CN115595343A - 樱桃番茄根际土壤微生物中活性次级代谢产物及其制备与应用 - Google Patents
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Abstract
本发明涉及樱桃番茄根际土壤微生物中活性次级代谢产物及其制备与应用，具体涉及对Bacillus sp.HNU24进行发酵获得8种活性次级代谢产物，其中化合物3对金黄色葡萄球菌、表皮葡萄球菌、青枯菌的MIC分别为3.125、12.5、50μg/mL；化合物4对金黄色葡萄球菌的MIC为12.5μg/mL；化合物3对HTC116细胞株的IC50为8.42±0.48μM。
Description
技术领域
本发明属于微生物次级代谢产物领域，具体涉及樱桃番茄根际土壤微生物中活性次级代谢产物及其制备与应用。
背景技术
樱桃番茄(Solanum lycopersicum var.cerasiforme)。发明人先前自海南省樱桃番茄重病田存活的健康植株的砧木根际土壤中分离出了一种贝莱斯芽孢杆菌Bacillusvelezensis HNU24，其菌种保藏信息如下：保藏单位名称：广东省微生物菌种保藏中心；保藏单位地址：广州市先烈中路100号大院59号楼5楼，广东省科学院微生物研究所；保藏日期：2020年10月15日；保藏编号：GDMCC No.61231；分类命名：Bacillus sp.。本发明对贝莱斯芽孢杆菌Bacillus sp.HNU24进行发酵，获得粗提物，初步活性显示，粗提物具有一定的抗菌及细胞毒活性，进一步分离获得8种代谢产物。
发明内容
本发明的另一实施方案提供一种抗菌、细胞毒活性粗提物，其特征在于所述粗提物由如下方法制备：
(1)将Bacillus sp.HNU24接入LB发酵培养基中，28～30℃静置培养7天得发酵物；
(2)步骤(1)得到的发酵物用等体积的乙酸乙酯萃取2～4次，合并萃取液后减压浓缩即得粗提物。
步骤(1)中所述LB培养基配置方法为：以1L为例，需10.0g蛋白胨、5.0 g酵母提取物、10.0g氯化钠、余量为蒸馏水。
本发明的另一实施方案提供Bacillus sp.HNU24在制备抗菌、细胞毒活性粗提物中的应用。
本发明的另一实施方案提供一种由Bacillus sp.HNU24同时制备化合物1-8 的方法，其特征在于包括如下步骤：
(1)将Bacillus sp.HNU24接入LB发酵培养基中，28～30℃静置培养7天得发酵物；
(2)步骤(1)得到的发酵物用等体积的乙酸乙酯萃取2～4次，合并萃取液后减压浓缩即得粗提物；
(3)步骤(2)得到的粗提物经过减压硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为90:10、80:20、70:30、60:40，50:50、 40:60、30:70、20:80、10:90、0:100，每个梯度收集两个柱体积，依次得到10个组分A-J，其中梯度80:20洗脱得到的为组分B，梯度70:30洗脱得到的为组分C；
组分B浓缩后，采用正相硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为：9:1、8:1、7:1、6:1、5:1、4:1、3:1、7:3，每个梯度收集两个柱体积，根据极性大小分成7个组分，其中梯度9:1洗脱得到的为组分1，梯度8:1洗脱得到的为组分2，梯度7:1洗脱得到的为组分3，梯度6:1 洗脱得到的为组分4，梯度5:1洗脱得到的为组分5，梯度4:1洗脱得到的为组分 6，梯度3:1、7:3洗脱得到的为组分7；其中组分2经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝65:35，得到化合物1、2；组分4经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝60:40，得到化合物3和4；
组分C浓缩后，经Sephadex LH-20凝胶柱层析，洗脱剂为CHCl3：MeOH＝1:1，再经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝70:30，得到化合物5、6、7、8。
其中所述洗脱剂或流动相的比例均为体积比。
本发明提供Bacillus sp.HNU24在同时制备化合物1-8中的应用。
本发明的另一实施方案提供上述粗提物、化合物1-8或其药学上可接受的盐在制备抗菌药物和/抗肿瘤药物中的应用。
