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CN117883436A - Use of endoperoxides alone or in combination with respiratory chain inhibitors for the preparation of antibacterial agents - Google Patents

Use of endoperoxides alone or in combination with respiratory chain inhibitors for the preparation of antibacterial agents Download PDF

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CN117883436A
CN117883436A CN202311614935.4A CN202311614935A CN117883436A CN 117883436 A CN117883436 A CN 117883436A CN 202311614935 A CN202311614935 A CN 202311614935A CN 117883436 A CN117883436 A CN 117883436A
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administration concentration
artemisinin
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respiratory chain
mycobacterium tuberculosis
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周兵
张旭
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Shenzhen Institute of Advanced Technology of CAS
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/06—Antibacterial agents for tuberculosis
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Abstract

The application discloses application of an endoperoxide compound in preparing an antimicrobial pathogenic bacteria drug, and under the anoxic condition, the artemisinin-like drug represented by the endoperoxide compound can partially and effectively inhibit survival of mycobacterium tuberculosis in a medium of the mycobacterium tuberculosis. The application also discloses application of the combination of the endoperoxide compound and the respiratory chain inhibitor in preparing antimicrobial pathogenic bacteria medicines, and under normal and anoxic conditions, the combination of the endoperoxide compound and various respiratory chain inhibitors has synergistic action in a culture medium of mycobacterium tuberculosis, and the combination has more effective inhibition effect on the mycobacterium tuberculosis. Internal peroxy compounds include artemisinin and its derivatives, as well as other internal peroxy compounds with a dioxy bridge structure, which may have a similar mechanism of action, the internal oxygen bridge being the key group for their function. The application aims at rapidly or effectively killing pathogenic bacteria by introducing endoperoxide compounds represented by artemisinin as a medicament, improving the cure efficiency or shortening the treatment course, overcoming the problem of drug resistance, and simultaneously reducing the medicament amount and reducing the side effect on patients.

Description

Use of endoperoxides alone or in combination with respiratory chain inhibitors for the preparation of antibacterial agents
Technical Field
The application relates to application of an endoperoxide compound in preparation of an antimicrobial pathogenic bacteria drug, and belongs to the technical field of biochemistry.
Background
Tuberculosis (tuberculosis) is one of the three infections identified by the World Health Organization (WHO) and is the leading cause of death in adults worldwide, with about 150 tens of thousands of deaths in 2020, most of which are in low and medium income countries. Mycobacterium tuberculosis is a pathogenic bacterium of tuberculosis, which is a class of slow-growing microaerophilic bacteria. Currently, the commonly used antitubercular drugs consist of three major classes of antibiotics, synthetic drugs and traditional Chinese medicines, wherein more than 20 western medicines are national basic therapeutic drugs, and the first-line therapeutic drugs mainly comprise isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, rifamycins and the like. Fluoroquinolones have also been used in anti-tubercular therapy in recent years, and play an important role in combination therapy. Rifampicin resistant tuberculosis and multi-drug resistant tuberculosis still cannot be diagnosed quickly and an effective treatment scheme is adopted timely, including effective management of adverse reactions of two-line drugs. This results in persistent epidemic spread, low cure rate, and drug-resistant tuberculosis spread. Patients with high drug resistance tuberculosis have poorer therapeutic effects, including high mortality, especially in patients who are also infected with aids virus, even if they are undergoing antiretroviral medication. Thus, there is a strong market for newer, shorter, more effective (non-injectable) therapeutic agents.
Artemisinin and its derivatives are antimalarial drugs, and have the advantages of strong species specificity, fast drug action, small toxic and side effects, etc. The dioxy bridge in the artemisinin structure is a key pharmacophore, and the opening or breaking of the dioxy bridge, namely the activation of artemisinin, is a precondition for the action of artemisinin, and the deoxidized artemisinin obtained by replacing the dioxy bridge with the monooxygen bridge loses antimalarial activity. Besides antimalarial effect, artemisinin drugs have the effects of killing parasites of other types and resisting viruses, and also have the treatment effect on diabetes and autoimmune disease lupus erythematosus.
At present, the tuberculosis is treated with low cure rate, large side effect of the medicine, long treatment period and serious drug resistance, a large number of medicine tablets are required to be orally taken during the treatment period and injected daily for a long time, and patients bear huge economic burden and physiological pain for a long time. Although the efficacy of artemisinin against tubercle bacillus is reported, the action mechanism of artemisinin is not clear for researchers, the use concentration of the medicine is extremely high, the effect is not ideal, and the method has no clinical application significance.
Disclosure of Invention
The first object of the present application is to provide an application of an endoperoxide compound in preparation of antibacterial drugs, so as to overcome the problems of drug resistance and large side effects of drugs in tuberculosis treatment in the prior art.
