracycline Substances 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
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- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
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- 229960004682 cefoperazone Drugs 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
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- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
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- 238000007865 diluting Methods 0.000 description 1
- NWOYIVRVSJDTLK-YSDBFZIDSA-L disodium;(2s,5r,6r)-6-[[(2r)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(1r,4s)-3,3-dimethyl-2,2,6-trioxo-2$l^{6}-thiabicyclo[3.2.0]heptane-4-carboxylate Chemical compound [Na+].[Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)C2C(=O)C[C@H]21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 NWOYIVRVSJDTLK-YSDBFZIDSA-L 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
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- 230000002068 genetic effect Effects 0.000 description 1
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 1
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229940041028 lincosamides Drugs 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 238000000238 one-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
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- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- DWHGNUUWCJZQHO-ZVDZYBSKSA-M potassium;(2s,5r,6r)-6-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 DWHGNUUWCJZQHO-ZVDZYBSKSA-M 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 108010043542 streptin Proteins 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明属于生物制药技术领域，公开了一种吡啶类生物碱及其应用，所述吡啶类生物碱分离自海洋放线菌Streptomyces sp. KCB‑132的次生代谢产物，命名为strepyridin A。经抗菌活性试验检测，其对于多重耐药“ESKAPE”病原体具备较强的抗菌活性，具有开发成应对多重耐药性造成感染与并发症的药物的潜力。本发明还公开了上述吡啶类生物碱作为抗生素的非治疗和非诊断应用，尤其是应用于抗菌药物的制备。
Description
技术领域
本发明属于生物制药技术领域，具体涉及一种吡啶类生物碱及其应用。
背景技术
抗生素通过杀死或抑制细菌生长，有效防止传染病的传播，大大延长了人类的预期寿命。然而，人类对抗生素的过度依赖使得抗生素耐药细菌的数量急剧增加，细菌感染的治疗变得更加困难。因此，研发新型高效且作用机制独特的抗生素新药具有重要的意义。
