CN118021802A - 化合物0683-0042作为ndm-1抑制剂在抗菌中的应用 - Google Patents
化合物0683-0042作为ndm-1抑制剂在抗菌中的应用 Download PDFInfo
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Abstract
本发明公开了化合物0683‑0042作为NDM‑1抑制剂在抗菌中的应用，属于微生物传染病及医药领域。本发明发现了化合物0683‑0042具有抑制NDM‑1酶活的作用，将化合物0683‑0042与美罗培南联用对含NDM‑1酶的耐药细菌有明显的杀菌效果。本发明提供了化合物0683‑0042与美罗培南联用在制备含NDM‑1细菌的抗菌药物或预防和/或治含NDM‑1细菌感染的药物中的应用。本发明将化合物0683‑0042与美罗培南联用，提高了含有NDM‑1细菌的治疗效果，降低了临床用药的压力。
Description
技术领域
本发明属于微生物传染病及医药领域，具体涉及化合物0683-0042作为NDM-1抑制剂在抗菌中的应用。
背景技术
在当前医学环境中，由携带新德里金属-β-内酰胺酶-1(NDM-1)的大肠杆菌感染已成为全球性挑战，因其对传统抗生素耐药性的增加，临床治疗选择变得异常困难。传统的全菌抑制筛选忽略了菌株特差异而缺乏特异性，并且不能确定具体药物靶点，这种情况促使了针对NDM-1酶活性的抑制剂的研究。而基于药物靶标所进行的计算机虚拟筛选能够快速、精确地找到具有潜力的候选化合物，为药物研发提供了高效的方法和策略。
发明内容
本发明发现了化合物0683-0042具有抑制NDM-1酶活的作用，将化合物0683-0042与美罗培南联用对含NDM-1酶的耐药细菌有明显的杀菌效果。
本发明的目的在于提供化合物0683-0042的应用，即提供化合物0683-0042作为NDM-1抑制剂在抗菌中的应用。
本发明的目的通过下述技术方案实现：
化合物0683-0042或其药学上可接受的盐作为NDM-1抑制剂的应用。
所述的化合物0683-0042的结构如下所示：
化合物0683-0042或其药学上可接受的盐在制备NDM-1抑制剂中的应用。
化合物0683-0042或其药学上可接受的盐在制备抗菌药物中的应用，所述的抗菌为抗含有NDM-1的细菌。
化合物0683-0042或其药学上可接受的盐在制备预防和/或治疗含有NDM-1的细菌感染的药物中的应用。
化合物0683-0042或其药学上可接受的盐与美罗培南在制备抗菌药物中的应用，所述的抗菌为抗含有NDM-1的细菌。
化合物0683-0042或其药学上可接受的盐与美罗培南在制备预防和/或治含有NDM-1的细菌感染的药物中的应用。
一种药物，其包含化合物0683-0042或其药学上可接受的盐，或包含化合物0683-0042或其药学上可接受的盐与美罗培南，还可进一步包含药学上可接受的载体或赋形剂。
本发明具有如下优点和有益效果：
(1)本发明发现了化合物0683-0042新的药用价值，为含NDM-1的细菌如耐药性大肠杆菌感染提供了新的防治药物。
(2)化合物0683-0042可以中和NDM-1的活性，缓解含有NDM-1细菌的耐药性。
(3)化合物0683-0042通过与美罗培南的联合作用，为治疗含NDM-1细菌感染提供一种新的、更有效的治疗选择，降低了临床用药的压力，减轻了传统抗生素治疗效果下降所带来的负面影响。
附图说明
图1是化合物0683-0042与NDM-1结合的分子模拟图。
图2是化合物0683-0042与NDM-1结合的SPR图。
图3是化合物0683-0042对NDM-1酶活的抑制曲线图。
图4是美罗培南和0683-0042单独或联合对含有NDM-1大肠杆菌ATCC25922(NDM-1)的时间-杀菌曲线测定。
图5是不同分组小鼠存活率结果。
具体实施方式
以下实施例用于进一步说明本发明，但不应理解为对本发明的限制。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
下述实施例中所用到的化合物0683-0042购自美国ChemDive公司，所用到的大肠杆菌ATCC25922(NDM-1)是在ATCC25922中转入了以pET-28a为载体能表达NDM-1基因的重组质粒。实施例结果统计分析采用双尾非配对t检验，*：P<0.05，**：P<0.01，***：P<0.001，****：P<0.0001。
实施例1