In order to achieve the above object, the present application adopts the technical scheme that:
use of an endoperoxide compound comprising the following structural units in the preparation of an antibacterial agent: 1, 2-dioxane, 1,2, 4-trioxane, 1,2,4, 5-tetraxane, 1, 2-dioxolane or 1,2, 4-trioxane; the antibacterial drug is used for inhibiting mycobacterium tuberculosis; under anoxic conditions, the administration concentration of the endoperoxide compound is as follows: the administration concentration is less than or equal to 100 mu M.
In this application, a sealed anoxic culture tube filled with Middlebrook 7H9 broth medium was used as a culture model for mycobacterium tuberculosis, which was inoculated to od600=0.01, and then continued to be cultured to anoxic conditions. Methylene blue was used as an indicator. The administration concentration of the internal peroxy compound is converted by the in-vitro administration concentration, and the internal peroxy compound has good inhibition effect on mycobacterium tuberculosis under the condition that the administration concentration is less than or equal to 100 mu M, and the administration concentration is low, so that the side effect of the drug is reduced.
Further, the endoperoxide compounds include artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivatives containing an internal oxygen bridge.
Wherein, artemisinin and its derivatives are antimalarial drugs, and have the advantages of strong species specificity, rapid drug action, small toxic and side effects, etc. The dioxy bridge in the artemisinin structure is a key pharmacophore, and the opening or breaking of the dioxy bridge, namely the activation of artemisinin, is a precondition for the action of artemisinin, and the deoxidized artemisinin obtained by replacing the dioxy bridge with the monooxygen bridge loses antimalarial activity. Besides antimalarial effect, artemisinin drugs have the effects of killing parasites of other types and resisting viruses, and also have the treatment effect on diabetes and autoimmune disease lupus erythematosus. Artifenomel (OZ 439) is an orally active, synthetic antimalarial compound containing an artemisinin pharmacophore with a mechanism of action similar to that of artemisinin. HEM is an extract of herba Senecionis Scandentis, and is an extraction mixture containing multiple eremophilanolid sesquiterpenes. Ascapidol is an extract of the traditional Chinese medicine mountain road years. majapolene A is an extract of Laurencia. yingzhaosu a is hawk claw a, also called hawk claw a, which is a sesquiterpene derivative with peroxy groups isolated from the root of the herb hawk claw. aceranol acetate is an extract of Acer palmatum.
Further, the administration concentration of the endoperoxide compound is: the administration concentration is less than or equal to 12.5 mu M and less than or equal to 50 mu M.
Further reduces the administration concentration, and experiments prove that the administration concentration of the endoperoxide has good inhibition effect on mycobacterium tuberculosis within the range of 12.5 mu M-50 mu M, thereby being beneficial to further reducing the side effect of the medicament.
A second object of the present application is to provide a use of an endoperoxide compound in combination with a respiratory chain inhibitor for the preparation of antibacterial drugs, in order to overcome the problems of drug resistance and great side effects of drugs in tuberculosis treatment in the prior art.
In order to achieve the above object, the present application adopts the technical scheme that:
the internal peroxy compound comprises the following structural units: 1, 2-dioxane, 1,2, 4-trioxane, 1,2,4, 5-tetraxane, -1, 2-dioxolane, or 1,2, 4-trimethoxy-valer-ne; the antibacterial drug is used for inhibiting mycobacterium tuberculosis; the respiratory chain inhibitor is Mycobacterium tuberculosis respiratory chain inhibitor.
In this application, a sealed culture tube containing a culture medium of Middlebrook 7H9 broth was used as a culture model of mycobacterium tuberculosis, and in the test of the culture model, the combination of an endoperoxide compound with a respiratory chain inhibitor was able to enhance the inhibitory effect of the respiratory chain inhibitor on mycobacterium tuberculosis.
Further, the endoperoxide compounds include artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivatives containing an internal oxygen bridge.
Further, the respiratory chain inhibitor of the mycobacterium tuberculosis is one or more of bedaquiline, Q203, aurachin D or lansoprazole.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, aurachin D or lansoprazole; under normal oxygen conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 100 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than or equal to 4 mu M; the dosing concentration of Q203 is: the administration concentration is less than 10nM; the dosing concentrations of Aurachin D were: the administration concentration is less than or equal to 20 mu M; the lansoprazole is administered at the following concentration: the administration concentration is less than or equal to 20 mu M.
