CN115487200A - Isoliquiritigenin and antibiotic combined pharmaceutical composition and application thereof - Google Patents

Isoliquiritigenin and antibiotic combined pharmaceutical composition and application thereof Download PDF

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CN115487200A
CN115487200A CN202211151036.0A CN202211151036A CN115487200A CN 115487200 A CN115487200 A CN 115487200A CN 202211151036 A CN202211151036 A CN 202211151036A CN 115487200 A CN115487200 A CN 115487200A
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isoliquiritigenin
cefoxitin
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gentamicin
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宋新波
李薇
丁辉
冉棋
冯京
邢龄艺
万慧颖
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Tianjin University of Traditional Chinese Medicine
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    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract

The invention discloses an isoliquiritigenin and antibiotic combined pharmaceutical composition and application thereof. The isoliquiritigenin and cefoxitin or gentamicin are combined for application, so that the toxic and side effects and the dosage of antibiotics can be obviously reduced, the MRSA (methicillin resistant Staphylococcus aureus) activity is stronger, even the drug resistance can be reversed, and a better synergistic antibacterial effect is shown; the isoliquiritigenin can improve the antibacterial action of beta-lactam antibiotics and aminoglycoside antibiotics, can provide reference for searching antibacterial sensitizing compounds, and can be used for preparing medicines for resisting methicillin-resistant staphylococcus aureus.

Description

Isoliquiritigenin and antibiotic combined pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of combined application of traditional Chinese medicines and antibiotics, in particular to a combined pharmaceutical composition of isoliquiritigenin and antibiotics and application thereof in preparing a methicillin-resistant staphylococcus aureus resistant medicament.
Background
Methicillin-resistant staphylococcus aureus (MRSA) is one of three common drug-resistant bacteria, is highly resistant to various antibiotics, is widely distributed in hospitals and communities, and can cause recurrent skin soft tissue infection, bacteremia, necrotizing pneumonia and other diseases. Glycopeptide antibiotics vancomycin, oxazolidinone antibiotics linezolid and the like are first-line drugs for treating MRSA infection at present, unfortunately, vancomycin-resistant strains appear in many areas due to overuse of antibiotics, and therefore, new antibacterial drugs or methods for relieving the current tension are urgently needed to be developed. In the development of new anti-MRSA drugs in the past, most researches are carried out to develop direct antibacterial antibiotics by modifying the structures of the existing antibacterial drugs, and the developed new drugs are often stopped in laboratory researches due to weak antibacterial activity or high toxicity. Therefore, the search for new antibacterial drugs with strong activity and low toxicity is of great significance. At present, the combination therapy is the most promising prevention and treatment method, and the drug combination can reduce the toxic and side effects and the dosage of antibiotics, thereby reducing the generation of bacterial drug resistance.
Cefoxitin (cefoxitin) is a cephamycin antibiotic in beta-lactam class, and is white to grey white crystal powder, and the antibacterial action mechanism of cefoxitin is that the cefoxitin is combined with one or more Penicillin Binding Proteins (PBPs) of bacterial cells to inhibit the cell wall synthesis of actively dividing bacterial cells, thereby playing the antibacterial action. Gentamicin (gentamicin) is an aminoglycoside antibiotic, is transparent amber liquid, and has an antibacterial action mechanism of acting on ribosomes in bacteria to inhibit the synthesis of bacterial proteins and destroy the integrity of bacterial cell membranes.
The isoliquiritigenin is an isoflavonoid compound separated and purified from glycyrrhiza plants, is yellow needle-shaped crystal, is insoluble in water, and is soluble in solvents with lower polarity such as diethyl ether and DMSO solution. Isoliquiritigenin has been proved to have many pharmacological activities, including anti-inflammatory, antiviral, antioxidant, anticancer, immunoregulatory, hepatoprotective, and cardioprotective effects. Research shows that isoliquiritigenin has good antibacterial activity on staphylococcus aureus, and the drug resistance of MRSA can be reversed when the isoliquiritigenin is combined with penicillin antibiotics in beta-lactam class. However, the effect of isoliquiritigenin in combination with cefoxitin and gentamicin in enhancing MRSA sensitivity and reversing drug resistance is not reported.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a combined drug composition of isoliquiritigenin and antibiotics and application thereof, wherein isoliquiritigenin and cefoxitin or gentamicin are combined for application, so that the curative effect of antibiotics is enhanced, the drug resistance of MRSA is resisted, and a new treatment strategy is provided for MRSA infection.
