WO2024098967A1 - Su3327在制备增强多黏菌素抗细菌感染效力的药物中的用途 - Google Patents

Su3327在制备增强多黏菌素抗细菌感染效力的药物中的用途 Download PDF

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WO2024098967A1
WO2024098967A1 PCT/CN2023/119768 CN2023119768W WO2024098967A1 WO 2024098967 A1 WO2024098967 A1 WO 2024098967A1 CN 2023119768 W CN2023119768 W CN 2023119768W WO 2024098967 A1 WO2024098967 A1 WO 2024098967A1
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polymyxin
use according
bacterial
drug
bacteria
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French (fr)
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沈建忠
代重山
陈洪亮
吴聪明
沈张奇
汪洋
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Xiamen Hanlixin Pharmaceutical Co Ltd
China Agricultural University
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Xiamen Hanlixin Pharmaceutical Co Ltd
China Agricultural University
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Priority to JP2024554152A priority patent/JP2025507179A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicine, specifically to the field of antibacterial agents, and in particular to a method for enhancing the antibacterial activity of polymyxin using the C-JUN N-terminal kinase inhibitor SU3327.
  • Polymyxin (also known as polymyxin) is an antibacterial polypeptide found in the culture fluid of Bacillus polymyxa. There are five types: A, B, C, D, and E. The antibacterial spectrum is similar to each other and has a wide range, especially against Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
  • Polymyxin E also known as colistin, Polymyxin E
  • CAS number 1066-17-7
  • English name Colistin
  • trade name anti-enemycin Colistin
  • colistin Chinese name: Colistin, trade name anti-enemycin, Colistin, and colistin.
  • Clinical application is mainly in the form of sulfate or methanesulfonate, that is, polymyxin E sulfate and polymyxin E methanesulfonate.
  • Polymyxin E is used to treat enteritis caused by Escherichia coli, pneumonia caused by Klebsiella pneumoniae, and other drug-resistant strains, as well as external use for local infection of Pseudomonas aeruginosa caused by burns and trauma and infection of sensitive bacteria in ears, eyes and other parts.
  • SU3327 (also known as halicin, CAS No.: 40045-50-9) is an N-terminal kinase inhibitor of C-JUN, and its structure is shown in Figure 1.
  • SU3327 is a potent, selective and substrate-competitive JNK inhibitor with an IC 50 of 0.7 ⁇ M.
  • SU3327 also inhibits the protein interaction between JNK and JIP with an IC 50 value of 239 nM.
  • SU3327 has low activity against p38 ⁇ and Akt kinases.
  • the present invention not only provides a synergistic enhancement experiment at the cell level for the combination of SU3327 and polymyxin, but also further provides an animal level experiment to confirm its good synergistic bactericidal effect. So far, there is no research report on the use of SU3327 as a polymyxin synergist in enhancing the antibacterial activity of polymyxin.
  • the present invention provides a method for enhancing the antibacterial activity of polymyxin, specifically using the N-terminal kinase inhibitor SU3327 of C-JUN in combination with polymyxin, preferably polymyxin E, the two are not just a simple addition of functions, but a synergistic antibacterial effect.
  • the present invention also discloses an antibacterial combination ratio of SU3327 and polymyxin E, which provides a new treatment strategy for clinical treatment of bacterial infections, especially multidrug-resistant Gram-negative bacterial infections, specifically bacterial infections with polymyxin resistance genes (MCR).
  • MCR polymyxin resistance genes
  • One aspect of the present invention provides use of SU3327, an N-terminal kinase inhibitor of C-JUN, in the preparation of a medicament for enhancing the efficacy of polymyxin against bacterial infection.
  • Another aspect of the present invention provides use of a combination of SU3327, an N-terminal kinase inhibitor of C-JUN, and polymyxin in the preparation of a drug with enhanced efficacy against bacterial infection.
  • polymyxin is polymyxin E (i.e., colistin) or polymyxin B.
  • bacteria are bacteria having polymyxin resistance genes.
  • bacteria are Gram-negative bacteria.
  • Gram-negative bacteria are multidrug-resistant Gram-negative bacteria.
  • the bacteria are one or more of Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Staphylococcus aureus; preferably, one or more of the Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Staphylococcus aureus have polymyxin resistance genes or are multidrug resistant.
  • the bacterium is Klebsiella pneumoniae; preferably, the bacterium is Klebsiella pneumoniae with a polymyxin resistance gene or multidrug resistance.
  • the mass ratio of SU3327 to polymyxin is: (2.5-10):1.
  • the dosage form of the composition of SU3327 and polymyxin is one of tablets, capsules, sustained-release tablets, controlled-release tablets, oral liquid, syrup, injection liquid, pills, and lyophilized powder injection.
  • the final therapeutic dose of the polymyxin E and the SU3327 is 10 mg/kg body weight.