Thus, artemisinin combined with bedaquiline, Q203, lansoprazole, or Aurachin D can reduce survival in combination with mycobacteria compared to the corresponding respiratory chain inhibitor alone under normal oxygen conditions. It has been shown that normally artemisinin in combination with a respiratory chain inhibitor can increase the inhibitory effect of respiratory chain inhibitors on mycobacterium tuberculosis. Under the condition of the administration concentration, the total administration concentration of artemisinin and the combination of the bedaquiline, the Q203, the lansoprazole or the Aurachin D is low, which is beneficial to reducing the side effect of the medicine.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, auracin D or lansoprazole; under normal oxygen conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 100 mu M; the administration concentration of the Q203 is as follows: the administration concentration is less than or equal to 1nM.
Thus, the administration concentration of Q203 is further reduced, and experiments prove that when the administration concentration of Q203 is not higher than 1nM, the combination of artemisinin and the administration concentration of Q203 has a good inhibition effect on mycobacterium tuberculosis, and the administration amount is further reduced, so that the side effect of the medicine is reduced.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, aurachin D or lansoprazole; under anoxic conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 50 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than 10 mu M; the dosing concentration of Q203 is: the administration concentration is less than 5nM; the dosing concentrations of Aurachin D were: the administration concentration is less than 20 mu M; the lansoprazole is administered at the following concentration: the administration concentration is less than 20 mu M.
Thus, artemisinin in combination with bedaquiline, Q203, lansoprazole, or Aurachin D can reduce survival in combination with mycobacteria compared to the corresponding respiratory chain inhibitor alone under hypoxic conditions. It can be seen that combination of artemisinin and respiratory chain inhibitors under hypoxia conditions can enhance the inhibitory effect of respiratory chain inhibitors on mycobacterium tuberculosis. Under the condition of the administration concentration, the total administration concentration of artemisinin and the combination of the bedaquiline, the Q203, the lansoprazole or the Aurachin D is low, which is beneficial to reducing the side effect of the medicine.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, aurachin D or lansoprazole; under anoxic conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 50 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than or equal to 2 mu M; the dosing concentration of Q203 is: the administration concentration is less than or equal to 0.5nM.
Thus, experiments prove that the administration concentration of the bedaquiline and Q203 is well inhibited by combining with artemisinin when the administration concentration of the bedaquiline is not higher than 2 mu M, and the administration concentration of the Q203 is well inhibited by combining with artemisinin when the administration concentration of the bedaquiline is not higher than 0.5nM, thereby being beneficial to further reducing the administration amount and further reducing the side effect of the medicine.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is two of bedaquiline, Q203, aurachin D or lansoprazole; under normal oxygen conditions, the administration concentrations of artemisinin and respiratory chain inhibitors are:
the administration concentration of artemisinin is less than or equal to 50 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than 10 mu M, and the administration concentration of Q203 is as follows: the administration concentration is less than 5nM;
or alternatively, the first and second heat exchangers may be,
the administration concentration of artemisinin is less than or equal to 50 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than 10 mu M, and lansoprazole is: the administration concentration is less than 10 mu M.
Thus, the test results show that under normal conditions, artemisinin is combined with Q203 and Auracin D, or artemisinin is combined with lansoprazole and Auracin D, and the survival rate of the combined mycobacterium is reduced compared with that of the single use of two corresponding respiratory chain inhibitors. It has been shown that the combination of artemisinin with various respiratory chain inhibitors can normally enhance the inhibitory effect of respiratory chain inhibitors on mycobacterium tuberculosis. Under the condition of the administration concentration, the total administration concentration of the artemisinin and the two respiratory chain inhibitors is low, which is favorable for reducing the side effect of the medicine.
Further, the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is two of bedaquiline, Q203, aurachin D or lansoprazole; under normal oxygen conditions, the administration concentrations of artemisinin and respiratory chain inhibitors are:
the administration concentration of artemisinin is less than or equal to 25 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than or equal to 2.5 mu M, and the administration concentration of Q203 is as follows: the administration concentration is less than or equal to 4nM;
or alternatively, the first and second heat exchangers may be,
the administration concentration of artemisinin is less than or equal to 25 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than or equal to 2.5 mu M, and lansoprazole is: the administration concentration is less than or equal to 2 mu M.
Thus, the administration concentration of Q203, auracin D and lansoprazole is further reduced, and experiments prove that under normal conditions, the administration concentration of Auracin D has good inhibition effect on mycobacterium tuberculosis when being combined with artemisinin when the administration concentration of Auracin D is not higher than 2.5 mu M, Q203 and is not higher than 4nM; the Aurachin D has good inhibition effect on mycobacterium tuberculosis when being combined with artemisinin when the administration concentration is not higher than 2.5 mu M and the lansoprazole administration concentration is not higher than 2 mu M, and is favorable for further reducing the administration amount so as to reduce the side effect of the medicine.