In order to solve the technical problems, the invention adopts the technical scheme that: a pharmaceutical composition containing isoliquiritigenin and antibiotic comprises isoliquiritigenin and antibiotic, wherein the antibiotic is cefoxitin or gentamicin.
The isoliquiritigenin and cefoxitin combined medicine has the mass ratio of (0.039-0.078): (0.00025-0.004); the isoliquiritigenin and gentamicin are combined by the following medicines in a mass ratio of (0.00975-0.078): (0.000975-0.00781).
Preferably, the liquiritigenin and cefoxitin combined medicine has a mass ratio of 0.039:0.002; the isoliquiritigenin and gentamicin are combined together according to the mass ratio of (0.0195-0.039) to (0.0019525-0.003905).
Also comprises pharmaceutically acceptable carriers, and can be made into tablet, granule, capsule, injection, controlled release preparation, etc.
The isoliquiritigenin and antibiotic combined medicine composition is used for preparing medicines for resisting methicillin-resistant staphylococcus aureus.
The beneficial effects of the invention are: the isoliquiritigenin and cefoxitin or gentamicin are combined for application, so that the toxic and side effects and the dosage of antibiotics can be obviously reduced, the MRSA (methicillin-resistant staphylococcus aureus) resisting activity is stronger, the drug resistance can be even reversed, and a better synergistic antibacterial effect is shown; the isoliquiritigenin can improve the antibacterial action of beta-lactam antibiotics and aminoglycoside antibiotics, and can provide reference for searching antibacterial sensitization compounds.
Drawings
FIG. 1 is a graph showing the lung bacterial load of rats administered with isoliquiritigenin and cefoxitin for four days ( *** P<0.001, compared to model set);
FIG. 2 is a graph showing the lung bacterial load of a six-day rat administered with isoliquiritigenin and cefoxitin *** P<0.001, compared to model group).
Detailed Description
The technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention; it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and all other embodiments obtained by those skilled in the art without any inventive work are within the scope of the present invention.
The active ingredients of the isoliquiritigenin and antibiotic combined medicine composition consist of isoliquiritigenin and antibiotic, and the antibiotic is cefoxitin or gentamicin.
The isoliquiritigenin and cefoxitin combined medicine has the mass ratio of (0.039-0.078): (0.00025-0.004); the isoliquiritigenin and gentamicin combined medicine composition comprises the following components in percentage by mass (0.00975-0.078): (0.000975-0.00781).
Preferably, the liquiritigenin and cefoxitin combined medicine has a mass ratio of 0.039:0.002; the isoliquiritigenin and gentamicin are combined together according to the mass ratio of (0.0195-0.039) to (0.0019525-0.003905).
Also comprises pharmaceutically acceptable carriers, and can be made into tablet, granule, capsule, injection, controlled release preparation, etc.
The isoliquiritigenin and antibiotic combined medicine composition is used for preparing medicines for resisting methicillin-resistant staphylococcus aureus.
The static research on the sensitivity of the isoliquiritigenin, cefoxitin and gentamicin to the MRSA is carried out; the therapeutic effect of isoliquiritigenin in combination with cefoxitin on the pneumonia of MRSA rats is explained in detail.
The isoliquiritigenin is extracted and separated from the traditional Chinese medicine liquorice or synthesized by an artificial mode, and can be extracted and prepared by any published literature or patent method. The static research of the invention is a micro chessboard dilution method in a chessboard method, and is one of the most common combined drug screening methods. The micro chessboard dilution method takes the minimum inhibitory concentration of the drugs as the highest concentration for dilution, and tries to find the combination of the two drugs which still can show stronger bacteriostatic activity under sub-inhibitory concentration. The FIC value is a combined bacteriostasis index value and is an evaluation index of the combined drug sensitivity of two drugs. When two antibacterial drugs are used simultaneously, five conditions of remarkable synergy, partial synergy, addition, irrelevance and antagonism can occur, and the interpretation standards are as follows: FIC is less than or equal to 0.5, and a synergistic effect is remarkable; FIC is 0.5-1, and partial synergistic effect is achieved; FIC =1, additive effect; FIC >1-4, independent effect; FIC is more than or equal to 4, and antagonistic effect is achieved. The pneumonia provided by the invention is bacterial pneumonia infected by MRSA, and the occurrence of the pneumonia is influenced by the age, immunity, basic diseases, antibiotic use history and the like of patients. The invention adopts the trachea puncture method to construct the MRSA infected rat pneumonia model, and the method can directly inject bacteria into the rat lung and has accurate dose.
