CN105476983B - 一种深海真菌来源化合物Prenylcandidusin C的用途 - Google Patents
一种深海真菌来源化合物Prenylcandidusin C的用途 Download PDFInfo
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Abstract
本发明公开了一种深海真菌来源化合物Prenylcandidusin C的用途。具体为抗菌的用途,比如能抑制超级细菌‑耐甲氧西林金黄色葡萄球菌的生长。所述深海真菌来源化合物Prenylcandidusin C可用于制备抗菌药物。
Description
技术领域
本发明涉及化合物抗菌领域,尤其涉及化合物Prenylcandidusin C的抗菌用途。
背景技术
海洋微生物具有极为丰富的生物多样性及功能多样性,由于其特殊的生存环境,在适应环境的进化过程中形成了独特的遗传代谢机制和化学防御机制,是目前新结构或新活性天然产物的主要来源。近年来,加强海洋微生物的活性筛选,寻找高效低毒的抗菌药物,直接用于临床或作为先导化合物进行结构修饰,已经成为海洋抗菌药物研究的发展趋势。另外,海洋微生物具有可规模化获取、环境友好、应用成本低等特点,其开发应用前景已获得国际共识。
金黄色葡萄球菌是临床上常见的毒性较强的细菌,自从上世纪40年代青霉素问世后,由金黄色葡萄球菌引起的感染性疾病受到了很大程度上的控制。但随着青霉素的广泛使用,有些金黄色葡萄球菌能够产生青霉素酶,水解β-内酰胺环,表现为对青霉素的耐药性。虽然科学家研究出了一种新的能耐青霉素酶的半合成青霉素,即甲氧西林(methicillin),1959年应用于临床后曾有效地控制了金黄色葡萄球菌青霉素酶产酶株的感染,但英国的Jevons于1961年就首次发现了耐甲氧西林金黄色葡萄球菌(MRSA),MRSA从发现至今感染已经几乎遍及全球,成为院内和社区感染的重要病原菌之一。
耐甲氧西林金黄色葡萄球菌(MRSA)是一种超级细菌,它能在人身上造成脓疮和毒疱,甚至逐渐使人的肌肉组织坏死。这种病菌的可怕之处并不在于它对人的杀伤力,而是它对普通杀菌药物——抗生素的抵抗能力。对于这种病菌,人们几乎无药可用。2010年,英国媒体爆出:南亚发现新型超级病菌NDM-1,抗药性极强可全球蔓延。
发明内容
本发明的目的在于提供化合物Prenylcandidusin C具有抗耐甲氧西林金黄色葡萄球菌的新用途。
为实现上述目的,本发明提供一种化合物Prenylcandidusin C或其药用盐在制备抗菌药物中的用途。所述化合物Prenylcandidusin C的化学结构式见图1所示。
进一步,所述菌是细菌。
进一步,所述菌是耐甲氧西林金黄色葡萄球菌。
进一步,所述用途是指能抑制耐甲氧西林金黄色葡萄球菌的生长。
进一步,所述最低抗菌浓度为3.125μg/mL。
进一步,该抗菌药物为片剂、丸剂、胶囊剂、颗粒剂、溶液剂、混悬剂或乳剂。
本发明的化合物Prenylcandidusin C是从海洋真菌亮白曲霉Aspergilluscandidus的乙酸乙酯提取物中分离得到的。其化学结构采用核磁共振技术和高分辨质谱技术进行鉴定结果见表1,并且与现有文献报道的化合物Prenylcandidusin C进行图谱比对,确认是同一种物质。结构见图1。最终确定其CAS号为1297472-20-8;分子式为C26H26O6,分子量为434.17294。参考文献:Cai,S.;Sun,S.;Zhou,H.;Kong,X.;Zhu,T.;Li,D.;Gu,Q.,Prenylated Polyhydroxy-p-terphenyls from Aspergillus taichungensis ZHN-7-07.Journal of natural products 2011,74,(5),1106-10.