  • the present invention proves the antibacterial activity of SU3327 synergistically enhancing polymyxin through the chessboard method minimum inhibitory concentration test and in vitro bacterial growth curve.
  • the present invention provides a mouse resistant bacterial infection model experiment, which confirms at the animal level that SU3327 can effectively enhance the effectiveness of polymyxin and its in vivo efficacy, which is more convincing for the next step of clinical application.
  • the present invention illustrates that SU3327 can restore the sensitivity of polymyxin-resistant bacteria, and further evaluates the effectiveness of the combined use of the two in vivo and in vitro, which will help to develop a new class of antibiotic enhancers to alleviate the increasingly serious problem of bacterial resistance.
  • the present invention provides a new use of SU3327 in enhancing the antibacterial activity of polymyxin antibiotics, which can solve technical problems such as clinical drug resistance and low therapeutic index of polymyxin.
  • FIG1 is a chemical structure diagram of SU3327 of the present invention.
  • FIG2 is a test result of the combined antibacterial activity of SU3327 and colistin E alone and in combination with the present invention on strains by the chessboard method;
  • Figures 3A-3B are in vitro bacterial growth curve results of SU3327 and polymyxin E used alone and in combination with K. Pneumoniae 1202 and K. Pneumoniae 1202-45-5 according to the present invention, wherein Figure 3A is an in vitro bacterial growth curve result of SU3327 and polymyxin E used alone and in combination with K. Pneumoniae 1202 strain, and Figure 3B is an in vitro bacterial growth curve result of SU3327 and polymyxin E used alone and in combination with K. Pneumoniae 1202-45-5 strain;
  • FIG4 shows the present invention for treating K. Pneumoniae 1202-45-5 with SU3327 and polymyxin E alone and in combination. Results of bacterial load in the thighs of mice treated with CTLA-4.
  • SU3327 was purchased from MCE Reagent Company in the United States, with a purity of ⁇ 99%.
  • Polymyxin E sulfate was purchased from Hebei Shengxue Dacheng Tangshan Pharmaceutical Company, with a potency of ⁇ 23000U/mg polymyxin E.
  • a certain amount of polymyxin E sulfate was weighed and configured into a mother liquor concentration of 16mg/mL aqueous solution.
  • SU3327 was configured into a mother liquor concentration of 40mg/mL using DMSO. All mother liquors were stored in a -20 degree refrigerator after preparation.
  • the strains of Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 used in the experiment were purchased from the Chinese Veterinary Supervision Institute. Methicillin-resistant Staphylococcus aureus USA300 (ATCC BAA-1717) was purchased from the American Standard Bacteria Collection.
  • E. coli B2, E. coli GZP08-8, K. Pneumoniae 1202-45-5, and Salmonella 1-5 are strains resistant to polymyxins containing MCR-1.
  • K. Pneumoniae 1202 and Shigella Y are clinical colistin-sensitive strains.
  • the MIC of SU3327 alone was detected by the doubling dilution method. Subsequently, the combined antibacterial activity test of SU3327 and colistin alone and in combination against the above-mentioned strains was carried out in a 96-well sterile microplate according to the checkerboard method, and the synergistic index (FICI) of combined use was further calculated.
  • the FICI of SU3327 and colistin MIC (colistin combined)/MIC (colistin) + MIC (SU3327 combined)/MIC (SU3327 alone).
  • E.coli B2 Escherichia coli B2
  • MCR-1 Escherichia coli B2
  • the MICs of polymyxin E and SU3327 were 8 ⁇ g/mL and 20 ⁇ g/mL, respectively.
  • the MICs of polymyxin E and SU3327 were reduced to 0.5 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.1875, which was judged to be a synergistic effect.
  • the MICs of polymyxin E and SU3327 were 1 ⁇ g/mL and 20 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 0.0625 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.1875, which was judged to be a synergistic effect.
  • Klebsiella pneumoniae 1202-45-5 K. Pneumoniae 1202-45-5 strain
  • the MICs of polymyxin E and SU3327 were 16 ⁇ g/mL and 20 ⁇ g/mL, respectively.
  • the MICs of polymyxin E and SU3327 were reduced to 0.25 ⁇ g/mL and 5 ⁇ g/mL, respectively, and the FICI was 0.266, which was judged to be a synergistic effect.
  • the MICs of polymyxin E and SU3327 were 16 ⁇ g/mL and 10 ⁇ g/Ml, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 0.25 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.266, which was judged to be a synergistic effect.
  • the MICs of polymyxin E and SU3327 were 0.125 ⁇ g/mL and 10 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 0.0625 ⁇ g/mL and 5 ⁇ g/mL, respectively, and the FICI was 1, which was judged to be an additive effect.
  • the MICs of polymyxin E and SU3327 were greater than 128 ⁇ g/mL and 5 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 64 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.75, which was judged to be an additive effect.