一种药物组合物，其特征在于该药物组合物以上述粗提物、化合物1-8或其药学上可接受的盐作为有效成分。该药物组合物还可包括其他抗菌剂或抗肿瘤化合物。该药物组合物还可包括药学上可接的辅料。该药物组合物的剂型优选固体制剂或液体制剂等。
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐，可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。
附图说明
图1是化合物1的1H NMR图；
图2是化合物1的13C NMR图；
图3是化合物2的1H NMR图；
图4是化合物2的13C NMR图；
图5是化合物3的1H NMR图；
图6是化合物3的13C NMR图；
图7是化合物4的1H NMR图；
图8是化合物4的13C NMR图；
图9是化合物5的1H NMR图；
图10是化合物5的13C NMR图；
图11是化合物6的1H NMR图；
图12是化合物6的13C NMR图；
图13是化合物7的1H NMR图；
图14是化合物7的13C NMR图；
图15是化合物8的1H NMR图；
图16是化合物8的13C NMR图。
具体实施方式
实施例1
(1)配制LB发酵培养基：配方为以1L为例，需10.0g蛋白胨、5.0g酵母提取物、10.0g氯化钠、余量为蒸馏水。120℃灭25–30分钟。共发酵50L。
将Bacillus sp.HNU24接入LB发酵培养基中，28～30℃静置培养7天得发酵物；
(2)步骤(1)得到的发酵物用等体积的乙酸乙酯萃取3次，合并萃取液后减压浓缩即得粗提物(约13.4g)；
(3)步骤(2)得到的粗提物经过减压硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为90:10、80:20、70:30、60:40，50:50、 40:60、30:70、20:80、10:90、0:100，每个梯度收集两个柱体积，分别浓缩得到 10个组分A-J，其中梯度80:20洗脱得到的为组分B，梯度70:30洗脱得到的为组分C；
组分B浓缩后(约2.5g)，采用正相硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为：9:1、8:1、7:1、6:1、5:1、4:1、3:1、7:3，每个梯度收集两个柱体积，根据极性大小分成7个组分，其中梯度9:1洗脱得到的为组分1，梯度8:1洗脱得到的为组分2，梯度7:1洗脱得到的为组分3，梯度 6:1洗脱得到的为组分4，梯度5:1洗脱得到的为组分5，梯度4:1洗脱得到的为组分6，梯度3:1、7:3洗脱得到的为组分7；其中组分2经高效液相色谱HPLC 制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝65:35，得到化合物1(14.2mg)、2(15.5mg)；组分4经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝60:40，得到化合物3(9.8mg)和4(7.4mg)；
组分C浓缩后(约1.2g)，经Sephadex LH-20凝胶柱层析，洗脱剂为CHCl3： MeOH＝1:1，再经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm， 7μm，流速为2mL/min，流动相为MeOH:H2O＝70:30，得到化合物5(5.4mg)、合物6(4.9mg)、化合物7(10.5mg)、8(5.3mg)。
化合物1-8的结构确证及解析如下：
化合物1为红色粉末状，ESIMS m/z:350.1[M-H]-，推测出其分子量为351.0，分子式为C24H21N3。在1H NMR谱中给出14个芳香氢信号δH[7.38(d,J＝8.0Hz, H-7'/7”),7.28(d,J＝8.4Hz,H-4'/4”),7.04(s,H-2'/2”),7.00(m,H-6'/6”),6.90(m, H-6”'),6.88(m,H-3”'),6.83(m,H-5'/5”),6.56(m,H-5”')和6.54(m,H-4”')]，1个次甲基氢信号δH3.43(d,J＝7.2Hz,H-2)，1个亚甲基氢信号δH4.77(t,J＝7.2Hz, H-1)。在13C NMR谱中给出了24个碳信号，包括17个芳香碳信号δC[(146-112.1), C-(3a'/3a”)-C-(7a'/7a”)和(C-1”'-C-6”')]，4个烯烃碳信号δC[123.2(C-2'/2”)和 120.1(C-3'/3”)]，1个次甲基碳信号δC[36.2(C-1)]，1个亚甲基碳信号δC[38.2 (C-2)]，确定化合物1为2-[2-(1H-Indol-2-yl)-2-(1H-indol-3-yl)ethyl]benzenamine。