Example 1 static Effect of Isoliquiritigenin in combination with cefoxitin and gentamicin on MRSA sensitivity
1. Experimental strains: methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus) ATCC 43300
2. The main reagents are as follows: cefoxitin sodium for injection (Guangzhou Baiyunshan Tianxin pharmacy Co., ltd.); gentamicin injection (changle pharmaceutical co., ltd, new county); phosphate buffer (beijing solibao science and technology ltd); MHB Medium (Beijing Sorbao science and technology Co., ltd.)
3. The experimental method comprises the following steps: three medicines of cefoxitin with the concentration of 64mg/ml, gentamicin with the concentration of 40mg/ml and isoliquiritigenin with the concentration of 50mg/ml are respectively added into a sterilized MHB culture medium to be dissolved, and a proper amount of dimethyl sulfoxide is added to assist the dissolution, so that a series of liquid medicines with diluted concentration are prepared. Mixing two corresponding medicines by adopting a chessboard design method and adding the medicines into a 96-pore plate, wherein each pore plate is simultaneously provided with a medicine group, a bacteria liquid positive control group and a bacteria liquid negative control group, and samples are sequentially added according to the following sample adding sequence: firstly, 70 mu LMHB culture media are respectively added into each component, and then 20 mu L of liquid medicines with different concentrations are respectively added into the mixed medicine component and the mixed medicine control component; respectively adding 20 μ L of medicinal liquid solvent into the bacterial liquid group and the negative control group. Finally, respectively adding 10 mu L of bacterial suspension into the mixed drug group and the bacterial liquid group; the drug control group and the negative control group were mixed and 10. Mu.L PBS buffer was added. After all samples were loaded, the 96-well plates were incubated in a 35 ℃ incubator, and after 18h, the clear solution in each well was recorded and its absorbance at 590nm was measured. The above experiment was repeated three times.
4. Data processing: calculating the bacteriostasis rate according to the following formulas (1 and 2), and calculating the corresponding FIC value according to the formula (3) according to the lowest bacteriostasis concentration when the two medicines are applied in combination.
OD Amount of change ＝OD Drug group -OD Drug control group (formula 1)
Figure BDA0003856374830000041
Figure BDA0003856374830000042
5. The experimental results are as follows: the concentration with the bacteriostasis rate of more than or equal to 90 percent is taken as the lowest bacteriostasis concentration when the two medicines are applied in a combined way, and the FIC value is calculated and shown in tables 1 to 4.
TABLE 1 antibacterial action of isoliquiritigenin in combination with cefoxitin on MRSA
Figure BDA0003856374830000043
Figure BDA0003856374830000051
Note: and (2) preparing: indicating non-detection
TABLE 2 Combined antibacterial action of isoliquiritigenin and cefoxitin
Figure BDA0003856374830000052
As can be seen from Table 1, cefoxitin with a concentration of 0.001mg/mL and isoliquiritigenin with a concentration of 0.039 mg/mL; the cefoxitin with the concentration of 0.001mg/mL, 0.002mg/mL and 0.004mg/mL and the isoliquiritigenin with the concentration of 0.0195mg/mL are ineffective compatibility combination. As can be seen from Table 2, the concentration of isoliquiritigenin is 0.078mg/mL, and the concentrations of cefoxitin are 0.002mg/mL, 0.001mg/mL, 0.0005mg/mL and 0.00025 mg/mL; the isoliquiritigenin with the concentration of 0.039mg/mL and the cefoxitin with the concentrations of 0.004mg/mL and 0.002mg/mL have synergistic effect, wherein the isoliquiritigenin with the concentration of 0.039mg/mL and the cefoxitin with the concentration of 0.002mg/mL are the optimal drug combination.