表1.Prenylcandidusin C的1H和13C NMR数据表
位点 | δH(J=Hz) | δC |
1 | 114.68 | |
2 | 7.39,s | 106.9 |
3 | 143.54 | |
3-OH | 9.07,brs | |
4 | 147.97 | |
5 | 7.38,s | 96.15 |
6 | 149.25 | |
4-OCH3 | 3.87,s | 56.04 |
1' | 113.69 | |
2' | 148.66 | |
3' | 135.92 | |
4' | 131.4 | |
5' | 6.70,s | 105.6 |
6' | 149.52 | |
3'-OCH3 | 3.78,s | 60.56 |
6'-OCH3 | 3.97,s | 55.86 |
1” | 128.58 | |
2” | 7.28,d(1.9) | 130.35 |
3” | 127.09 | |
4” | 154.38 | |
4”-OH | 9.49,brs | |
5” | 6.87,d(8.6) | 114.54 |
6” | 7.24,dd(8.2,2.3) | 127.58 |
1”' | 3.28,d(7.3) | 28.16 |
2”' | 5.34,t(6.9) | 122.92 |
3”' | 131.2 | |
4”' | 1.69,s | 25.59 |
5”' | 1.69,s | 17.69 |
本发明的化合物Prenylcandidusin C也可以通过化学合成方法制备得到。
从实施例可以看出,本发明的化合物Prenylcandidusin C能够有效抑制耐甲氧西林金黄色葡萄球菌的生长。
本发明所述的化合物Prenylcandidusin C可以抗菌,包括但不限于,球菌、杆菌和螺旋菌。具体可以是,大肠杆菌,链球菌或葡萄球菌等等。
附图说明
图1是本发明化合物Prenylcandidusin C的结构式。
图2是实施例2抗菌实验的结果图。
具体实施方式
下面详细描述本发明的实施例,所述实施例的示例在附图中示出,其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市场采购获得的常规产品。
实施例1:化合物Prenylcandidusin C的制备与鉴定
菌种的准备:使用海水PDA培养基,高温灭菌,制成平板,置于常温状态下,接种曲霉Aspergillus candidus(可从中国海洋微生物菌种保藏管理中心购买得到,保藏编号:MCCC 3A00245)菌丝体,28℃下静置培养4-5天,作为菌种;所述海水PDA培养基成分为马铃薯200g,葡萄糖20g,琼脂15-20g,1L海水;
发酵种子液制备:在多个锥形瓶中分别装入海水PDA液体培养基,高温灭菌后,接种上述菌种,28℃下以180rpm/min振荡培养2-3天,将该培养物作为种子液;
接种:采用固体发酵方式,准备发酵瓶,加入大米固体发酵培养基,高温灭菌,接种上述种子液,28℃培养箱放置28天;所述大米固体发酵培养基为每1L的三角锥瓶装大米105g,小黄米45g;
萃取:待真菌发酵成熟后(本实施例培养28天),加入乙酸乙酯500mL/瓶浸泡发酵产物,发酵产物溶入乙醇溶液中,浸泡后,将上层乙醇溶液倒出,下层为固体发酵产物;加入新的乙酸乙酯500mL/瓶,此步骤反复3次,每次浸泡常温过夜,如此制备得到乙酸乙酯初提液;以乙酸乙酯为溶剂,采用高压乳化切割机分散提取下层的固体发酵产物,得到胞内提取物,然后与乙酸乙酯初提液合并,用旋转蒸发仪浓缩至固态,即得到初级浸膏;
分离:将初级浸膏悬浮于水中,依次用石油醚、乙酸乙酯萃取,将乙酸乙酯萃取液浓缩后,经硅胶柱层析,以氯仿-甲醇为洗脱剂,从体积比95:5-10:90进行梯度洗脱,其中梯度洗脱下来的组分在薄层层析中能用氯仿-丙酮比为4:1溶液系统展开的组分,再经Sephadex LH-20柱子纯化,用氯仿-丙酮体积比为1:1的溶液体系洗脱,洗脱液以12ml为一管,收集10管,编号1-10,挑取编号为6-10的管合并,浓缩至干后得到黄色粉末状化合物Prenylcandidusin C。
将所得采用核磁共振技术和高分辨质谱技术进行鉴定,结果见表1,并且与现有文献报道的化合物Prenylcandidusin C进行图谱比对,确认是同一种物质,结构见图1。最终确定其CAS号为1297472-20-8;分子式为C26H26O6,分子量为434.17294。参考文献:Cai,S.;Sun,S.;Zhou,H.;Kong,X.;Zhu,T.;Li,D.;Gu,Q.,Prenylated Polyhydroxy-p-terphenylsfrom Aspergillus taichungensis ZHN-7-07.Journal of natural products 2011,74,(5),1106-10.