化合物2为红色粉末状，ESIMS m/z:337.1[M+H]+，推测出其分子量为336.1，分子式为C24H20N2。在1H NMR谱中给出2个氨基氢信号δH[10.93(2H,s,H-1'/1”)， 15个芳香氢信号δH[7.40(d,J＝8.0Hz,H-7'/7”),7.36(d,J＝8.4Hz,H-4'/4”),7.27 (s,H-2'/2”),7.23(m,H-6'/6”),7.17(m,H-6”'),7.05(m,H-3”'/5”'),6.83(m,H-5'/5”), 6.81(m,H-2”'/6”')]，1个次甲基氢信号δH3.44(d,J＝7.6Hz,H-2)，1个亚甲基氢信号δH4.79(t,J＝7.6Hz,H-1)。在13C NMR谱中给出了24个碳信号，包括17 个芳香碳信号δC[(141.4-111.2),C-(3a'/3a”)-C-(7a'/7a”)和(C-1”'-C-6”')]，4个烯烃碳信号δC[122.1(C-2'/2”)和119.8(C-3'/3”)]，1个次甲基碳信号δC36.4(C-1)，1 个亚甲基碳信号δC41.7(C-2)，确定化合物2为3,3'-(2-phenylethylidene)bis-1H- Indole。
化合物3为红色粉末状，ESIMS m/z:323.1[M+H]+，推测出其分子量为322.1，分子式为C23H18N2。在1H NMR谱中给出2个氨基氢信号δH[10.90(2H,s,H-1'/1”)， 15个芳香氢信号δH[7.34(d,J＝8.0Hz,H-7'/7”),7.33(d,J＝8.4Hz,H-4'/4”),7.26 (s,H-2'/2”),7.25(m,H-6'/6”),7.18(m,H-6”'),7.03(m,H-3”'/5”'),6.85(m,H-5'/5”), 6.82(m,H-2”'/6”')]，1个次甲基氢信号δH5.82(s,H-1)。在13C NMR谱中给出了 23个碳信号，包括17个芳香碳信号δC[(144.9-111.4),C-(3a'/3a”)-C-(7a'/7a”)和 (C-1”'-C-6”')]，4个烯烃碳信号δC[123.2(C-2'/2”)和120.1(C-3'/3”)]，1个次甲基碳信号δC39.6(C-1)，确定化合物3为phenyl-2-bis-indolylmethane。
化合物4为棕色粉末状，ESIMS m/z:260.1[M+H]+，推测出其分子量为261.0，分子式为C18H16N2。在1H NMR低场区给出2个活泼氢信号δH7.85(brs,H-1'/1”)，在1H NMR谱中给出1个信号10个芳香氢信号δH[7.57(d,J＝8.0Hz,H-4'/4”), 7.33(d,J＝8.4Hz,H-7'/7”),7.16(t,J＝7.6Hz,H-6'/6”),7.03(t,J＝7.6Hz,H-5'/5”), 6.90(d,J＝2.4Hz,H-2'),一个次甲基氢信号δH4.67(q,J＝7.2Hz,H-1)，一个甲基氢信号δH1.80(d,J＝6.8Hz,H-2)。在13CNMR谱中给出了18个碳信号，包括12个芳香碳信号δC[(136.8-111.2),C-(3a'/3a”)-C-(7a'/7a”)]，四个烯烃碳信号δC [121.8(C-2'/2”)和121.9(C-3'/3”)]，一个次甲基碳信号δC[28.3(C-1)]，一个甲基碳信号δC[21.9(C-2)]，确定化合物4为vibrindole A。
化合物5为白色粉末状固体，ESIMS m/z:211.3[M+H]+，推测出其分子量为 210.0，分子式为C11H18N2O2，不饱和度为4。在1H NMR高场区给出1个氨基氢信号δH7.26(1H,s,8-NH)，4个亚甲基氢信号δH3.35(2H,m,H-3)，2.38(2H,m, H-5)，2.02(2H,m,H-4)和1.75(2H,m,H-10)，3个次甲基氢信号δH4.06(1H,s, H-9)，4.00(1H,m,H-6)和1.48(1H,m,H-11)，以及2个甲基氢信号δH0.97(3H,m, H-12/13)；在13C NMR谱中给出了11个碳信号，包括2个酮羰基碳信号δC[170.3 (C-7),165.5(C-1)]，4个亚甲基碳信号δC[(42.9-22.8),C-3/4/5/10]，3个次甲基碳信号δC[(67.9-36.5),C-6/9/11]，两个甲基碳信号δC[22.4(C-12),21.9(C-13)，确定化合物5为cyclo(L-Pro-L-Leu)。