  • the MICs of polymyxin E and SU3327 were greater than 128 ⁇ g/mL and 20 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 1 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.25, which was judged to be a synergistic effect.
  • the MICs of polymyxin E and SU3327 were greater than 128 ⁇ g/mL and 5 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 32 ⁇ g/mL and 1.25 ⁇ g/mL, respectively, and the FICI was 0.25, which was judged to be a synergistic effect.
  • the MICs of polymyxin E and SU3327 were 0.125 ⁇ g/mL and 5 ⁇ g/mL, respectively. After combined use, the MICs of polymyxin E and SU3327 were reduced to 0.032 ⁇ g/mL and 2.5 ⁇ g/mL, respectively, and the FICI was 0.75, which was judged to be an additive effect.
  • the bacterial concentration was diluted to 10 to the sixth power of the colony count using a turbidimeter.
  • the drug treatment concentrations were set as: polymyxin E (0.25 ⁇ g/mL), SU3327 (10 ⁇ g/m L), SU3327 (10 ⁇ g/m L) + polymyxin E (0.25 ⁇ g/m L); the control group bacteria were given 0.1% DMSO solvent; for Klebsiella pneumoniae 1202-45-5, the drug treatment concentrations were set as: polymyxin E (1 ⁇ g/mL), SU3327 (20 ⁇ g/mL), SU3327 (20 ⁇ g/mL) + polymyxin E (1 ⁇ g/mL); 100 ⁇ L of the bacterial solution was spread on the agar plate at 1h, 3h, 6h, 12h and 24h of drug treatment, and the colonies were counted after
  • Figures 3A and 3B The results of the in vitro bacterial growth curves of SU3327 and polymyxin E alone and in combination with K. pneumoniae 1202 (K. Pneumoniae 1202) and K. pneumoniae 1202-45-5 (K. Pneumoniae 1202-45-5) are shown in Figures 3A and 3B, wherein Figure 3A is a graph showing the in vitro bacterial growth curves of SU3327 and polymyxin E alone and in combination with K. Pneumoniae 1202 strains, and Figure 3B is a graph showing the in vitro bacterial growth curves of SU3327 and polymyxin E alone and in combination with K. Pneumoniae 1202-45-5 strains. The specific results are analyzed as follows:
  • the results for Klebsiella pneumoniae 1202 showed that the bactericidal effect of the combined treatment group of SU3327 (10 ⁇ g/mL) and polymyxin E (0.25 ⁇ g/mL) was significantly improved compared with the single treatment of SU3327 or polymyxin E; after 24 hours of continuous treatment, the bacterial colony count was 9.4 Log10 CFU/mL in the control treatment group, 8.9 Log10 CFU/mL in the polymyxin E treatment group, 8.35 Log10 CFU/mL in the SU3327 treatment group, and 2.05 Log10 CFU/mL in the combined treatment group of polymyxin E and SU3327; this shows that the bactericidal effect is significantly improved after the combined treatment of polymyxin E and SU3327.
  • Klebsiella pneumoniae 1202-45-5 showed that the bactericidal effect of the combined treatment group of SU3327 (20 ⁇ g/mL) and polymyxin E (1 ⁇ g/mL) was significantly improved compared with the treatment with SU3327 or polymyxin E alone.
  • the bacterial colony counts in the control group were 9.35 Log10 CFU/mL, those in the polymyxin E group were 9.3 Log10 CFU/mL, those in the SU3327 group were 6.65 Log10 CFU/mL, and those in the combined treatment group of polymyxin E and SU3327 were 2.7 Log10 CFU/mL; This shows that the bactericidal effect was significantly improved after polymyxin E combined with SU3327 treatment.
  • mice were given cyclophosphamide twice, 4 days and 1 day before infection, respectively, each time intraperitoneally injected with 100 mg/kg, causing neutropenia and immunodeficiency in mice.
  • 24 6-8 week old BALB/c female mice weighing about 20g
  • logarithmic phase Klebsiella pneumoniae 1202-45-5 bacteria were resuspended in PBS buffer to prepare a suspension with a concentration of 1x10 7 CFU/mL; in mice, the total amount of bacteria finally injected into the thigh of each mouse was 1x10 6 CFUs. Then they were randomly divided into a model control group (i.e.