实施例2:抗菌活性实验
采用刃天青显色法作为检测活性的方法。刃天青显色法的原理是:活细胞中的乳酸脱氢酶能将刃天青(蓝色)转化为荧光物质试卤灵(粉红红色),产生荧光信号。试卤灵会继续被细胞还原为无荧光的物质二氢试卤灵(白色),使荧光信号下降,无活性的或死亡的细胞丧失了代谢能力而不能还原刃天青,也就不能产生荧光信号,所以该法能特异性检测活性细胞。
抑菌实验采用96孔板操作,96孔中颜色呈蓝色,则代表样品对目标菌株有抑制活性;96孔中颜色呈粉红色或红色,则代表样品对目标菌株没有抑制活性。
目标菌株菌悬液制备:取抗甲氧西林金黄色葡萄球菌(商购来源:ATCC,保藏编号:43300)以10体积%接种于5mLMHB培养液(厂商:北京拜尔迪生物技术有限公司,货号:CM0405)中,于37℃180rpm/min振荡培养6到8小时后,用酶标仪测OD值(OD600=0.08,可近似看成菌悬液浓度为108CFU/mL,以MHB培养液稀释菌悬液浓度到105CFU/mL(菌落数/毫升)。
刃天青溶液:用无菌水配置5000μg/mL的刃天青(商购来源:国药化学试剂有限公司,货号:71035931)溶液。
抗菌实验在96微孔板进行,化合物以DMSO溶解,梯度稀释,同时设化合物阴性对照,溶剂阴性对照,阳性对照和空白对照,每个实验浓度和所有对照均重复3次。抗菌实验及MIC(最低抑制浓度)的测定参考文献Wibowo,A.;Ahmat,N.;Hamzah,A.S.;Low,A.L.;Mohamad,S.A.;Khong,H.Y.;Sufian,A.S.;Manshoor,N.;Takayama,H.,Malaysianol B,anoligostilbenoid derivative from Dryobalanops lanceolata.Fitoterapia 2012,83,1569-75。
实验组(见图2):
A1-C1:化合物溶液(2000μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A2-C2:化合物溶液(1000μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A3-C3:化合物溶液(500μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A4-C4:化合物溶液(250μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A5-C5:化合物溶液(125μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A6-C6:化合物溶液(62.5μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A7-C7:化合物溶液(31.25μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
A8-C8:化合物溶液(15.63μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
化合物阴性对照组G1-G3:DMSO 5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
阳性对照组G10-G12:氯霉素溶液(2000μg/mL)5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
溶剂阴性对照组H1-H3:MHB培养液5μL+菌悬液(ATCC 43300)175.5μL+刃天青溶液19.5μL;
空白对照组H10-12:DMSO 5μL+MHB培养液175.5μL+刃天青溶液19.5μL。
试验结果见图2。从图2可以看出,化合物阴性对照G1-G3为红色,溶剂阴性对照H1-H3为红色;化合物阳性对照G10-G12为蓝色,溶剂阳性对照H10-H12为蓝色,说明阴阳性试验结果正确,没有污染;A1-C1为蓝色,A2-C2为蓝色,A3-C3为蓝色,A4-C4为蓝色,A5-C5为蓝色,A6-C6为红色,A7-C7为红色,A8-C8为红色,说明当本化合物溶液浓度从50μg/mL降到3.125μg/mL,均具有抗菌效果,当浓度为1.562μg/mL甚至更低时,则完全失去了抗菌效果。
综上可知,化合物IUE-1799a对MRSA(ATCC 43300)的最低抑菌浓度为3.125μg/mL。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (3)
1.化合物Prenylcandidusin C或其药用盐在制备抗菌药物中的用途,其特征在于,所述抗菌药物中的菌是耐甲氧西林金黄色葡萄球菌。
2.权利要求1的用途,其特征在于,所述最低抗菌浓度为3.125μg/mL。
3.权利要求1的用途,其特征在于,所述抗菌药物为片剂、丸剂、胶囊剂、颗粒剂、溶液剂、混悬剂或乳剂。
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