从RCSB数据库获取蛋白质NDM-1(Gene ID：69464970)，将NDM-1与0683-0042对接。对接通过软件MOE完成，对NDM-1进行对接预处理，包括质子化、去掉溶剂水、能量最小化等过程。对接结果包含30种不同的对接构象，此处仅展示结合力最强的对接构象。对接结果(图1)显示0449-0141结合在Lys216、Ala215、Ser217、Ala74、Ala72、Val73、Lys211、Leu218、Asn220、Gly219、His189、Phe70、Met67、His250、His122、Trp93、Asp124、Gln123、Asp223形成的疏水口袋中。
实施例2
实验使用CM5传感器芯片在BIAcore T200上进行，并按照制造商的说明使用BIAcore T200评估软件(GE Healthcare)分析数据。用200μM 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)和50μM N-羟基琥珀酰亚胺(NHS)的混合液以10μL/min激活CM5传感器芯片10分钟，然后固定20μL NDM-1蛋白(1mg/mL)。将0683-0042储备液(10mM，溶于DMSO中)用PBS稀释至一系列浓度，并在每次运行中以30μL/min流动150秒。每次流动结束时，使用10mM甘氨酸-HCl(pH 2.0)溶液以10μL/min再生芯片5min，使用BIAcore T200控制软件(v.2.0，GE Healthcare)收集样品电池的数据，并减去参考电池的数据。使用BIAcore T200评估软件(v.2.0，GE Healthcare)将数据全局拟合到1:1Langmuir结合模型(图2)，测出小分子0683-0042和NDM-1的亲和力为24.6μM，属于较强的结合。
实施例3
将0683-0042溶解在含有0.05％ Tween-20的50mM HEPES(pH＝7.4)中配制成不同浓度0683-0042的溶液。将NDM-1蛋白溶解在含有0.05％ Tween-20、10μM ZnSO4的50mMHEPES(pH＝7.4)中。NDM-1蛋白溶液与不同浓度的0683-0042溶液在30℃下预孵育20分钟。通过将亚胺培南添加到NDM-1和0683-0042的混合液中来启动测定，体系中NDM-1终浓度为1nM，亚胺培南为100μM，以及10种不同终浓度的0683-0042(0、10、20、30、40、50、60、70、80、90μM)。将反应溶液加到96孔板中在30℃下孵育30分钟，采用酶标仪监测300nm波长吸光度的变化。通过将亚胺培南上的残留酶活性(％)与0683-0042浓度作图获得酶活抑制曲线，结果见图3。
实施例4
将过夜培养的大肠杆菌ATCC25922(NDM-1)进行转接活化，生长至对数中期以后用新鲜的MH肉汤调节菌量至108CFU/mL左右，分别添加32μg/mL美罗培南、10μg/mL 0683-0042或二者联合(32μg/mL美罗培南+10μg/mL 0683-0042)，通过细菌计数评估其12h杀菌效果，以未添加药物的细菌组菌量作为对照。时间杀菌曲线结果见图4，单独使用美罗培南时可以在12个小时杀灭4个对数的细菌，而与0683-0042联用可以在12h杀灭8个对数即全部的细菌。
实施例5
下述实验所用小鼠为七周龄雌性KM小鼠，购自华联科生物公司。动物实验符合动物伦理，所有实验均在华联科动物实验保护监督控制委员会(HLK-20231212-001)指导下进行。
小鼠随机分成美罗培南治疗组、美罗培南+0683-0042治疗组、大肠杆菌ATCC25922(NDM-1)感染组和PBS组四组，每组10只。将过夜培养的大肠杆菌ATCC25922(NDM-1)按体积比1:100转入LB培养基中，37℃培养至OD600为0.5左右。4℃4000r/min离心5min后收集菌体，用PBS重悬混匀待用。美罗培南治疗组、美罗培南+0683-0042治疗组、大肠杆菌ATCC25922(NDM-1)感染组，每只小鼠注射2.5×107CFU的菌量。感染2小时后，美罗培南治疗组小鼠腹腔注射美罗培南，给药剂量为5mg/kg；美罗培南+0683-0042治疗组小鼠腹腔注射美罗培南、0683-0042，给药剂量为2.5mg/kg美罗培南+2.5mg/kg 0683-0042，间隔12小时给药一次，连续治疗三天。PBS组注射同体积的PBS。根据实验结果构建的小鼠生存曲线如图5所示，美罗培南单用存活率为20％，但美罗培南+0683-0042治疗组的小鼠存活率达到90％。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (8)
1.化合物0683-0042或其药学上可接受的盐作为NDM-1抑制剂的应用，其特征在于：所述的化合物0683-0042的结构如下所示：