  • Solvent control treatment group 0.1 mL of Klebsiella pneumoniae 1202-45-5 suspension was injected into the right thigh muscle of the mice; 1 hour later, 200 ⁇ L of PBS buffer was injected into the abdominal cavity of the mice;
  • Polymyxin E treatment group 0.1 mL of Klebsiella pneumoniae 1202-45-5 suspension was injected into the right thigh muscle of the mice; 1 hour later, 200 ⁇ L of polymyxin E solution (1 mg/mL) was injected into the abdomen of the mice; the final dose was 10 mg/kg body weight;
  • SU3327 treatment group 0.1 mL of Klebsiella pneumoniae 1202-45-5 suspension was injected into the right thigh muscle of the mice; 1 hour later, 200 ⁇ L of SU3327 solution (1 mg/mL) was injected into the abdomen of the mice; the final dose was 10 mg/kg body weight;
  • SU3327 (10 mg/kg) + polymyxin E (10 mg/kg) combined treatment group 0.1 mL of Escherichia coli suspension was injected into the right thigh muscle of the mouse abdominal cavity; 1 hour later, the mouse was intraperitoneally injected with a mixed solution of SU3327 (1 mg/mL) and 200 ⁇ L of polymyxin E (1 mg/m L). The final dose was 10 mg/kg body weight for both SU3327 and polymyxin E. The treatment was performed twice, with an interval of 8 hours each time. At 24 hours after infection, all mice were euthanized and the right thigh muscles of the mice were taken, placed in 3 mL of PBS solution, and crushed using a low-temperature tissue crusher. Finally, 100 ⁇ L of the crushing solution was plated for colony counting.
  • the bacterial load in the thighs of mice in the polymyxin E treatment group was 6.82 Log10 CFU/mL. There was no significant difference with the control group; compared with the solvent control group, the bacterial load in the thighs of mice in the SU3327 alone treatment group was 6.55 Log10 CFU/mL, which was significantly different from the control group; compared with the solvent control group, the bacterial load in the thighs of mice in the polymyxin E and SU3327 combined treatment group was 5.28 Log10 CFU/mL, which was significantly different from the control group, and compared with the SU3327 alone treatment group or the polymyxin E alone treatment group, respectively, there were significant differences.

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Abstract