A third object of the present application is to provide an antibacterial agent comprising an effective amount of an endoperoxide compound together with a respiratory chain inhibitor of mycobacterium tuberculosis and a pharmaceutically acceptable carrier; the respiratory chain inhibitor of the mycobacterium tuberculosis is one or more of bedaquiline, Q203, aurachin D or lansoprazole; the endoperoxide compounds include artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivatives containing an internal oxygen bridge.
The application aims to more rapidly or effectively kill pathogenic bacteria, especially mycobacterium tuberculosis, by introducing endoperoxide represented by artemisinin as a medicament, has potential application in treating tuberculosis, improves cure efficiency or shortens treatment course, overcomes the problem of drug resistance, and simultaneously reduces side effects of drug quantity reduction on patients. Compared with the prior art, the application can bring the following technical effects:
1) The difference of action mechanisms is helpful for overcoming the drug resistance problem;
2) The dosage of the medicine can be reduced, and the side effect of the medicine is reduced;
3) Compared with the prior art, the traditional Chinese medicine composition is safer and has small toxic and side effects;
4) Is helpful for shortening the course of treatment, reducing the treatment expense and relieving the burden of patients and medical systems.
Drawings
FIG. 1 is a schematic representation of the inhibition of Mycobacterium tuberculosis by artemisinin in combination with a respiratory chain inhibitor in the examples of the application.
FIG. 2 is an analysis of the inhibition of Mycobacterium tuberculosis using artemisinin and bedaquiline alone under normal and hypoxic conditions in example 1, comparative example 1 and comparative example 1 of the present application.
FIG. 3 is an analysis of the inhibition of Mycobacterium tuberculosis using artemisinin in combination with bedaquiline, Q203, auracin D or lansoprazole, respectively, under normal conditions in example 2 of the present application.
FIG. 4 is an analysis of the inhibition of Mycobacterium tuberculosis using artemisinin at different dosing concentrations in combination with Q203 and bedaquiline at fixed dosing concentrations, respectively, under normal and hypoxic conditions, in example 3 of the present application.
FIG. 5 is an analysis of the inhibition of Mycobacterium tuberculosis using artemisinin and Aurachin D in combination with Q203 or lansoprazole, respectively, under normal conditions in the examples of the present application.
In the figure, normal, aerobic means ART-artemsinin-Artemisinin, bedaquiline-Bedaquiline, lansoprazole-Lansoprazole under normal oxygen conditions.
Detailed Description
The present application is further illustrated, but not limited, by the following examples.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified. In this application, normal conditions refer to normal oxygen conditions; under anaerobic conditions, it means that the methylene blue indicator changes color, typically with an oxygen content of less than 5%, in a sealed anaerobic culture tube.
Description of the terminology:
HEM: a senecio scandens extract comprising an extract mixture of a plurality of eremophilanolid sesquiterpenes.
ascapidol: mountain road year extract, CAS:512-85-6
majapolene a: extract of Laurencia, NSC-692207, CHEMBL450193, [4- (4-bromo-3, 3-dimethylcylohexyl) -2, 3-dioxabilic [2.2.2] oct-5-en-1-yl ] methane-anol
yingzhaosu a: eaglewood claw A, also called eaglewood claw A; CAS:73301-54-9
Artefenomel(OZ439)：CAS:1029939-86-3
aceranol acetate：CAS:1221260-33-8
OD600: OD600 refers to the absorbance of a solution at 600nm, which is proportional to the concentration of the light absorbing substance in the solution, and can be used to characterize the cell density of the cells;
OADC: (=oleic acid, album, dextrose and catalase), i.e. oleic acid, albumin, dextrose and catalase mixture;
middlebrook 7H9 broth: purchased from beiku labs science and technology limited, cat No.: MKC301; how to configure: configured according to the product instruction book.
Q203: CAS number 1334719-95-7;
aurachin D: CAS number 108354-13-8.
Example 1: the present example demonstrates the effect of artemisinin in anti-mycobacterium tuberculosis by in vitro experiments comprising the steps of:
s1: dissolving artemisinin powder in dimethyl sulfoxide to prepare artemisinin solution;
s2: mycobacterium tuberculosis was inoculated to OD600 = 0.01 in a sealed anoxic culture tube filled with Middlebrook 7H9 broth medium, and then culture was continued until anoxic conditions. The methylene blue indicator added in the culture medium can deplete oxygen in the culture tube when bacteria grow to a certain degree, and the indicator changes color, which indicates that the anoxic condition is reached.