2.化合物0683-0042或其药学上可接受的盐在制备NDM-1抑制剂中的应用，其特征在于：所述的化合物0683-0042的结构如下所示：
3.化合物0683-0042或其药学上可接受的盐在制备抗菌药物中的应用，其特征在于：所述的抗菌为抗含有NDM-1的细菌；所述的化合物0683-0042的结构如下所示：
4.化合物0683-0042或其药学上可接受的盐在制备预防和/或治疗含有NDM-1的细菌感染的药物中的应用，其特征在于：所述的化合物0683-0042的结构如下所示：
5.化合物0683-0042或其药学上可接受的盐与美罗培南在制备抗菌药物中的应用，其特征在于：所述的抗菌为抗含有NDM-1的细菌；所述的化合物0683-0042的结构如下所示：
6.化合物0683-0042或其药学上可接受的盐与美罗培南在制备预防和/或治含有NDM-1的细菌感染的药物中的应用，其特征在于：所述的化合物0683-0042的结构如下所示：
7.一种药物，其特征在于：包含化合物0683-0042或其药学上可接受的盐，或包含化合物0683-0042或其药学上可接受的盐与美罗培南；所述的化合物0683-0042的结构如下所示：
8.根据权利要求7所述的药物，其特征在于：还包含药学上可接受的载体或赋形剂。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111867600A (zh) * | 2018-03-15 | 2020-10-30 | 辉瑞大药厂 | 用作抗菌剂的吡啶酮和嘧啶酮磷酸盐和硼酸盐 |
| CN113384587A (zh) * | 2021-08-06 | 2021-09-14 | 吉林大学 | 委陵菜酸在制备碳青霉烯酶抑制剂中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111867600A (zh) * | 2018-03-15 | 2020-10-30 | 辉瑞大药厂 | 用作抗菌剂的吡啶酮和嘧啶酮磷酸盐和硼酸盐 |
| CN113384587A (zh) * | 2021-08-06 | 2021-09-14 | 吉林大学 | 委陵菜酸在制备碳青霉烯酶抑制剂中的应用 |
Non-Patent Citations (4)
| Title |
|---|
| MEIQI LI等: "A Unimolecular System Combining Efficient Inhibition of NDM-1 by Coordination Interactions with High ROS for Synergistically Tackling Drug-Resistant Bacteria", 《ADV. MATER. INTERFACES》, no. 9, 30 September 2022 (2022-09-30), pages 2201329 * |
| RUQAIYYAH SIDDIQUI等: "Antibacterial Effects of Derivatives of Porphyrin, Naphthalene diimide, Aminophenol and Benzodioxane on Methicillin Resistant Staphylococcus aureus and Neuropathogenic Escherichia coli K1", 《ANTI-INFECTIVE AGENTS》, vol. 17, no. 1, 31 December 2019 (2019-12-31), pages 1 - 10 * |
| TAMARA ZOLTAN等: "Synthesis, Photochemical and Photoinduced Antibacterial Activity Studies of meso-Tetra(pyren-1-yl)porphyrin and its Ni, Cu and Zn Complexes", 《SCIENTIA PHARMACEUTICA》, no. 78, 7 August 2010 (2010-08-07), pages 767 * |
| 罗小凤等: "枸杞槲皮素对金黄色葡萄球菌产 β-内酰胺酶的抑制作用", 《中国畜牧兽医》, vol. 51, no. 1, 28 December 2023 (2023-12-28), pages 382 - 391 * |
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