本发明提供一种C-JUN的N末端激酶抑制剂SU3327在制备增强多黏菌素抗细菌感染效力的药物中的用途，以及SU3327和多黏菌素的组合物在制备抗细菌感染效力增强的药物中的用途，所述多黏菌素优选为多黏菌素E。本发明不仅通过棋盘法最小抑菌浓度试验、体外细菌生长曲线证明SU3327协同增效多黏菌素的抗菌活性，同时利用小鼠耐药细菌感染模型实验在动物水平证实了SU3327可以有效增强多黏菌素以及在体内的有效性。本发明提供了SU3327在增效多黏菌素类抗生素抗菌活性中的新用途，可解决多黏菌素临床耐药性和治疗指数低等技术问题。

Description

SU3327在制备增强多黏菌素抗细菌感染效力的药物中的用途 技术领域
本发明涉及医药领域，具体涉及抗菌领域，特别涉及一种利用C-JUN N末端激酶抑制剂SU3327增强多黏菌素抗菌活性的方法。
背景技术
多黏菌素(又称多粘菌素，polymyxin)是发现于多粘杆菌(Bacillus polymyxa)培养液中的抗菌性多肽，有A、B、C、D、E等五种。抗菌谱相互类似而范围宽广，特别对革兰氏阴性细菌作用颇强，如大肠杆菌、肺炎杆菌、绿脓杆菌等。多黏菌素E(又称黏菌素，Polymyxin E)，CAS号:1066-17-7，英文名称:Colistin，商品名抗敌素、可立斯丁、粘菌素。临床应用主要是硫酸盐或甲磺酸盐形式，即硫酸多黏菌素E和甲磺酸盐多黏菌素E。多黏菌素E用于治疗大肠杆菌性造成的肠炎、肺炎克雷伯菌造成的肺炎、和治疗其他药物耐药的菌株，以及外用于烧伤和外伤引起的绿脓杆菌局部感染和耳、眼等部位敏感菌感染。
近10年来，多重耐药革兰氏阴性细菌造成的感染严重威胁动物和人类健康。目前，多黏菌素类抗菌药物被认为是临床治疗多重耐药革兰氏阴性细菌(主要包括耐碳青霉烯类大肠杆菌、多重耐药肺炎克雷伯菌等)感染的最后一线治疗选择。然而，由于多黏菌素耐药基因(MCR)的出现，导致临床多黏菌素的治疗输出显著降低，严重危险这一重要抗菌药物的使用寿命。因此，开发有效的黏菌素增效剂，基于黏菌素的联合给药，已经成为临床治疗治疗这些危害生命的多重耐药革兰氏阴性细菌的重要治疗策略。
为应对临床“细菌耐药性危机”，联合用药已成为临床应用多黏菌素治疗MDR-GNR最重要的用药策略，已有文献公开了多黏菌素的多种联合用药。测定17种不同抗菌药物对135株碳青霉烯耐药肺炎克雷伯菌(Carbapenem resistant Klebaiella pneumoniae,CRKP)的最低抑菌浓度，评价CRKP菌株药物敏感性。评价以Colistin为基础联合比阿培南、头孢他啶-阿维巴坦2种联合用药方案对CRKP的协同抗菌活性,为临床用药选择提供理论依据(参见：“Colistin联合其它抗菌药物对碳青霉烯耐药肺炎克雷伯的体外抗菌活性研究”，白艳等，《2016年北京药学年会》，2016年公开)。建立药效学模型描述多黏菌素E(colistin E)与其他抗菌药联用对泛耐药鲍曼不动杆菌(XDR-AB)的体外杀菌作用，所建立的药效学模型较好的 描述了多黏菌素E对XDR-AB杀菌作用的特点,为抗菌药体外联用的药动学/药效学数据建模提供了范例(参见：“多黏菌素E联用其他抗菌药物治疗鲍曼不动杆菌感染的药效学模型研究”，付文婷等，《安徽医药》，2020年12期)。
SU3327(又称halicin、海立信，CAS No.:40045-50-9)是一种C-JUN的N末端激酶抑制剂，结构见图1。SU3327是一种有效的，选择性的且具有底物竞争性的JNK抑制剂，IC50为0.7μM。SU3327还以IC50值为239nM抑制JNK和JIP之间的蛋白相互作用。SU3327对p38α和Akt激酶的活性较低。
目前，虽然现有技术已经公开了多黏菌素联用其他抗菌药物，但大多数成药性很差，本发明不仅提供了SU3327和多黏菌素的联用细胞水平的协同增效实验，还进一步提供动物水平实验证实其较好的协同杀菌效果。至今尚无研究报道关于SU3327作为多黏菌素增效剂，在增强多黏菌素抗菌活性中的应用。
发明内容
为了解决多重耐药革兰氏阴性细菌治疗的技术问题，本发明提供一种增强多黏菌素抗菌活性的方法，具体采用C-JUN的N末端激酶抑制剂SU3327联用多黏菌素，多黏菌素优选多黏菌素E，二者不仅是简单的功能相加，而是达到协同增效抗菌作用。本发明还公开了SU3327和多黏菌素E的抗菌组合配比，为临床治疗细菌感染，特别是多重耐药革兰氏阴性细菌感染，具体如存在多黏菌素耐药基因(MCR)的细菌感染提供了新的治疗策略。
本发明的一方面提供C-JUN的N末端激酶抑制剂SU3327在制备增强多黏菌素抗细菌感染效力的药物中的用途。
本发明的另一方面提供C-JUN的N末端激酶抑制剂SU3327和多黏菌素的组合物在制备抗细菌感染效力增强的药物中的用途。
进一步地，所述多黏菌素为多黏菌素E(即黏菌素)或多黏菌素B。
进一步地，所述细菌为存在多黏菌素耐药基因的细菌。
进一步地，所述细菌为革兰氏阴性细菌。
进一步地，所述革兰氏阴性细菌为多重耐药革兰氏阴性细菌。
进一步地，所述细菌为大肠杆菌、肺炎克雷伯、沙门氏菌、志贺杆菌、金黄色葡萄球菌中的一种或多种；优选地，所述大肠杆菌、肺炎克雷伯、沙门氏菌、志贺杆菌、金黄色葡萄球菌中的一种或多种为存在多黏菌素耐药基因的或多重耐药的。
进一步地，所述细菌为肺炎克雷伯菌；优选地，所述细菌为存在多黏菌素耐药基因的或多重耐药的肺炎克雷伯菌。
进一步地，所述SU3327和多黏菌素的组合物中SU3327、多黏菌素质量比为：(2.5-10):1。
进一步地，所述SU3327和多黏菌素的组合物的剂型为片剂、胶囊、缓释片、控释片、口服液、糖浆、注射液剂型、滴丸、冻干粉针剂型中的一种。
进一步地，所述多黏菌素E和所述SU3327的最终治疗剂量为10mg/kg体重。