研究表明，天然产物在参与生命生理过程中具有无可比拟的优势，这得益于其化学结构的多样性和易于与生物大分子结合的特点，同时也奠定了其作为活性先导化合物进而创制新药的重要地位。放线菌是抗生素等活性天然产物的重要来源，而海洋环境的特殊性又赋予了海洋放线菌特定的生理性状和遗传代谢，使其次生代谢产物结构更加多样、生物活性更加独特。因此，从海洋放线菌中寻找新型先导化合物具有巨大的药用潜力。
发明内容
本发明提供一种吡啶类生物碱及其应用。该吡啶类生物碱具有抗生素活性，具有开发成应对多重耐药性造成感染与并发症的药物的潜力。
具体技术方案如下：
本发明的目的之一是提供一种吡啶类生物碱，其化学结构如下式所示：
。
上述吡啶类生物碱分离自海洋放线菌Streptomyces sp.KCB-132的次生代谢产物，命名为strepyridin A。对多重耐药“ESKAPE”病原体的抗菌活性实验发现，化合物strepyridin A对革兰氏阳性菌（金黄色葡萄球菌和屎肠球菌）的活性较低，MIC为16 μg/mL，而对革兰氏阴性菌（大肠杆菌和肺炎克雷伯菌）更具活性，MIC值为4 μg/mL。
所述的海洋放线菌Streptomyces sp.KCB-132从海底沉积物分离获得，于2022年6月23日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏地址为北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No. 25176，分类命名为链霉菌Streptomyces sp.。
进一步，所述吡啶类生物碱的制备方法包括：对海洋放线菌Streptomyces sp.KCB-132进行培养，收获发酵产物；并对发酵产物进行纯化。
再进一步，培养海洋放线菌Streptomyces sp. KCB-132使用的培养基为ISP2培养基或纯海水ISP2培养基，优选为半海水ISP2培养基。
具体地，培养方法如下：将海洋放线菌株Streptomyces sp.KCB-132划线接种于固体培养基上培养，直至长出孢子；然后将孢子接种到液体培养基发酵培养，收获发酵产物。
其中，在固体培养基上于25~28℃培养3~5天。
其中，孢子在液体培养基于25~28℃培养7~10天。
再进一步，所述的纯化包括：对发酵产物进行层析纯化。
具体地，所述的纯化方法如下：过滤发酵产物，获得发酵液和菌丝体，发酵液经大孔吸附树脂柱吸附、洗脱及减压浓缩；菌丝体经超声破碎、提取、减压浓缩；合并减压浓缩物，利用有机溶剂萃取，减压浓缩得粗提物。粗提物经过硅胶柱层析，二氯甲烷-甲醇洗脱，洗脱液加压浓缩，得浓缩浸膏。浓缩浸膏通过ODS凝胶柱层析，甲醇-水梯度洗脱，并通过薄层层析检测处理洗脱组分，然后将洗脱组分通过HPLC进一步纯化，得到新化合物strepyridin A（5.82 mg，tR=8.02 min）。
其中，大孔吸附树脂柱吸附后，使用有机醇洗脱，所述的有机醇优选为甲醇或/和乙醇，最优选为甲醇。
其中，所述的大孔吸附树脂柱为弱极性或非极性的大孔吸附树脂柱，优选弱极性大孔吸附树脂柱。
其中，菌丝体超声破碎中加入甲醇。
其中，菌丝体经超声破碎后，使用有机溶剂提取，所述的有机溶剂优选为三氯甲烷、乙酸乙酯、正丁醇中的至少一种，最优选为乙酸乙酯。
其中，合并发酵液与菌丝体的减压浓缩物后，萃取用的有机溶剂优选为乙酸乙酯。
其中，硅胶柱层析中，二氯甲烷-甲醇（99:1，体积比）洗脱。
其中，ODS凝胶柱层析中，甲醇-水（10:90~100:0，体积比）梯度洗脱。
其中，HPLC纯化中，HPLC的柱层析填料优选为C-18或C-8，最优选为C-18。
本发明的目的之二是提供上述吡啶类生物碱strepyridin A作为抗生素的非治疗和非诊断应用。所述的应用包括但不限于科学研究、农业、畜牧业、食品工业、纺织工业、造纸工业或皮革工业。
进一步，将所述的吡啶类生物碱应用于抗菌药物的制备。
再进一步，所述的抗菌药物应用于应对多重耐药性病原体，所述的多重耐药性病原体优选为屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌、大肠杆菌中的至少一种。
本发明的有益效果如下：
本发明从海洋放线菌Streptomyces sp.KCB-132中获得一种新的吡啶类生物碱strepyridin A。经抗菌活性试验检测，其对于多重耐药“ESKAPE”病原体具备较强的抗菌活性。其对革兰氏阳性菌（金黄色葡萄球菌和屎肠球菌）的活性较低，MIC为16 μg/mL，而对革兰氏阴性菌（大肠杆菌和肺炎克雷伯菌）更具活性，MIC值为4 μg/mL。化合物strepyridin A具有开发成应对多重耐药性造成感染与并发症的药物的潜力。
附图说明
图1为化合物strepyridin A的化学结构式；
图2为化合物strepyridin A的1H NMR谱图；
图3为化合物strepyridin A的13C NMR谱图；
图4为化合物strepyridin A的1H-1H COSY谱图；