化合物6为白色粉末状固体，ESIMS m/z:197.2[M+H]+，推测出其分子量为 196.0，分子式为C10H16N2O2。在1H NMR高场区给出1个氨基氢信号δH7.21(1H, s,8-NH)，3个亚甲基氢信号δH3.95(2H,m,H-3)，1.89(2H,m,H-5)，1.83(2H,m, H-4)，3个次甲基氢信号δH4.44(1H,m,H-9)，3.96(1H,m,H-6)，2.75(1H,m,H-10)，以及2个甲基氢信号δH0.96(3H,m,H-11)和0.95(3H,m,H-12)；在13C NMR谱中给出了10个碳信号，包括2个酮羰基碳信号δC[173.1(C-7)和168.3(C-1)]，3 个亚甲基碳信号δC[(45.6-23.9),C-4/5/6]，3个次甲基碳信号δC[(69.1-34.9), C-6/9/10]，2个甲基碳信号δC[14.9(C-11)和12.2(C-12)]，确定化合物6为 cyclo-(L-Val-L-Pro)。
化合物7为无色油状液体，ESIMS m/z:167.2[M+H]+，推测出其分子量为 166.0，分子式为C9H10O3。在1H NMR高场区给出4个芳香氢信号δH7.02(2H,d, J＝8.4Hz,H-3/H-5)，6.70(2H,d,J＝8.4Hz,H-2/H-6)，2个亚甲基氢信号δH2.73 (2H,t,J＝7.6Hz,H-1’)和2.51(2H,t,J＝7.6Hz,H-2’)；在13C NMR谱中给出了 9个碳信号，包括1个羰基碳信号δC177.1(C-3')，6个芳香碳信号δC[(156.6-116.1), C-1/2/3/4/5/6]，2个亚甲基碳信号δC[37.1(C-2')和31.2(C-1')，确定化合物7为 4-hydroxy-benzenepropanoic acid。
化合物8为黄色油状液体，ESIMS m/z:201.4[M+H]+，推测出其分子量为 200.0，分子式为C13H20O。在1H NMR高场区给出1个羟基氢信号δH4.80(1H,s, H-1)，1个次甲基氢信号δH1.62(1H,m,H-12)，10个亚甲基氢信号δH[(1.21-3.21), H-(2-11)]，2个甲基氢信号δH(0.77s,H-13)和δH(0.79s,H-14)；在13C NMR谱中给出了13个碳信号，包括1个次甲基碳信号δC28.1(C-12)，10个亚甲基碳信号δC[(62.8-29.6),C-(2-11)]，2个甲基碳信号δC[26.2(C-13)和23.0(C-14)，确定化合物8为11-methyldodecanol。
实施例2活性初筛
采用滤纸片和MTT法分别粗提物的抑菌活性及细胞毒活性，初筛结果显示，在200μg/mL的浓度下，粗提物对金黄色葡萄球菌、HTC116细胞显示出一定的抑制活性。
实施例3
(1)抗菌活性测试
通过微孔板测定法评估了化合物1-8对8种病原菌：金黄色葡萄球菌、大肠杆菌、表皮葡萄球菌、哈维氏弧菌、溶藻弧菌、副溶血弧菌、铜绿假单胞菌和青枯菌的抗菌活性。以含病原菌的肉汤培养基为空白组，DMSO为阴性对照，环丙沙星和链霉素为阳性对照。
(2)细胞毒活性测试
通过MTT方法，测试细胞毒活性，细胞株选自A549,Hela,HTC116, NCI-1650,RKO,MCF-7，NCM460。样品浓度配置为20、10、5、2.5、1.25和 0.625μg/mL 6个梯度，实验重复3次以上，实验数据用全波长酶标仪测试(测试波长为492nm).DMSO为阴性对照，盐酸阿霉素为阳性对照，每个样品的抑制率按下式计算：抑制率＝[(ODcompound-ODDMSO)/ODDMSO]×100％，使用GraphPad Prism软件计算出IC50值。
结果表明，化合物3对金黄色葡萄球菌、表皮葡萄球菌、青枯菌的MIC分别为3.125、12.5、50μg/mL；化合物4对金黄色葡萄球菌的MIC为12.5μg/mL；化合物3对HTC116细胞株的IC50为8.42±0.48μM。
Claims (8)
1.一种抗菌、细胞毒活性粗提物，其特征在于所述粗提物由如下方法制备：
(1)将Bacillus sp.HNU24接入LB发酵培养基中，28～30℃静置培养7天得发酵物；
