CN116966271A - 多黏菌素e联合5-氟胞嘧啶核苷在制备用于抑制革兰氏阴性菌药物中的应用 - Google Patents
多黏菌素e联合5-氟胞嘧啶核苷在制备用于抑制革兰氏阴性菌药物中的应用 Download PDFInfo
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- 229940124350 antibacterial drug Drugs 0.000 abstract description 2
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Abstract
本发明涉及医药技术领域,提供了多黏菌素E联合5‑氟胞嘧啶核苷在制备用于抑制革兰氏阴性菌药物中的应用,限定了5‑氟胞嘧啶核苷的浓度为4~64μg/mL;所述多黏菌素E的浓度为0.25~2μg/mL。本发明提供了5‑氟胞嘧啶核苷联合多黏菌素E在制备抑制mcr阳性细菌的药物中的应用,5‑氟胞嘧啶核苷能够协同多黏菌素发挥抗菌作用,并逆转耐药菌对多黏菌素的耐药性,在降低抗菌药物使用量的同时,实现杀灭细菌的效果。
Description
技术领域
本发明涉及医药技术领域,尤其涉及多黏菌素E联合5-氟胞嘧啶核苷在制备用于抑菌的药物中的应用。
背景技术
多黏菌素(polymyxin/colistin)属聚阳离子抗菌肽,对大多数革兰阴性菌有较强较快的杀菌作用。多黏菌素抗菌机理是:其能与革兰阴性菌细胞膜中带负电荷的LPS结合,造成细菌细胞膜通透性改变,导致细菌核酸、氨基酸等重要物质外漏,从而抑制细菌生长并导致细菌死亡。近年来,随着细菌耐药性形式日益严峻,多黏菌素成为临床治疗多重耐药革兰阴性杆菌感染的“最后一道防线”之一。
2015年底我国学者首次报道了从人和动物分离的大肠埃希菌中分离到质粒介导的多黏菌素耐药基因mcr-1,随后在越来越多的CRE菌株中检出mcr基因。目前发现mcr-1基因主要存在于大肠杆菌的IncI2、IncX4及IncHI2型质粒上,且已在全球6大洲超过60个国家广泛流行。mcr的出现及广泛流行严重威胁了多黏菌素的临床应用。因此,急需找到多黏菌素增效剂,使细菌恢复对多黏菌素敏感性的方法。
5-氟胞嘧啶核苷是一种核酸类似物,但截至目前,国内外未见5-氟胞嘧啶核苷联合多黏菌素在制备抑制mcr阳性细菌的药物中的应用
发明内容
本发明的目的在于提供多黏菌素E联合5-氟胞嘧啶核苷在制备抑制革兰氏阴性菌药物中的应用,增加革兰氏阴性菌对多黏菌素E的敏感性,通过联合用药减少多黏菌素E和5-氟胞嘧啶核苷的使用量。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了多黏菌素E联合5-氟胞嘧啶核苷在制备抑制革兰氏阴性菌药物中的应用。
优选的,所述革兰氏阴性菌为耐多黏菌素E的革兰氏阴性菌。
优选的,所述耐多黏菌素E的革兰氏阴性菌为mcr-1阳性大肠杆菌。
本发明还提供了一种应用于抑制革兰氏阴性菌的药物,所述药物包含5-氟胞嘧啶核苷和多黏菌素E。
优选的,所述5-氟胞嘧啶核苷的浓度为为4~64μg/mL;所述多黏菌素E的最低浓度为0.25~2μg/mL。
本发明提供了5-氟胞嘧啶核苷联合多黏菌素E在制备抑制mcr-1阳性细菌的药物中的应用,本发明通过棋盘法验证5-氟胞嘧啶核苷与多黏菌素E联用后能恢复多黏菌素E对mcr-1阳性大肠杆菌的作用,并逆转耐药菌对多黏菌素的耐药性,在降低抗菌药物使用量的同时,实现杀灭细菌的效果。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据提供的附图获得其他的附图。
图1为实施例1中5-氟胞嘧啶核苷联合多黏菌素E对mcr-1阳性大肠杆菌的棋盘法最小抑菌浓度。
具体实施方式
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
1、试验药物
多黏菌素E:有效含量98%,购于北京偶合科技有限公司;
5-氟胞嘧啶核苷:有效含量99.19%,购于上海陶术生物科技有限公司;
多黏菌素E用去离子水配置成初始浓度2560μg/mL的储存液,稀释后的药物使用无菌注射器和高压灭菌后的0.22μm滤膜进行过滤后于-80℃备用;
5-氟胞嘧啶核苷用去离子水配置成初始浓度1280μg/mL的储存液,于-80℃备用。
2、培养基