本发明提供的C-JUN的N末端激酶抑制剂SU3327的新用途，用于增强多黏菌素抗菌活性的方法具有以下优异的技术效果：
(1)本发明通过棋盘法最小抑菌浓度试验、体外细菌生长曲线证明SU3327协同增效多黏菌素的抗菌活性。
(2)区别于已有的多黏菌素与抗生素联用，本发明给出了小鼠耐药细菌感染模型实验，在动物水平证实了SU3327可以有效增强多黏菌素以及在体内的有效性，对下一步临床应用更有证明力。
(3)本发明阐明了SU3327可以恢复耐多黏菌素细菌的敏感性，并进一步评价了两者联合使用在体内外的有效性，有助于开发出一类新型的抗生素增效剂，缓解危害日趋严重的细菌耐药性问题。
(4)本发明提供了SU3327在增效多黏菌素类抗生素抗菌活性中的新用途，可解决多黏菌素临床耐药性和治疗指数低等技术问题。
附图说明
图1为本发明SU3327的化学结构图；
图2为本发明SU3327和多黏菌素E单用及二者联用的棋盘法对菌株的联合抑菌活性试验结果；
图3A-图3B为本发明针对K.Pneumoniae 1202和K.Pneumoniae 1202-45-5，SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图，其中图3A为针对K.Pneumoniae 1202菌株SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图，图3B为针对K.Pneumoniae 1202-45-5菌株SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图；
图4为本发明针对K.Pneumoniae 1202-45-5，SU3327和多黏菌素E单用及二者联用治 疗的小鼠大腿载菌量结果图。
具体实施方式
本发明实施例采用药物：SU3327购买自美国MCE试剂公司，纯度≥99％。硫酸多黏菌素E购买自河北圣雪大成唐山制药公司，效价≥23000U/mg多黏菌素E。称取一定量的硫酸多黏菌素E配置成母液浓度为16mg/mL水溶液。SU3327使用DMSO配置成母液浓度为40mg/mL浓度的母液。所有母液制备好后储存在-20度冰箱。
实施例1 SU3327和多黏菌素联合用药的协同抗菌活性评价
1.1试验菌株
试验中所用菌株大肠杆菌ATCC 25922(E.coli 25922)、金黄色葡萄球菌ATCC 29213(S.aureus 29213)菌株购自中国兽医监察所菌种保存中心。耐甲氧西林金黄色葡萄球菌USA300(ATCC BAA-1717)购自美国标准菌种库。其他实验中所用菌株大肠杆菌B2(E.coli B2)、大肠杆菌GZP08-8(E.coli GZP08-8)、肺炎克雷伯1202(K.Pneumoniae 1202)、肺炎克雷伯1202-45-5(K.Pneumoniae 1202-45-5)、沙门氏菌1-5(Salmonella 1-5)、志贺杆菌Y(Shigella Y)菌株均来自中国农业大学国家兽药安全评价中心保存。其中，大肠杆菌B2(E.coli B2)、大肠杆菌GZP08-8(E.coli GZP08-8)、肺炎克雷伯1202-45-5(K.Pneumoniae 1202-45-5)、沙门氏菌1-5(Salmonella 1-5)为含有MCR-1的耐多黏菌素的菌株。肺炎克雷伯1202(K.Pneumoniae 1202)、志贺杆菌Y(Shigella Y)为临床黏菌素敏感菌株。
1.2试验方法
使用倍比稀释法检测SU3327单独用药的MIC。随后，在96孔无菌微孔板内依照棋盘法分别进行SU3327和多黏菌素E(Colistin)单用及二者联用对上述菌株的联合抑菌活性试验，并进一步计算联合使用协同指数(FICI)。SU3327和多黏菌素E的FICI＝MIC(多黏菌素E联合)/MIC(多黏菌素E)+MIC(SU3327联合)/MIC(SU3327单用)。当FICI≤0.5判定为协同；当0.5<FICI≤1时，判定为相加作用；当0.5<FICI<4，判定为无关效应。
1.3试验结果
SU3327和多黏菌素E单用及二者联用的棋盘法对菌株的联合抑菌活性试验结果见图2，具体结果分析如下：
针对含有MCR-1的大肠杆菌B2(E.coli B2)，多黏菌素E和SU3327的MIC分别为8μg/mL和20μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.5μg/mL和2.5μg/mL，FICI为0.1875，判定为协同作用。
针对临床黏菌素敏感菌肺炎克雷伯菌1202(K.Pneumoniae 1202)菌株，多黏菌素E和SU3327的MIC分别为1μg/mL和20μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.0625μg/mL和2.5μg/mL，FICI为0.1875，判定为协同作用。
针对黏菌素敏感菌肺炎克雷伯菌1202-45-5(K.Pneumoniae 1202-45-5)菌株，多黏菌素E和SU3327的MIC分别为16μg/mL和20μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.25μg/mL和5μg/mL，FICI为0.266，判定为协同作用。
针黏菌素敏感菌大肠杆菌GZP08-8(E.coli GZP08-8)菌株，多黏菌素E和SU3327的MIC分别为16μg/mL和10μg/Ml，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.25μg/mL和2.5μg/mL，FICI为0.266，判定为协同作用。