S3: firstly, preparing a dimethyl sulfoxide stock solution of 200mM artemisinin, adding different amounts of artemisinin stock solution into an experimental group according to the requirement when in use, and diluting with dimethyl sulfoxide to ensure that the concentration of artemisinin in a culture medium is 6.25 mu M, 12.5 mu M, 25 mu M, 50 mu M and 100 mu M respectively, and continuously incubating at 37 ℃ for 6 days, wherein only solvent dimethyl sulfoxide is added into a control group.
Comparative example 1:
substantially the same as the implementation method of example 1 was conducted, except that: (1) the test is performed under normal (aerobic) conditions;
(2) In step S2, the density of mycobacterium tuberculosis is od600=0.003.
Adjuvant example 1:
the effectiveness of the experimental procedure was confirmed by adjuvant example 1, and by treating Mycobacterium tuberculosis (the concentrations of the drug treatments were 0.25. Mu.M, 0.5. Mu.M, 1. Mu.M, 2. Mu.M, and 4. Mu.M, respectively) in the same manner as in example 1 using the clinically applied antituberculotic drug Beda quinoline, a remarkable inhibitory effect was observed under both normal and hypoxic conditions.
Example 1 in combination with control 1, adjuvant 1 and fig. 2, it can be seen that: under normal conditions, artemisinin at different concentrations was incubated with the same amount of mycobacterium tuberculosis (od600=0.003), and after incubation at 37 ℃ for 6 days, the survival rate of mycobacterium tuberculosis was not significantly different from that of the control group; under the anoxic condition, the artemisinin with different concentrations is incubated with the same quantity (OD 600 = 0.01) of mycobacterium tuberculosis, after the culture is carried out for 6 days at 37 ℃, compared with a control group, the survival rate of the mycobacterium tuberculosis is obviously reduced, and 25 mu M artemisinin can obviously inhibit the survival rate of the mycobacterium tuberculosis.
Example 2:
substantially the same as the implementation method of example 1 was conducted, except that: (1) the test is performed under normal (aerobic) conditions; (2) The combinations and concentrations of the treatment drugs were varied, and specific combinations and concentrations of the drugs are shown in table 1.
Table 1 drug concentration for each set of experiments in example 2
The test results are shown in FIG. 3, which shows that artemisinin combined with Bedaquin, Q203, lansoprazole, or Auracin D can reduce survival rate of bound mycobacteria under normal conditions compared to the corresponding respiratory chain inhibitor alone. It has been shown that normally artemisinin in combination with a respiratory chain inhibitor can increase the inhibitory effect of respiratory chain inhibitors on mycobacterium tuberculosis. The concentration of artemisinin administered was 6.25. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M.
Specifically, as shown in fig. 3, the binding assay data were analyzed as follows:
experiments 1-18, under normal conditions, bedapsone alone, and as the concentration of Bedapsone administered was increased (0.03125. Mu.M, 0.0625. Mu.M, 0.125. Mu.M, 0.25. Mu.M, 0.5. Mu.M, 1. Mu.M), the survival rate of Mycobacterium tuberculosis was gradually decreased. When artemisinin is combined with the bedaquiline, the addition of artemisinin can obviously improve the inhibition effect of bedaquiline on mycobacterium tuberculosis at each administration concentration in the test.
Test 19-36, Q203 alone, under normal conditions, progressively decreased survival of M.tuberculosis as the concentration of Q203 administered was increased (0.03 nM, 0.0625nM, 0.125nM, 0.25nM, 0.5nM, 1 nM). When artemisinin is combined with Q203, the addition of artemisinin can significantly increase the inhibitory effect of Q203 on Mycobacterium tuberculosis at each dosing concentration in the assay. In addition, experiments (not shown in the graph) with the administration concentration of Q203 of 2nM, 4nM and 8nM are also carried out, and the experimental results prove that under normal conditions, the addition of artemisinin can obviously improve the inhibition effect of Q203 on mycobacterium tuberculosis, and the survival rate of the mycobacterium tuberculosis is below 10%.
Test 37-54, lansoprazole alone under normal conditions, showed a substantially reduced survival rate of M.tuberculosis as the concentration of Lansoprazole administered was increased (0.625. Mu.M, 1.25. Mu.M, 2.5. Mu.M, 5. Mu.M, 10. Mu.M, 20. Mu.M). When artemisinin is combined with lansoprazole, the addition of artemisinin can significantly improve the inhibitory effect of bedaquiline on mycobacterium tuberculosis at each dosing concentration in the test.