TABLE 3 bacteriostatic action of isoliquiritigenin in combination with gentamicin on MRSA
Figure BDA0003856374830000053
Figure BDA0003856374830000061
Note: and (2): indicating not detected
TABLE 4 Combined antibacterial action of Isoliquiritigenin and gentamicin
Figure BDA0003856374830000062
As can be seen from Table 3, the concentration of gentamicin is 0.000488125mg/mL and the concentration of isoliquiritigenin is 0.078 mg/mL; the concentration of the gentamicin is 0.00097625mg/mL and the concentration of the isoliquiritigenin is 0.039 mg/mL; the concentration of gentamicin is 0.0019525mg/mL and the concentration of isoliquiritigenin is 0.0195 mg/mL; the concentration of the gentamicin is 0.003905 and the concentration of the isoliquiritigenin is 0.00975 mg/mL; the concentration of gentamicin is 0.00781mg/mL, and the concentration of isoliquiritigenin is 0.004875, which are ineffective in compatibility. As can be seen from Table 4, the concentration of isoliquiritigenin is 0.078mg/mL and the concentrations of gentamicin are 0.003905mg/mL, 0.0019525mg/mL and 0.000975 mg/mL; isoliquiritigenin with concentration of 0.039mg/mL and gentamicin with concentrations of 0.00781mg/mL, 0.003905mg/mL and 0.0019525mg/mL; isoliquiritigenin with concentration of 0.0195mg/mL and gentamicin with concentration of 0.00781mg/mL and 0.003905mg/mL; the nine groups of medicine compositions have synergistic effect, wherein the concentration of the isoliquiritigenin is 0.00975mg/mL, and the concentration of the gentamicin is 0.00781mg/mL, and the concentration of the isoliquiritigenin is 0.039mg/mL, and the concentration of the gentamicin is 0.003905mg/mL; the concentration of the isoliquiritigenin is 0.039mg/mL, and the concentration of the gentamicin is 0.0019525mg/mL; the isoliquiritigenin concentration is 0.0195mg/mL, and the gentamicin concentration is 0.003905mg/mL, which are the optimal drug combination.
Example 2 therapeutic Effect of Isoliquiritigenin in combination with cefoxitin on pneumonia in MRSA rats
1. Experimental materials: methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus) ATCC 43300; SD rats, SPF grade, weight 200-220g, purchased from Beijing Wintolidian laboratory animal technology, inc.; linezolid tablets (Pfizer Pharmaceuticals LLC); rat IL-6ELISA Kit (Wuhan doctor De bioengineering, inc.); rat TNF-alpha ELISA Kit (Wuhan doctor De bioengineering Co., ltd.)
2. The experimental method comprises the following steps: except the blank group, the rest rats are anesthetized by chloral hydrate, part of dermatosis is cut off to separate an air outlet pipe, cultured bacteria liquid (0.8 mL/kg) is injected from the air pipe, and the rats are slightly shaken for several times in an upright state after the skin is sutured, so that the bacteria liquid is uniformly distributed in the lungs on two sides. The positive control drugs linezolid group (54 mg/kg), cefoxitin group (45 mg/kg), isoliquiritigenin (90 mg/kg), cefoxitin + isoliquiritigenin group (45 mg/kg +45 mg/kg), blank control group and model group were gavaged with 0.5% sodium carboxymethylcellulose, 5 per group at each time point. After two days of modeling, each group starts to perform the gavage treatment, the dosage is 1mL/100g and 2 times/day, and five rats are randomly selected from each group for the subsequent experimental treatment in two days, four days and six days of administration respectively. Detecting the bacteria carrying amount of lung tissue and the contents of TNF-alpha and IL-6 in the serum of rat.
3. The experimental results are as follows: the results of the pulmonary bacterial load of the rats in each group on four days of administration are shown in fig. 1, and the results of the pulmonary bacterial load of the rats in each group on four six days of administration are shown in fig. 2. The change of TNF-alpha content in rat serum is shown in Table 6, and the change of IL-6 content in rat serum is shown in Table 7.