针对大肠杆菌标准菌株ATCC 25922(E.coli 25922)，多黏菌素E和SU3327的MIC分别为0.125μg/mL和10μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.0625μg/mL和5μg/mL，FICI为1，判定为相加作用。
针对金黄色葡萄球菌标准菌株ATCC 29213(S.aureus 29213)，多黏菌素E和SU3327的MIC分别为大于128μg/mL和5μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到64μg/mL和2.5μg/mL，FICI为0.75，判定为相加作用。
针对黏菌素耐药菌株沙门氏菌1-5(Salmonella 1-5)，多黏菌素E和SU3327的MIC分别为大于128μg/mL和20μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到1μg/mL和2.5μg/mL，FICI为0.25，判定为协同作用。
针对耐甲氧西林金黄色葡萄球菌USA300(S.aureus USA300)菌株，多黏菌素E和SU3327的MIC分别为大于128μg/mL和5μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到32μg/mL和1.25μg/mL，FICI为0.25，判定为协同作用。
针对黏菌素敏感菌株志贺菌Y(Shigella Y)，多黏菌素E和SU3327的MIC分别为0.125μg/mL和5μg/mL，联合使用后，多黏菌素E和SU3327的MIC分别降低到0.032μg/mL和2.5μg/mL，FICI为0.75，判定为相加作用。
实施例2多黏菌素E联合SU3327使用的协同杀菌曲线
2.1 MHA培养基配制
取牛肉粉6.0g，可溶性淀粉1.5g，酸水解酪蛋白17.5g，琼脂17.0g，加入900mL蒸馏水，调节pH至7.3，定容至1000mL。121℃高压灭菌15分钟，待冷至50℃时倾入无菌平皿，晾干备用。
2.2试验方法
将肺炎克雷伯1202菌(K.Pneumoniae 1202)和肺炎克雷伯1202-45-5菌(K.Pneumoniae 1202-45-5)在BHI肉汤中培养6-8小时后，使用比浊仪将细菌浓度稀释为10的六次方菌落数。其中，对肺炎克雷伯1202菌，设置药物处理浓度为：多黏菌素E(0.25μg/mL)、SU3327(10μg/m L)、SU3327(10μg/m L)+多黏菌素E(0.25μg/m L)；对照组细菌给予0.1％的DMSO溶剂；对肺炎克雷伯1202-45-5菌，设置药物处理浓度为：多黏菌素E(1μg/mL)、SU3327(20μg/mL)、SU3327(20μg/mL)+多黏菌素E(1μg/mL)；在分别于药物处理第1h、3h、6h、12h和24h取菌液100μL涂布于琼脂平板上，培养至少16h后，进行菌落计数。
2.3试验结果
针对肺炎克雷伯1202菌(K.Pneumoniae 1202)和肺炎克雷伯1202-45-5菌(K.Pneumoniae 1202-45-5)，SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图见图3A-图3B，其中图3A为针对K.Pneumoniae 1202菌株SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图，图3B为针对K.Pneumoniae 1202-45-5菌株SU3327和多黏菌素E单用及二者联用的体外细菌生长曲线结果图。具体结果分析如下：
对肺炎克雷伯1202菌结果显示，在SU3327(10μg/mL)和多黏菌素E(0.25μg/mL)联合处理组，杀菌效果较SU3327或多黏菌素E单药处理均得到明显提高；在连续处理24h后，细菌菌落数在对照处理组为9.4 Log10 CFU/mL，多黏菌素E处理组为8.9 Log10 CFU/mL，SU3327处理组为8.35 Log10 CFU/mL，多黏菌素E和SU3327联合处理组为2.05 Log10 CFU/mL；表明多黏菌素E联合SU3327处理后，杀菌效果得到显著提高。
对肺炎克雷伯1202-45-5菌结果显示，在SU3327(20μg/m L)和多黏菌素E(1μg/m L)联合处理组，杀菌效果较SU3327或多黏菌素E单药处理均得到明显提高；在连续处理24h后，细菌菌落数在对照处理组为9.35 Log10 CFU/mL，多黏菌素E处理组为9.3 Log10 CFU/mL，SU3327处理组为6.65 Log10 CFU/mL，多黏菌素E和SU3327联合处理组为2.7  Log10 CFU/mL；表明多黏菌素E联合SU3327处理后，杀菌效果得到显著提高。
试验例3多黏菌素E和SU3327单独和联合使用在治疗BALB/c小鼠耐药细菌感染模型中的效果
3.1动物分组和处理
为了避免小鼠自身免疫力对实验的影响，所有小鼠在感染前4天和前1天分别预先分别给予环磷酰胺2次，每次腹腔注射100mg/kg，造成小鼠中性粒细胞减少及免疫缺陷。24只6-8周龄BALB/c雌性小鼠(体重约20g)，对数期的肺炎克雷伯1202-45-5菌用PBS缓冲液重悬，制备成悬浮液，浓度为1x107CFU/mL；在小鼠中，每只小鼠大腿最后注射的细菌总量为1x106CFUs。然后随机分成模型对照组(即溶剂治疗组)、多黏菌素E治疗组(10mg/kg体重)、SU3327治疗组(10mg/kg体重)、和SU3327(10mg/kg体重)+多黏菌素E(10mg/kg体重)联合治疗组(每组6只)。具体处理如下：