Test 55-72, aurachin D alone under normal conditions, showed no significant change in survival rate of M.tuberculosis as Aurachin D administration concentration was increased (0.625. Mu.M, 1.25. Mu.M, 2.5. Mu.M, 5. Mu.M, 10. Mu.M, 20. Mu.M) compared to control. When artemisinin is combined with respiratory chain inhibitor Auracin D, the administration concentration of artemisinin is 0-50 mu M, and the administration concentration of Auracin D is 0.625-5 mu M, artemisinin cannot improve the inhibition effect of Auracin D on mycobacterium tuberculosis. However, when the administration concentration of Auracin D is 10-20 mu M and the administration concentration of artemisinin is 100-200 mu M, the addition of artemisinin can obviously improve the inhibition effect of Auracin D on mycobacterium tuberculosis.
Example 3:
substantially the same procedures as in example 1 and comparative example 1 were conducted, except that Mycobacterium tuberculosis were treated with artemisinin and Q203, artemisinin and bendazole under normal and anoxic conditions, respectively; the combinations and concentrations of the treatment drugs are shown in table 2. ( Under normal conditions, the concentration of mycobacterium tuberculosis is od600=0.003; under anoxic conditions, the concentration of mycobacterium tuberculosis is od600=0.01 )
Table 2 drug concentration for each set of experiments in example 3
The test results are shown in FIG. 4, which shows that under normal conditions, artemisinin combined with Beda quinoline/Q203 can reduce survival rate of Mycobacterium tuberculosis compared with either artemisinin alone or Beda quinoline/Q203 alone.
Under normal conditions, when artemisinin alone was used, the survival rate of Mycobacterium tuberculosis decreased with increasing concentration of artemisinin administration (12.5. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M), and when artemisinin administration concentration was 100. Mu.M, the survival rate of Mycobacterium tuberculosis was 88.62%.
Under normal conditions, the survival rate of Mycobacterium tuberculosis was 60.22% using 4. Mu.M bedaquiline alone. When artemisinin is combined with 4 mu M of beraquinoline, the survival rate of the mycobacterium tuberculosis is reduced along with the increase of the administration concentration of artemisinin, the survival rate of the mycobacterium tuberculosis can be reduced to 14.65% when the administration concentration of artemisinin is 50 mu M, and the survival rate of the mycobacterium tuberculosis is further reduced to 7.08% when the administration concentration of artemisinin is increased to 100 mu M. It can be seen that the combination of artemisinin and bedaquiline under normal conditions can improve the inhibitory effect of artemisinin and bedaquiline on mycobacterium tuberculosis.
Under normal conditions, the survival rate of Mycobacterium tuberculosis was 51.03% using 1nM Q203 alone. When artemisinin is combined with 1nM Q203, the survival rate of the mycobacterium tuberculosis is reduced along with the increase of the administration concentration of artemisinin, and when the administration concentration of artemisinin is 50 mu M, the survival rate of the mycobacterium tuberculosis can be reduced to 7.42%, and the administration concentration of artemisinin is continuously increased to 100 mu M, so that the survival rate of the mycobacterium tuberculosis is not obviously influenced. It can be seen that under normal conditions, combination of artemisinin with Q203 can increase the inhibitory effect of artemisinin and Q203 on Mycobacterium tuberculosis.
Under anoxic conditions, less administration concentration is required to have a better inhibitory effect on mycobacterium tuberculosis than under normal conditions. Specifically, when artemisinin alone was used, the survival rate of Mycobacterium tuberculosis decreased with an increase in the concentration of artemisinin administration (6.25. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M), and when artemisinin administration concentration was 25. Mu.M, the survival rate of Mycobacterium tuberculosis was 49.48%, the concentration of artemisinin administration increased to 50. Mu.M, and the survival rate was further decreased to 37.69%. It can be seen that artemisinin can effectively inhibit mycobacterium tuberculosis under anoxic conditions.
Under anoxic conditions, the survival rate of mycobacterium tuberculosis was 56.76% using 2 μm bedaquiline alone. When artemisinin is combined with 2 mu M of beraquinoline, the survival rate of the mycobacterium tuberculosis is reduced along with the increase of the administration concentration of artemisinin, the survival rate of the mycobacterium tuberculosis can be reduced to 16.09% when the administration concentration of artemisinin is 25 mu M, and the survival rate of the mycobacterium tuberculosis is further reduced to 5.97% when the administration concentration of artemisinin is increased to 50 mu M. Under the condition of hypoxia, the combination of the artemisinin and the bedaquiline can improve the inhibition effect of the artemisinin and the bedaquiline on mycobacterium tuberculosis.
