CN115990148B - Application of alpha-biotinone in preparation of medicines for treating carbapenem antibiotic drug-resistant bacteria infection - Google Patents
Application of alpha-biotinone in preparation of medicines for treating carbapenem antibiotic drug-resistant bacteria infection Download PDFInfo
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an application of alpha-thujaone in preparing a medicine for treating carbapenem antibiotic drug-resistant bacteria infection. According to the invention, the research shows that when the compound alpha-thujanone is used in combination with carbapenem antibiotics, the synergistic antibacterial effect can be generated on carbapenem antibiotic resistant bacteria, so that the treatment effect of carbapenem antibiotic resistant bacteria infection related diseases is remarkably improved, meanwhile, the drug resistant function of alpha-thujanone for inhibiting carbapenem antibiotic meropenem resistant genes is further researched, the antibacterial effect is mechanically clarified, and the invention is expected to be applied to clinical treatment of serious bacterial infection, so that the invention has important clinical significance and social benefit.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of alpha-thujaone in preparing a medicine for treating carbapenem antibiotic drug-resistant bacteria infection.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Carbapenem antibiotics are the antibiotics with the widest antibacterial spectrum and the strongest antibacterial activity so far, and have become one of the most main antibacterial drugs for clinically treating serious bacterial infection due to the characteristics of stability to broad-spectrum beta-lactamase, low toxicity and the like. However, with the wide application of carbapenem antibiotics, bacteria gradually acquire drug resistance through the ways of generating carbapenemase, efflux pump, PBP binding protein mutation and the like, so that the drug resistance of the carbapenem antibiotics of the bacteria is continuously increased, and the method brings serious challenges to clinical anti-infection treatment. Therefore, the synergist for screening the carbapenem antibiotics is applied to treating carbapenem antibiotic drug-resistant bacteria infection, and has important clinical significance.
The low-toxicity and high-efficiency natural active substances are screened from plants, so that the development of novel therapeutic drugs has great market value. Alpha-thujaone is monoterpene ketone mainly from biota, sage, mugwort and juniper berries, has fresh and sweet smell, and has various pharmacological activities such as disinsection, anti-tumor activity, central nervous system excitation, menstruation and cell regeneration promotion. However, no report on the application of alpha-biotone in treating carbapenem antibiotic resistant bacteria infection is currently found at home and abroad.
The molecular structural formula of the alpha-biotone is as follows:
disclosure of Invention
In order to overcome the defects in the prior art, the inventor provides a synergist alpha-biotinone of carbapenem antibiotics through long-term technical and practical exploration. When the compound alpha-biotinone is combined with carbapenem antibiotics, the carbapenem antibiotics resistant bacteria can be effectively killed. Based on the above results, the present invention has been completed.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides the use of alpha-thujaone in the manufacture of a medicament for the treatment of carbapenem antibiotic resistant bacteria infections. According to the invention, the research shows that when the compound alpha-biotinone is used in combination with the carbapenem antibiotics, the synergistic antibacterial effect can be generated on the carbapenem antibiotic resistant bacteria, so that the treatment effect of the carbapenem antibiotic resistant bacteria infection related diseases is remarkably improved, and meanwhile, the drug resistant function of the alpha-biotinone for inhibiting the carbapenem antibiotic meropenem resistant gene is further researched, so that the antibacterial effect is mechanically clarified.
Wherein the carbapenem antibiotics include, but are not limited to, imipenem, meropenem, panipenem, faropenem, ertapenem and biapenem.
The carbapenem antibiotic resistant bacteria include, but are not limited to, carbapenem resistant enterobacteria, carbapenem resistant acinetobacter baumannii and carbapenem resistant pseudomonas aeruginosa which are well known in clinic.
In a second aspect, the invention provides the use of an alpha-thujanone in combination with a carbapenem antibiotic for the preparation of a pharmaceutical composition for the treatment of a carbapenem antibiotic resistant bacterial infection.
Wherein the mass ratio of the alpha-biotone to the carbapenem antibiotics is 0.1-20:1.
The carbapenem antibiotic resistant bacteria include, but are not limited to, carbapenem resistant enterobacteria, carbapenem resistant acinetobacter baumannii and carbapenem resistant pseudomonas aeruginosa which are well known in clinic.
The carbapenem antibiotics include, but are not limited to, imipenem, meropenem, panipenem, faropenem, ertapenem, and biapenem.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising α -thujaone and a carbapenem antibiotic;
the mass ratio of the alpha-biotone to the carbapenem antibiotics is 0.1-20:1.
The pharmaceutical composition can be used for treating related diseases caused by carbapenem antibiotic drug-resistant bacteria infection.
In a fourth aspect of the invention, there is provided a method for treating carbapenem antibiotic-resistant bacterial infection, the method comprising administering to a subject the above pharmaceutical composition.