(2)步骤(1)得到的发酵物用等体积的乙酸乙酯萃取2～4次，合并萃取液后减压浓缩即得粗提物。
2.一种由Bacillus sp.HNU24同时制备化合物1-8的方法，其特征在于包括如下步骤：
将权利要求1步骤(2)得到的粗提物经过减压硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为90:10、80:20、70:30、60:40、50:50、40:60、30:70、20:80、10:90、0:100，每个梯度收集两个柱体积，依次得到10个组分A-J，其中梯度80:20洗脱得到的为组分B，梯度70:30洗脱得到的为组分C；
组分B浓缩后，采用正相硅胶柱层析，采用石油醚-乙酸乙酯作为洗脱剂进行梯度洗脱，洗脱梯度分别为：9:1、8:1、7:1、6:1、5:1、4:1、3:1、7:3，每个梯度收集两个柱体积，根据极性大小分成7个组分，其中梯度9:1洗脱得到的为组分1，梯度8:1洗脱得到的为组分2，梯度7:1洗脱得到的为组分3，梯度6:1洗脱得到的为组分4，梯度5:1洗脱得到的为组分5，梯度4:1洗脱得到的为组分6，梯度3:1和7:3洗脱得到的为组分7；其中组分2经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250 mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝65:35，得到化合物1、2；组分4经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝60:40，得到化合物3和4；
组分C浓缩后，经Sephadex LH-20凝胶柱层析，洗脱剂为CHCl3：MeOH＝1:1，再经高效液相色谱HPLC制备，色谱柱为Waters C18，9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H2O＝70:30，得到化合物5、6、7、8；
所述化合物1-8结构如下：
3.Bacillus sp.HNU24在制备抗菌、细胞毒活性粗提物中的应用。
4.Bacillus sp.HNU24在同时制备化合物1-8中的应用。
5.权利要求1所述的粗提物、权利要求2制备的化合物1-8或其药学上可接受的盐在制备抗菌药物和/抗肿瘤药物中的应用。
6.一种药物组合物，其特征在于该药物组合物以权利要求1所述的粗提物、权利要求2制备的化合物1-8或其药学上可接受的盐作为有效成分。
7.权利要求6所述的药物组合物，其特征在于该药物组合物还可包括其他抗菌剂或抗肿瘤化合物。该药物组合物还可包括药学上可接的辅料。该药物组合物的剂型优选固体制剂或液体制剂等。
8.权利要求1-4任一项所述的Bacillus sp.HNU24，其特征在于其菌种保藏信息如下：保藏单位名称：广东省微生物菌种保藏中心；保藏单位地址：广州市先烈中路100号大院59号楼5楼，广东省科学院微生物研究所；保藏日期：2020年10月15日；保藏编号：GDMCCNo.61231；分类命名：Bacillus sp.。
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| CN114181865A (zh) * | 2021-12-21 | 2022-03-15 | 海南师范大学 | 一种对茄雷尔氏菌有高效拮抗作用的芽孢菌及其应用 |
| CN117683697A (zh) * | 2024-02-01 | 2024-03-12 | 临沂大学 | 一株贝莱斯芽孢杆菌y01及其在抑菌和提高动物生长性能中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114181865A (zh) * | 2021-12-21 | 2022-03-15 | 海南师范大学 | 一种对茄雷尔氏菌有高效拮抗作用的芽孢菌及其应用 |
| CN117683697A (zh) * | 2024-02-01 | 2024-03-12 | 临沂大学 | 一株贝莱斯芽孢杆菌y01及其在抑菌和提高动物生长性能中的应用 |
| CN117683697B (zh) * | 2024-02-01 | 2024-04-19 | 临沂大学 | 一株贝莱斯芽孢杆菌y01及其在抑菌和提高动物生长性能中的应用 |
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