Under anaerobic conditions, 0.5nM Q203 alone, survival rate of Mycobacterium tuberculosis was 52.64%. When artemisinin is combined with 0.5nM Q203, the survival rate of the mycobacterium tuberculosis is reduced along with the increase of the administration concentration of artemisinin, the survival rate of the mycobacterium tuberculosis can be reduced to 12.09 when the administration concentration of artemisinin is 25 mu M, and the survival rate of the mycobacterium tuberculosis is further reduced to 5.19 when the administration concentration of artemisinin is increased to 50 mu M. It can be seen that combination of artemisinin with Q203 under hypoxia conditions can increase the inhibitory effect of artemisinin and Q203 on Mycobacterium tuberculosis.
In addition, experiments (not shown in the graph) were performed with the administration concentrations of bedaquiline at 4. Mu.M, 6. Mu.M, and 8. Mu.M, and with the administration concentration of artemisinin at 50. Mu.M. Test results prove that under the anoxic condition, the addition of artemisinin can obviously improve the inhibition effect of the bedaquiline on mycobacterium tuberculosis, and the survival rate of the mycobacterium tuberculosis is below 10 percent.
In addition, experiments (not shown in the graph) were performed with Q203 at 1nM, 2nM, and 4nM, and artemisinin at 50. Mu.M. Test results prove that under the anoxic condition, the addition of artemisinin can obviously improve the inhibition effect of Q203 on mycobacterium tuberculosis, and the survival rate of the mycobacterium tuberculosis is below 10%.
Example 4:
substantially the same as the implementation method of example 1 was conducted, except that: (1) the test is performed under normal (aerobic) conditions; (2) The combinations and concentrations of the treatment drugs were varied, and specific combinations and concentrations of the drugs are shown in table 3.
Table 3 drug concentration for each set of experiments in example 4
The test results are shown in FIG. 5, and the test results show that under normal conditions, artemisinin is combined with Q203 and Auracin D, or artemisinin is combined with lansoprazole and Auracin D, and the survival rate of the combined mycobacterium is reduced compared with that of the single use of two corresponding respiratory chain inhibitors. It has been shown that the combination of artemisinin with various respiratory chain inhibitors can normally enhance the inhibitory effect of respiratory chain inhibitors on mycobacterium tuberculosis.
In addition, experiments were performed with Q203 at 1nM, 2nM and 4nM, auracin D at 5. Mu.M and 6.25. Mu.M, and artemisinin at 50. Mu.M (not shown in the graph), and the results of the experiments showed that under normal conditions, artemisinin was combined with Q203 and Auracin D to reduce survival rate of bound mycobacteria by less than 10% when two corresponding respiratory chain inhibitors were used alone.
In addition, experiments were performed with lansoprazole drug delivery concentrations of 4 μM, 6 μM, and 8 μM, with Auracin D drug delivery concentrations of 5 μM and 6.25 μM, and artemisinin drug delivery concentration of 50 μM (not shown in the graph), and the results of the experiments showed that, under normal conditions, artemisinin was combined with lansoprazole and Auracin D, and the survival rate of the combined mycobacteria was reduced to within 10% as compared to the use of two corresponding respiratory chain inhibitors alone.
As shown in FIG. 1, the possible mechanism of inhibiting Mycobacterium tuberculosis by the drug related in the present invention is that Q203 and lansoprazole inhibit Mycobacterium tuberculosis cytochrome oxidase bcc-aa3, auracin D inhibits cytochrome oxidase bd, bedaquinoline inhibits ATP synthase, artemisinin is activated by electrons generated by respiratory chain to destroy cell membrane potential, and when downstream of electron transfer chain is inhibited by inhibitor, respiratory chain transfers more electrons to activate artemisinin, thereby enhancing effect of artemisinin killing cells.
While the present application has been described with reference to an illustrative embodiment, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the present application. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the application without departing from the scope thereof. Therefore, it is intended that the present application not be limited to the particular embodiments disclosed for carrying out this application, but that the application will include all embodiments falling within the scope of the appended claims.

Claims (13)

1. Use of an endoperoxide compound in the preparation of an antibacterial agent characterized in that: the internal peroxy compound comprises the following structural units: 1, 2-dioxane, 1,2, 4-trioxane, 1,2,4, 5-tetraxane, 1, 2-dioxolane or 1,2, 4-trioxane; the antibacterial drug is a drug for inhibiting mycobacterium tuberculosis; under anoxic conditions, the administration concentration of the endoperoxide compound is as follows: the administration concentration is less than or equal to 100 mu M.
2. Use of an endoperoxide compound according to claim 1 for the preparation of an antibacterial drug, characterized in that: the endoperoxide compound comprises artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivative containing an internal oxygen bridge.
3. Use of an endoperoxide compound according to claim 2 for the preparation of an antibacterial drug, characterized in that: the administration concentration of the inner peroxy compound is as follows: the administration concentration is less than or equal to 12.5 mu M and less than or equal to 50 mu M.