Compared with the prior art, the one or more technical schemes have the following beneficial effects:
according to the technical scheme, when the compound alpha-thujanone and the carbapenem antibiotics are combined for use, the carbapenem antibiotics resistant bacteria can be effectively killed, and the compound alpha-thujanone and the carbapenem antibiotics resistant bacteria are expected to be applied to clinical treatment of severe bacterial infection, so that the compound alpha-thujanone has important clinical significance and social benefit.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In an exemplary embodiment of the present invention, there is provided the use of alpha-thujaone in the manufacture of a medicament for the treatment of carbapenem antibiotic resistant bacteria infection. According to the invention, the research shows that when the compound alpha-biotinone is used in combination with the carbapenem antibiotics, the synergistic antibacterial effect can be generated on the carbapenem antibiotic resistant bacteria, so that the treatment effect of the carbapenem antibiotic resistant bacteria infection related diseases is remarkably improved, and meanwhile, the drug resistant function of the alpha-biotinone for inhibiting the carbapenem antibiotic meropenem resistant gene is further researched, so that the antibacterial effect is mechanically clarified.
Wherein the carbapenem antibiotics include, but are not limited to, imipenem, meropenem, panipenem, faropenem, ertapenem and biapenem.
The carbapenem antibiotic resistant bacteria include, but are not limited to, carbapenem resistant enterobacteria, carbapenem resistant acinetobacter baumannii and carbapenem resistant pseudomonas aeruginosa which are well known in clinic; in one embodiment of the present invention, experimental verification was performed using multi-drug resistant enterobacteria Enterobacter roggenkampii POL 1.
In yet another embodiment of the present invention, there is provided the use of an α -thujanone in combination with a carbapenem antibiotic in the manufacture of a pharmaceutical composition for the treatment of a carbapenem antibiotic resistant bacteria infection.
In yet another embodiment of the present invention, the mass ratio of the α -thujaone to the carbapenem antibiotic is from 0.1 to 20:1.
The carbapenem antibiotic resistant bacteria include, but are not limited to, carbapenem resistant enterobacteria, carbapenem resistant acinetobacter baumannii and carbapenem resistant pseudomonas aeruginosa which are well known in clinic.
The carbapenem antibiotics include, but are not limited to, imipenem, meropenem, panipenem, faropenem, ertapenem, and biapenem.
In yet another embodiment of the present invention, a pharmaceutical composition is provided, comprising an α -thujaone and a carbapenem antibiotic;
the mass ratio of the alpha-biotone to the carbapenem antibiotics is 0.1-20:1.
The pharmaceutical composition can be used for treating related diseases caused by carbapenem antibiotic drug-resistant bacteria infection; in one embodiment of the invention, the disease includes, but is not limited to, nosocomial pneumonia, sepsis, peritonitis, and the like.
The pharmaceutical composition further comprises a non-pharmaceutically active ingredient comprising a pharmaceutically acceptable carrier, excipient and/or diluent.
In yet another embodiment of the present invention, the non-pharmaceutically active ingredient comprises:
pharmaceutically compatible inorganic or organic acids or bases, polymers, copolymers, block copolymers, monosaccharides, polysaccharides, ionic and nonionic surfactants or lipids;
pharmacologically harmless salts (preferably sodium chloride), flavoring agents, vitamins (preferably vitamin a or vitamin E, tocopherol or provitamin), antioxidants (preferably ascorbic acid), and stabilizers and/or preservatives.
The administration forms of the pharmaceutical preparation include: liquid dosage forms, solid dosage forms, external preparations and sprays;
in yet another embodiment of the invention, the following dosage forms are included: true solutions, colloids, microparticle dosage forms, emulsion dosage forms, mixed rotation dosage forms, tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injection, inclusion compounds, landfill agents, patches and liniment.
In yet another embodiment of the present invention, there is provided a method for treating carbapenem antibiotic-resistant bacterial infection, the method comprising administering to a subject the above-described α -thujaone or pharmaceutical composition.
The invention is further illustrated by the following examples, which are given for the purpose of illustration only and are not intended to be limiting. Any simple modification, equivalent variation and modification of the implementation mode according to the technical substance of the invention are all within the scope of the technical proposal of the invention.
Example 1 synergistic antibacterial action against multiple resistant bacteria when meropenem and alpha-thujaone are used in combination
In this example, the multidrug resistant strain Enterobacter roggenkampii POL1 was isolated and stored in the laboratory, meropenem CAS:119478-56-7 (. Gtoreq.98%) from Sigma, alpha-thujanone CAS:546-80-5 (. Gtoreq.96%) from Sigma Co. Meropenem is prepared into a mother solution of 32mg/mL by using sterile water, and the mother solution is packaged into a sterile centrifuge tube after being filtered by a 0.22 mu m filter membrane, and then the mother solution is preserved by-80. The alpha-biotone is prepared into mother liquor of 1mg/mL by DMSO, filtered by a 0.22 mu m filter membrane and packaged into a sterile centrifuge tube for storage at-80.