TABLE 5 rat blood TNF-alpha content (pg/mL)
Figure BDA0003856374830000071
Figure BDA0003856374830000081
Note: p <0.05, P <0.01, P <0.001 compared to the blank group; compared with the model group, # P <0.05, # P <0.01, # P <0.001
As shown in Table 5, the TNF-. Alpha.content of the blank group did not change significantly within six days of administration, and the TNF-. Alpha.content of the model group was significantly increased compared to that of the blank group (P < 0.05). After four days of administration, the content of TNF-alpha in the linezolid and isoliquiritigenin group begins to decrease (P < 0.05); after six days of administration, the content of TNF-alpha in each administration group is obviously reduced compared with that in a model group (P < 0.01), wherein the content of linezolid, isoliquiritigenin and TNF-alpha in a combined group is not statistically different from that in a blank group (P > 0.05).
TABLE 6 serum IL-6 content (pg/mL) of each group of rats
Figure BDA0003856374830000082
Note: p <0.05, P <0.01, P <0.001; compared with the model group, # P <0.05, # P <0.01, # P <0.001
As can be seen from Table 6, the IL-6 content in the blank group did not change significantly within six days of administration, and the IL-6 content in the model group remained high (P < 0.001) within six days of administration. Compared with the model group, the content of IL-6 in the positive drug linezolid group is obviously reduced (P < 0.001) and the content of IL-6 in the isoliquiritigenin and the combined group is reduced without statistical difference (P > 0.05) after the administration for two days; after four days of administration, the IL-6 content of the linezolid group and the combined group is obviously reduced (P < 0.001), and the two single medicine groups have no obvious change (P > 0.05); after six days of administration, the contents of linezolid, cefoxitin, isoliquiritigenin and IL-6 in the combined group are all obviously reduced, wherein the content of IL-6 in the combined group is close to that in the blank group (P is more than 0.05), but the content of IL-6 in cefoxitin is still higher.
4 conclusion of the experiment
According to the lung bacterial load, the isoliquiritigenin can improve the bacteriostatic action in cefoxitin. Each administration group has different degrees of inhibition on the content of TNF-alpha and IL-6, and the combined group has stronger inhibition on IL-6. The isoliquiritigenin combined with cefoxitin can relieve bacterial infection pneumonia caused by MRSA.
The above-mentioned embodiments are only for illustrating the technical idea and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and to implement the present invention accordingly, but not to limit the scope of the present invention by only the embodiments, i.e. all equivalent changes or modifications made within the spirit of the present invention disclosed in the present invention still fall within the scope of the present invention.

Claims (5)

1. A pharmaceutical composition containing isoliquiritigenin and antibiotic is characterized in that the active ingredients comprise isoliquiritigenin and antibiotic, and the antibiotic is cefoxitin or gentamicin.
2. The isoliquiritigenin and antibiotic combination pharmaceutical composition of claim 1, wherein the isoliquiritigenin and cefoxitin combination pharmaceutical composition comprises the following components in a mass ratio of (0.039-0.078): (0.00025-0.004); the isoliquiritigenin and gentamicin combined medicine composition comprises the following components in percentage by mass (0.00975-0.078): (0.000975-0.00781).
3. The isoliquiritigenin and antibiotic combination pharmaceutical composition of claim 2, wherein the weight ratio of the isoliquiritigenin to cefoxitin combination pharmaceutical composition is 0.039:0.002; the isoliquiritigenin and gentamicin are combined together according to the mass ratio of (0.0195-0.039) to (0.0019525-0.003905).
4. The isoliquiritigenin in combination with antibiotic composition of any one of claims 1-3, further comprising a pharmaceutically acceptable carrier.
5. Use of the isoliquiritigenin and antibiotic combination pharmaceutical composition of any one of claims 1-3 for preparing a medicament against methicillin-resistant staphylococcus aureus.
CN202211151036.0A 2022-09-21 2022-09-21 Isoliquiritigenin and antibiotic combined pharmaceutical composition and application thereof Pending CN115487200A (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RASHMI GAUR等: "Drug Resistance Reversal Potential of Isoliquiritigenin and Liquiritigenin Isolated from Glycyrrhiza glabra Against Methicillin-Resistant Staphylococcus aureus (MRSA", 《PHYTOTHER. RES.》 *
刘树玲;左国营;徐贵丽;: "抗耐药菌中草药成分的研究进展", 医学综述 *

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Application publication date: 20221220