图5为化合物strepyridin A的HSQC谱图；
图6为化合物strepyridin A的HMBC谱图；
图7为化合物strepyridin A的高分辨质谱图。
具体实施方式
以下结合实例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径获取。
使用半海水ISP2培养基培养海洋放线菌Streptomyces sp.KCB-132，将海洋放线菌Streptomyces sp.KCB-132划线接种于固体培养基上，于28℃培养3天，直至长出孢子，然后将孢子接种到液体培养基，在28℃条件下，摇床培养7天，收获发酵物。
过滤发酵物获得发酵液和菌丝体，发酵液经弱极性大孔吸附树脂柱吸附，然后用甲醇洗脱，再减压浓缩；向菌丝体加入甲醇超声破碎，然后用乙酸乙酯提取、减压浓缩；合并减压浓缩物，利用乙酸乙酯萃取，减压浓缩得粗提物。粗提物经过硅胶柱层析，二氯甲烷-甲醇（99:1，体积比）洗脱，洗脱液加压浓缩，得浓缩浸膏。浓缩浸膏通过ODS凝胶柱层析，甲醇-水（10:90、20:80、30:70、40:60、50:50、60:40、70:30、80:20、90:10、100:0，体积比）梯度洗脱，并根据薄层层析检测分为10个洗脱组分，分别编号为洗脱组分1~10。洗脱组分6通过制备型HPLC系统（YMC-Pack ODS-A，C18，250 mm×4.6 mm，5μm，UV=210 nm），甲醇-水（40:60，体积比）进一步纯化，得新化合物strepyridin A（5.82 mg，tR=8.02 min）。
（1）仪器与材料
Autopol VI (Serial #91058)旋光仪，Waters ACQUITY UPLC I Class-Vion IMSQT高分辨率质谱仪，Applied photophysics 9798QB光谱仪，Waters 2489 紫外/可见光液相色谱仪，Bruker AVANCE IIITM 600核磁共振仪。
（2）化学结构确定
strepyridin A：淡黄色油状，[α]D 20– 18.7 (甲醇, c 0.08)；UV (乙腈)：λmax(log ε) 230 (3.5), 258 (3.2), 273 (3.3), 283 (3.3), 301 (3.0), 313 (3.2) nm；1D 和2D-NMR (600 MHz, DMSO-d 6 )数据见表1及图2~图6；HRESIMS m/z：[M + H]+238.10745见图7。
表1 strepyridin A的1H NMR及13C NMR数据
依据以上化合物的理化参数、波谱数据（图2~7），确定新化合物strepyridin A的结构如下式所示：
。
采用微量肉汤稀释法对多种耐药“ESKAPE”病原体（屎肠球菌Enterococcus faecium、金黄色葡萄球菌Staphylococcus aureus、肺炎克雷伯菌Klebsiella Pneumoniae、鲍曼不动杆菌Acinetobacter baumannii、铜绿假单胞菌Pseudomonas aeruginosa和大肠杆菌Escherichia coli）进行抗菌活性测试。将37℃增菌4~6 h的受试菌用MH肉汤稀释成1ｘ105~5ｘ105菌数/mL接种物，以无菌操作每孔加入100 μL，以微量二倍稀释法将化合物浓度稀释为64 μg/mL、32 μg/mL、16 μg/mL、8 g/mL、4 μg/mL、2 μg/mL和1 μg/mL，以空白肉汤为阴性对照，以氨苄西林、阿米卡星和环丙沙星为阳性对照，密封后于37℃孵育18~20 h，以肉眼无菌生长的最低浓度孔为MIC（最小抑菌浓度）。结果如表2所示。
表2 strepyridin A的抗菌活性
注：“－” 代表最小抑菌浓度MIC≥64μg/mL。
a 对抗生素耐药性如下：β-内酰胺类[氨苄西林（MIC≥32 μg/mL）、青霉素（MIC≥64μg/mL）]、大环内酯类[红霉素（MIC≥8 μg/mL）]、4-喹诺酮类[左氧氟沙星（MIC≥8 μg/mL）、环丙沙星（MIC≥8 μg/mL）]、万古霉素（MIC≥32 μg/mL）。
b 对抗生素耐药性如下：β-内酰胺类[苯唑西林（MIC≥4 μg/mL），青霉素（MIC≥0.5μg/mL）]、氨基糖苷类 [庆大霉素(MIC ≥ 16μg/mL)]、4-喹诺酮类[左氧氟沙星（MIC≥8 μg/mL），环丙沙星（MIC ≥8 μg/mL）、莫西沙星 (MIC ≥ 4μg/mL)]、四环素 (MIC ≥ 16μg/mL)、林可酰胺类 [克林霉素 (MIC ≥ 8μg/mL)]、利福平 (MIC ≥ 32μg/mL)、大环内酯类[红霉素 (MIC ≥ 8 μg/mL)]。