The Minimum Inhibitory Concentrations (MICs) of meropenem and alpha-thuringienones on multidrug resistant bacteria POL1 were determined using the mini broth dilution method, with reference to CLSI specifications. As shown in Table 1, the MICs of the POL1 strain to meropenem are >128mg/L, and the MICs of the POL1 strain to meropenem (8 mg/L) are significantly reduced when 5mg/L of alpha-thujanone is added, which indicates that the combination of meropenem and alpha-thujanone has a synergistic bacteriostatic effect on the POL1 strain.
TABLE 1 MICs of multiple resistant bacteria (mg/L)
Example 2 Effect of meropenem and alpha-thujanone combination treatment of acute peritonitis in mice
A mouse acute peritonitis model is established by intraperitoneal injection of Enterobacter roggenkampii POL strain, meropenem (10 mg/kg) or meropenem plus alpha-biotone (10 mg/kg) are injected into a dosing group 2 times a day, an equal volume of physiological saline is injected into a non-dosing group, then peritoneal fluid is extracted for bacterial culture, identification and counting at 24 hours, 48 hours and 72 hours, and meanwhile, the total number of peripheral blood white blood cells is counted by taking tail vein blood, so that the anti-infection treatment effect of combined application of meropenem and alpha-biotone is observed. The results showed that the combined meropenem and α -thujanone administration group had cleared the bacterial infection at 72 hours, no bacteria were detected in the peritoneal fluid, and the total number of peripheral blood leukocytes was in the normal range (table 2). While the meropenem alone or the non-administered group still exhibited symptoms of peritonitis at 72 hours and few test mice died.
TABLE 2 Abdominal fluid bacterial and peripheral blood leukocyte counts of each group of mice for 72 hours
EXAMPLE 3 alpha-biotinone inhibiting drug resistance function of meropenem resistance Gene
The inventor confirms that one of the drug resistance genes related to meropenem drug resistance in POL1 is LMJ44_RS09805/LMJ44_RS09810/LMJ44_RS09815, which codes for an antibiotic efflux pump. The meropenem drug resistance gene in the POL1 strain (primer F: aatattgaaaaaggaagagtatgaccttttttcatcgctc, SEQ ID NO.1, R: ttatgcctgcggcgtgatct, SEQ ID NO. 2) is amplified through overlapping PCR and connected to the downstream of the escherichia coli promoter, and the recombinant vector is converted into the escherichia coli DH5 alpha strain after sequencing verification, so as to obtain the heterologous expression recombinant strain P9815.MIC detection shows that the MIC value of meropenem of the P9815 strain is respectively more than 128mg/mL, the MIC value of the P9815 strain is less than 2mg/L when 1mg/L-5mg/L of alpha-thujanone is added (table 3), the MIC value of meropenem of the starting strain DH5 alpha is less than 2mg/L, and the MIC value of alpha-thujanone is more than 128mg/L, so that the alpha-thujanone can inhibit the drug resistance function of the meropenem drug resistance gene.
TABLE 3 meropenem MICs of multiple resistant bacteria (mg/L)
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (4)
1. The application of alpha-biotone in preparing medicines for treating carbapenem antibiotic drug-resistant bacteria infection; wherein the carbapenem antibiotic is meropenem.
2. The use according to claim 1, wherein the carbapenem antibiotic resistant bacteria is carbapenem resistant enterobacteria.
3. A pharmaceutical composition, characterized in that the pharmaceutical active ingredients of the pharmaceutical composition are alpha-biotinone and carbapenem antibiotics; wherein the carbapenem antibiotic is meropenem;
the mass ratio of the alpha-biotone to the carbapenem antibiotics is 0.1-20:1.
4. A pharmaceutical composition according to claim 3, further comprising a non-pharmaceutically active ingredient comprising a pharmaceutically acceptable carrier, excipient and/or diluent.
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| FR2867947A1 (en) * | 2004-03-29 | 2005-09-30 | Hightech Bio Activities Holdin | VEGETABLE BIODECONTAMINANT COMPLEX HAVING BACTERICIDAL, FUNGICIDAL AND VIRUCID PROPERTIES FOR TREATMENT OF WATER |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2867947A1 (en) * | 2004-03-29 | 2005-09-30 | Hightech Bio Activities Holdin | VEGETABLE BIODECONTAMINANT COMPLEX HAVING BACTERICIDAL, FUNGICIDAL AND VIRUCID PROPERTIES FOR TREATMENT OF WATER |
Non-Patent Citations (2)
| Title |
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| A comprehensive review of the antibacterial, antifungal and antiviral potential of essential oils and their chemical constituents against drug-resistant microbial pathogens;Saika Tariq;Microbial Pathogenesis;20190611;第134卷;103580, 2.2.Antibacterial effects of essential oils * |
| Modulation of genotoxicity and DNA repair by plant monoterpenes camphor, eucalyptol and thujone in Escherichia coli and mammalian cells;Biljana Nikolic;Food and Chemical Toxicology;20110519;第49卷;2035-2045 * |
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