溶剂对照治疗组：小鼠腹腔右侧大腿肌肉注射肺炎克雷伯1202-45-5菌悬浮液0.1mL；1小时后小鼠腹腔注射200μL PBS缓冲液；
多黏菌素E治疗组：小鼠腹腔右侧大腿肌肉注射肺炎克雷伯1202-45-5菌悬浮液0.1mL；1小时后小鼠腹腔注射200μL多黏菌素E药液(1mg/m L)；最终剂量为10mg/kg体重；
SU3327治疗组：小鼠腹腔右侧大腿肌肉注射肺炎克雷伯1202-45-5菌悬浮液0.1mL；1小时后小鼠腹腔注射200μL SU3327药液(1mg/mL)；最终剂量为10mg/kg体重；
SU3327(10mg/kg)+多黏菌素E(10mg/kg)联合治疗组：小鼠腹腔右侧大腿肌肉注射大肠杆菌悬浮液0.1mL；1小时后小鼠腹腔注射SU3327(1mg/mL)和200μL多黏菌素E(1mg/m L)的混合药液。最终剂量为SU3327和多黏菌素E的剂量均为10mg/kg体重。治疗2次，每次间隔8小时。在感染后第24小时，所有小鼠进行安乐死后取小鼠右侧大腿肌肉，放置于3mL PBS溶液中，使用低温组织破碎仪破碎，最后取100μL破碎液涂板进行菌落计数。
3.2试验结果
针对肺炎克雷伯1202-45-5菌，SU3327和多黏菌素E单用及二者联用治疗的小鼠大腿载菌量结果图见图4，结果如下：
与溶剂对照组相比，多黏菌素E单独治疗组中小鼠大腿载菌量为6.82 Log10 CFU/mL， 与对照组无显著差异；与溶剂对照组相比，SU3327单独治疗组中小鼠大腿载菌量为6.55 Log10 CFU/mL，与对照组相比差异显著；与溶剂对照组相比，多黏菌素E和SU3327联合治疗组中小鼠大腿载菌量为5.28 Log10 CFU/mL，与对照组相比差异显著，且分别与SU3327单独治疗组或多黏菌素E单独治疗组相比，均差异显著。这些结果表明了SU3327可以有效增强多黏菌素E和在体内的有效性，为耐药性革兰氏阴性细菌引起的感染性疾病的治疗提供了新的治疗方案。
本公开的上述实施例仅是为清楚地说明本公开所作的举例，而并非是对本公开的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其他不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本公开的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本公开权利要求的保护范围之内。

Claims (11)

  1. C-JUN的N末端激酶抑制剂SU3327在制备增强多黏菌素抗细菌感染效力的药物中的用途。
  2. C-JUN的N末端激酶抑制剂SU3327和多黏菌素的组合物在制备抗细菌感染效力增强的药物中的用途。
  3. 根据权利要求1或2所述的用途，其特征在于，所述多黏菌素为多黏菌素E或多黏菌素B；优选地，所述多黏菌素为多黏菌素E。
  4. 根据权利要求1-3任一项所述的用途，其特征在于，所述细菌为存在多黏菌素耐药基因的细菌。
  5. 根据权利要求1-3任一项所述的用途，其特征在于，所述细菌为革兰氏阴性细菌。
  6. 根据权利要求5所述的用途，其特征在于，所述革兰氏阴性细菌为多重耐药革兰氏阴性细菌。
  7. 根据权利要求1-3任一项所述的用途，其特征在于，所述细菌为大肠杆菌、肺炎克雷伯、沙门氏菌、志贺杆菌、金黄色葡萄球菌中的一种或多种；优选地，所述大肠杆菌、肺炎克雷伯、沙门氏菌、志贺杆菌、金黄色葡萄球菌中的一种或多种为存在多黏菌素耐药基因的或多重耐药的。
  8. 根据权利要求1-3任一项所述的用途，其特征在于，所述细菌为肺炎克雷伯菌；优选地，所述细菌为存在多黏菌素耐药基因的或多重耐药的肺炎克雷伯菌。
  9. 根据权利要求2-8任一项所述的用途，其特征在于，所述SU3327和多黏菌素的组合物中SU3327、多黏菌素质量比为(2.5-10):1。
  10. 根据权利要求2-8任一项所述的用途，其特征在于，所述SU3327和多黏菌素的组合物的剂型为片剂、胶囊、缓释片、控释片、口服液、糖浆、注射液剂型、滴丸、冻干粉针剂型中的一种。
  11. 根据权利要求2-8任一项所述的用途，其特征在于，所述多黏菌素E和所述SU3327的最终治疗剂量为10mg/kg体重。
PCT/CN2023/119768 2022-11-08 2023-09-19 Su3327在制备增强多黏菌素抗细菌感染效力的药物中的用途 Ceased WO2024098967A1 (zh)

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US18/841,685 US20250170106A1 (en) 2022-11-08 2023-09-19 Use of su3327 in preparation of medicament for enhancing efficacy of polymyxin against bacterial infection
JP2024554152A JP2025507179A (ja) 2022-11-08 2023-09-19 ポリミキシンの抗細菌感染効果を増強する薬剤の製造におけるｓｕ３３２７の用途

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