试验所用培养基包括:MH肉汤培养基、MH琼脂培养基、LB肉汤培养基、LB琼脂培养基;均购于北京陆桥技术股份有限公司;
固体培养基(MH琼脂培养基和LB琼脂培养基)的配制(500mL体系):称取19g MH琼脂培养基或20g LB琼脂培养基加入约500mL的蒸馏水,混合均匀;高压蒸汽灭菌121℃,20min,放置冷却至50℃左右,按需加入药品,倒平板后冷却晾干;
液体培养基(MH肉汤培养基和LB肉汤培养基)的配制(500mL体系):称取25g MH肉汤培养基或25g LB肉汤培养基加入约500mL的蒸馏水,混合均匀;高压蒸汽灭菌121℃,20min,放置冷却备用。
3、仪器
电子分析天平(德国Satrorius);
自动立式压力蒸汽灭菌器(日本三洋公司);
恒温振荡培养箱(上海华岩仪器设备有限公司);
单道微量可调加样器(德国Eppendorf公司);
多道可调微量加样器(德国Eppendorf公司);
超低温冰箱(德国Thermo Scientific Inc);
0.22μm滤器(美国Pall公司);
超净工作台(苏州净化设备有限公司)。
4、实验菌株
临床分离的多黏菌素E耐药株大肠杆菌ZJ807,mcr-1阳性(详情见发明人前一专利,专利公布号为CN 114869999 A)。
实施例1
采用棋盘法检测5-氟胞嘧啶核苷联合多黏菌素E对mcr-1阳性大肠杆菌ZJ807的最小抑菌浓度
根据CLSIM27-A3药敏试验标准采用棋盘法检测5-氟胞嘧啶核苷单用、多黏菌素E单用和“5-氟胞嘧啶核苷和多黏菌素E联用”对多黏菌素E耐药菌(mcr-1阳性大肠杆菌ZJ807)的抑菌活性,进而获得对多黏菌素E耐药菌的最小抑菌浓度。具体步骤如下:
1、取生长至对数生长期的mcr-1阳性大肠杆菌ZJ807菌液,用麦氏比浊仪调节至麦氏0.5,之后用MH肉汤培养基稀释100倍,得到mcr-1阳性大肠杆菌ZJ807稀释液。mcr-1阳性大肠杆菌ZJ807稀释液中,mcr-1阳性大肠杆菌ZJ807的浓度约为1×106CFU/mL。
2、取96孔微孔板,每孔接种100μLmcr-1阳性大肠杆菌ZJ807稀释液和100μL药物溶液(由多黏菌素E储存液和5-氟胞嘧啶核苷储存液混合而成及5-氟胞嘧啶核苷储存液单用、多黏菌素E储存液单用)。
3、于96孔无菌微孔板内按棋盘法(如图1所示)进行5-氟胞嘧啶核苷储存液单用、多黏菌素E储存液单用及二者联用抗mcr-1阳性大肠杆菌的抑菌活性实验;
4、取步骤3中96孔微孔板,37℃孵育17h;
5、计算每孔的MIC值,进一步计算联合抑菌分数FIC。
评价方法与结果判读
FIC=MIC(多黏菌素E联合)/MIC(多黏菌素E单用)+MIC(5-氟胞嘧啶核苷联合)/MIC(5-氟胞嘧啶核苷单用)
结果如表1所示:
表1多黏菌素E与5-氟胞嘧啶核苷单用及二者联用的最低抑菌浓度及联合作用指数
可以看出5-氟胞嘧啶核苷与多黏菌素E联用能够降低多黏菌素E对mcr-1阳性大肠杆菌的MIC值8倍。因此,不同浓度的5-氟胞嘧啶核苷均显著降低了mcr-1阳性大肠杆菌ZJ807对多黏菌素E的MIC值,使得大部分菌株的多黏菌素E的MIC值低于敏感值(2μg/mL);
FIC指数的判断标准为:FIC指数≤0.5为协同作用;0.5~1为相加作用;1~2为无关作用;≥2为拮抗作用。通过表1的记载可以看出FIC的指数为0.156,小于0.5,所以,本发明对于5-氟胞嘧啶核苷和多黏菌素E的协同作用好。因此可以治疗mcr-1阳性大肠杆菌ZJ807引发的感染。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.多黏菌素E联合5-氟胞嘧啶核苷在制备抑制革兰氏阴性菌药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述革兰氏阴性菌为耐多黏菌素E的革兰氏阴性菌。
3.如权利要求2所述的应用,其特征在于,所述耐多黏菌素E的革兰氏阴性菌为mcr-1阳性大肠杆菌。
4.一种权利要求1~3任一项所述的应用中的药物,其特征在于,所述药物包含5-氟胞嘧啶核苷和多黏菌素E。
5.如权利要求4所述的药物,其特征在于,所述5-氟胞嘧啶核苷的浓度为为4~64μg/mL;所述多黏菌素E的最低浓度为0.25~2μg/mL。
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