4. Use of an endoperoxide compound in combination with a respiratory chain inhibitor for the preparation of an antibacterial agent, characterized in that: the internal peroxy compound comprises the following structural units: 1, 2-dioxane, 1,2, 4-trioxane, 1,2,4, 5-tetraxane, -1, 2-dioxolane, or 1,2, 4-trimethoxy-valer-ne; the antibacterial drug is a drug for inhibiting mycobacterium tuberculosis; the respiratory chain inhibitor is mycobacterium tuberculosis respiratory chain inhibitor.
5. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 4 for the preparation of an antibacterial drug, characterized in that: the endoperoxide compound comprises artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivative containing an internal oxygen bridge.
6. The use of an endoperoxide compound in combination with a respiratory chain inhibitor for the preparation of an antibacterial drug according to claim 4, wherein the respiratory chain inhibitor of mycobacterium tuberculosis is one or more of bedaquiline, Q203, aurachin D or lansoprazole.
7. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 6 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, auracin D or lansoprazole; under normal oxygen conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 100 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than or equal to 4 mu M; the administration concentration of the Q203 is as follows: the administration concentration is less than 10nM; the administration concentration of Aurachin D is as follows: the administration concentration is less than or equal to 20 mu M; the administration concentration of lansoprazole is as follows: the administration concentration is less than or equal to 20 mu M.
8. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 7 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, auracin D or lansoprazole; under normal oxygen conditions, the administration concentration of artemisinin is as follows: the administration concentration is less than or equal to 100 mu M; the administration concentration of the Q203 is as follows: the administration concentration is less than or equal to 1nM.
9. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 6 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, auracin D or lansoprazole; under the anoxic condition, the administration concentration of the artemisinin is as follows: the administration concentration is less than or equal to 50 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than 10 mu M; the administration concentration of the Q203 is as follows: the administration concentration is less than 5nM; the administration concentration of Aurachin D is as follows: the administration concentration is less than 20 mu M; the administration concentration of lansoprazole is as follows: the administration concentration is less than 20 mu M.
10. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 9 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is one of bedaquiline, Q203, auracin D or lansoprazole; under the anoxic condition, the administration concentration of the artemisinin is as follows: the administration concentration is less than or equal to 50 mu M; the administration concentration of the bedaquiline is as follows: the administration concentration is less than or equal to 2 mu M; the administration concentration of the Q203 is as follows: the administration concentration is less than or equal to 0.5nM.
11. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 6 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is two of bedaquiline, Q203, auracin D or lansoprazole; under normal oxygen conditions, the artemisinin and respiratory chain inhibitor are administered at the following concentrations:
the administration concentration of artemisinin is less than or equal to 50 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than 10 mu M, and the administration concentration of the Q203 is as follows: the administration concentration is less than 5nM;
or alternatively, the first and second heat exchangers may be,
the administration concentration of artemisinin is less than or equal to 50 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than 10 mu M, and the lansoprazole is: the administration concentration is less than 10 mu M.
12. Use of an endoperoxide compound in combination with a respiratory chain inhibitor according to claim 11 for the preparation of an antibacterial drug, characterized in that: the internal peroxy compound is artemisinin, and the mycobacterium tuberculosis respiratory chain inhibitor is two of bedaquiline, Q203, auracin D or lansoprazole; under normal oxygen conditions, the artemisinin and respiratory chain inhibitor are administered at the following concentrations:
the administration concentration of artemisinin is less than or equal to 25 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than or equal to 2.5 mu M, and the administration concentration of the Q203 is as follows: the administration concentration is less than or equal to 4nM;
or alternatively, the first and second heat exchangers may be,
the administration concentration of artemisinin is less than or equal to 25 mu M, and the administration concentration of Auracin D is as follows: the administration concentration is less than or equal to 2.5 mu M, and the lansoprazole is: the administration concentration is less than or equal to 2 mu M.
13. An antibacterial agent characterized in that: comprises an effective content of endoperoxide, a respiratory chain inhibitor of mycobacterium tuberculosis and a pharmaceutically acceptable carrier; the mycobacterium tuberculosis respiratory chain inhibitor is one or more of bedaquiline, Q203, aurachin D or lansoprazole; the endoperoxide compound comprises artemisinin, dihydroartemisinin, artemether, arteether, artesunate, HEM, ascaridol, majapolene A, norterpene Peroxides, yinzaosu A, artefenomel (OZ 439), aceranol acetate, deoxycholic acid derivative containing an internal oxygen bridge.
CN202311614935.4A 2023-11-29 2023-11-29 Use of endoperoxides alone or in combination with respiratory chain inhibitors for the preparation of antibacterial agents Pending CN117883436A (en)

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