c 对抗生素耐药性如下：β-内酰胺类[阿莫西林/克拉维酸 (MIC ≥ 32μg/mL)，哌拉西林/他唑巴坦 (MIC ≥ 128μg/mL)，头孢呋辛、头孢呋肟酯、头孢西丁、头孢他啶、头孢曲松、头孢哌酮/舒巴坦 ( MIC均 ≥ 64μg/mL)， 头孢吡肟 (MIC ≥ 32μg/mL)，厄他培南(MIC ≥ 8μg/mL)，亚胺培南(MIC ≥ 16μg/mL)]、4-喹诺酮类[左氧氟沙星 (MIC ≥ 8μg/mL)]。
d 对抗生素耐药性如下：β-内酰胺类[氨苄青霉素/舒巴坦 (MIC ≥ 32μg/mL)，哌拉西林 (MIC ≥ 128μg/mL)， 头孢唑林、头孢呋辛、头孢呋肟酯、头孢曲松 ( MIC均 ≥ 64μg/mL)]、氨基糖苷类[庆大霉素(MIC ≥ 16μg/mL)， 妥布霉素 (MIC ≥ 16μg/mL)]、4-喹诺酮类[左氧氟沙星 (MIC ≥ 8μg/mL)，环丙沙星 (MIC ≥ 4μg/mL)]、呋喃妥因 (MIC ≥256μg/mL)。
通过表2可见，化合物strepyridin A对革兰氏阳性菌（金黄色葡萄球菌和屎肠球菌）的活性较低，MIC为16 μg/mL，而对革兰氏阴性菌（大肠杆菌和肺炎克雷伯菌）更具活性，MIC值为4 μg/mL。可见，化合物strepyridin A具有开发成应对多重耐药性造成感染与并发症的药物的潜力。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种吡啶类生物碱，其特征在于，其化学结构如下式所示：
。
2.根据权利要求1所述的吡啶类生物碱，其特征在于，其分离自海洋放线菌Streptomyces sp. KCB-132的次生代谢产物。
3.根据权利要求2所述的吡啶类生物碱，其特征在于，所述的海洋放线菌Streptomyces sp. KCB-132于2022年6月23日保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏地址为北京市朝阳区北辰西路1号院3号，保藏编号为CGMCC No. 25176，分类命名为链霉菌Streptomyces sp.。
4.根据权利要求2所述的吡啶类生物碱，其特征在于，其制备方法包括：对海洋放线菌Streptomyces sp. KCB-132进行培养，收获发酵产物；并对发酵产物进行纯化。
5.根据权利要求4所述的吡啶类生物碱，其特征在于，培养海洋放线菌Streptomyces sp. KCB-132使用的培养基为半海水ISP2培养基或纯海水ISP2培养基。
6.根据权利要求4所述的吡啶类生物碱，其特征在于，所述的纯化包括：对发酵产物进行层析纯化。
7.一种如权利要求1~6任一项所述的吡啶类生物碱作为抗生素的非治疗和非诊断应用。
8.根据权利要求7所述的应用，其特征在于，将所述的吡啶类生物碱应用于抗菌药物的制备。
9.根据权利要求8所述的应用，其特征在于，所述的抗菌药物应用于应对多重耐药性病原体。
10.根据权利要求9所述的应用，其特征在于，所述的多重耐药性病原体为屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌、大肠杆菌中的至少一种。
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|---|---|---|---|---|
| FR2855M (fr) * | 1962-04-04 | 1964-10-19 | Upjohn Co | Dérivés antibiotiques de l'actinospectacine. |
| JPH05146298A (ja) * | 1991-10-09 | 1993-06-15 | Microbial Chem Res Found | ３−ヒドロキシ−２−メチル−４−ピリドンの製造法 |
| CN102206179A (zh) * | 2009-12-17 | 2011-10-05 | 中国海洋大学 | 联吡啶生物碱类化合物及其制备方法和用途 |
-
2023
- 2023-08-24 CN CN202311068990.8A patent/CN116836112B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2855M (fr) * | 1962-04-04 | 1964-10-19 | Upjohn Co | Dérivés antibiotiques de l'actinospectacine. |
| JPH05146298A (ja) * | 1991-10-09 | 1993-06-15 | Microbial Chem Res Found | ３−ヒドロキシ−２−メチル−４−ピリドンの製造法 |
| CN102206179A (zh) * | 2009-12-17 | 2011-10-05 | 中国海洋大学 | 联吡啶生物碱类化合物及其制备方法和用途 |
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