CN110974814A - Potential application of disulfiram in bacterial infection diseases - Google Patents

Potential application of disulfiram in bacterial infection diseases Download PDF

Info

Publication number
CN110974814A
CN110974814A CN201911248183.8A CN201911248183A CN110974814A CN 110974814 A CN110974814 A CN 110974814A CN 201911248183 A CN201911248183 A CN 201911248183A CN 110974814 A CN110974814 A CN 110974814A
Authority
CN
China
Prior art keywords
disulfiram
polymyxin
meropenem
composition
final concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN201911248183.8A
Other languages
Chinese (zh)
Inventor
刘源
王志强
贾瑜倩
仝梓稳
杨康妮
史静茹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yangzhou University
Original Assignee
Yangzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yangzhou University filed Critical Yangzhou University
Priority to CN201911248183.8A priority Critical patent/CN110974814A/en
Publication of CN110974814A publication Critical patent/CN110974814A/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses application of disulfiram or acceptable salts thereof in preparation of medicines for treating bacterial infectious diseases or antibiotic synergists. The invention also discloses two compositions, which comprise disulfiram or acceptable salt thereof and the antibiotic meropenem; or disulfiram or an acceptable salt thereof and polymyxin. The invention clarifies that the disulfiram can effectively enhance the in vitro and in vivo antibacterial activity of the meropenem and the polymyxin to multi-drug resistant bacteria, and provides a new solution for the treatment of clinical infectious diseases.

Description

Potential application of disulfiram in bacterial infection diseases
Technical Field
The invention belongs to the technical field of medicines, relates to a new application of disulfiram, in particular to a potential application of disulfiram in bacterial infection diseases, and in particular relates to a synergistic antibacterial effect of disulfiram and antibiotics in vitro and in vivo.
Background
In recent years, the generation, propagation and rapid diffusion of multi-drug resistant bacteria have brought a great threat to human health and livestock breeding. It has been difficult to achieve a good therapeutic effect by using an antibiotic alone for treating bacterial infectious diseases. Thus, there is an urgent need for new antibacterial strategies such as the use of antibiotics in combination with antibiotic synergists to cope with the growing bacterial resistance.
Disulfiram was at first only one catalyst of the rubber industry. In 1948, it was found that disulfiram is absorbed by human body to cause adverse symptoms such as headache, sweating and palpitation, and the symptoms are obviously aggravated after drinking, and the symptom is named as disulfiram-like reaction. Further research shows that the disulfiram can inhibit acetaldehyde dehydrogenase in liver when being used together with ethanol, so that ethanol can not be further decomposed and oxidized after being oxidized into acetaldehyde in vivo, and acetaldehyde is accumulated in vivo to generate a series of reactions. Based on this, disulfiram is widely used as an alcohol withdrawal drug in clinic. In addition, disulfiram was found to be a potential anti-cataract drug in 2007. In 2012, disulfiram was found to kill glioma cells in combination with chemotherapeutic drugs. Nevertheless, the use of disulfiram in bacterial infectious diseases has not been reported, and particularly in the treatment of gram-negative bacterial infectious diseases.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention discovers that disulfiram approved as a drug for abstinence is a novel antibiotic synergist of carbapenem antibiotics and polymyxin by screening antibiotics synergist from compounds approved to be marketed and not used for antibacterial purpose, and can effectively recover the in vitro and in vivo antibacterial activity of the two antibiotics on drug-resistant bacteria.
In particular, the disulfiram of the invention can be used as a potential synergist for carbapenem antibiotics such as meropenem and polymyxin, thereby enhancing the in vitro and in vivo antibacterial activity of the two antibiotics.
The technical scheme is as follows: in order to solve the technical problems, the invention provides the application of disulfiram or acceptable salts thereof in preparing medicines for bacterial infectious diseases or antibiotic synergists.
Preferably, the bacterium is a gram-negative bacterium, in particular escherichia coli.
Wherein the bacterial infectious disease drug or antibiotic synergist is a single component or compound preparation.
The present disclosure also includes a composition comprising disulfiram or an acceptable salt thereof and an antibiotic.
Wherein, the antibiotics include but are not limited to meropenem and polymyxin, and other carbapenem antibiotics, such as imipenem, panipenem, ertapenem, biapenem and doripenem are also within the protection scope of the present invention.
Wherein the composition comprises disulfiram and polymyxin, disulfiram and meropenem.
Wherein the mass ratio of the disulfiram or the acceptable salt thereof to the polymyxin is 0.97-4000: 1.
Wherein the mass ratio of the disulfiram or the acceptable salt thereof to the meropenem is 0.24-1000: 1.
Wherein the concentration of disulfiram in the disulfiram or acceptable salt thereof is 15.63-1000 mug/mL.
Wherein the concentration of the polymyxin is 0.25-16 mug/mL; the concentration of meropenem is 1-64 μ g/mL
The invention also comprises the application of the composition in preparing medicines or antibiotic synergists for bacterial infectious diseases.
Wherein the medicament or the antibiotic synergist for the bacterial infectious diseases is one of tablets, capsules, sustained-release tablets, controlled-release tablets, oral liquid, syrup, dropping pills, injection and freeze-dried powder injections.
Has the advantages that: compared with the prior art, the invention has the advantages that:
1) the invention firstly discovers that the disulfiram can be used for treating bacterial infectious diseases, particularly for treating gram-negative bacterial infectious diseases, and belongs to the new application of the disulfiram.
2) The invention clarifies that disulfiram can restore the sensitivity of drug-resistant bacteria to meropenem and polymyxin, systematically evaluates the effectiveness of the combined use of the disulfiram and the polymyxin in vivo and in vitro, is beneficial to developing a novel antibiotic synergist and relieves the problem of bacterial drug resistance which is increasingly harmful.
Drawings
FIG. 1 is a graph showing the synergistic antibacterial effect of disulfiram with different antibiotics on multidrug-resistant E.coli;
FIG. 2 is a time sterilization curve for the combined use of polymyxin or meropenem and disulfiram; colistin, polymyxin (2. mu.g/mL); meropenem, Meropenem (8. mu.g/mL); disulfiam, Disulfiram (125. mu.g/mL); colistin + Disulfiam, polymyxin + Disulfiram (2+ 125. mu.g/mL); meropenem + Disulfiam, Meropenem + Disulfiram (8+ 125. mu.g/mL);
FIG. 3 is a graph showing the effectiveness of polymyxin (10mg/kg) or/and meropenem (20mg/kg) or/and disulfiram (20mg/kg), alone and in combination, in the treatment of a BALB/c mouse drug-resistant bacterial infection model.
Detailed Description
The present invention is further illustrated by the following specific examples, it should be noted that, for those skilled in the art, variations and modifications can be made without departing from the principle of the present invention, and these should also be construed as falling within the scope of the present invention. The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. In the quantitative experiments in the following examples, three replicates were set up and the results averaged.
MHB broth medium is an aqueous solution containing 6.0g/L beef powder, 1.5g/L soluble starch and 17.5g/L acid hydrolyzed casein.
PBS buffer: weighing 8g of NaCl, 0.2g of KCl and NaH2PO41.44g and KH2PO4Dissolving 0.24g of the aqueous solution in 800 mL of distilled water, adjusting the pH value to 7.2 by using HCl, and fixing the volume of the distilled water to 1L. Autoclaved at 121 ℃ for 15 minutes and stored at room temperature.
EXAMPLE 1 disulfiram and polymyxin composition
Composition 1: preparing a composition 1 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 15.63 mu g/mL, and the final concentration of polymyxin is 16 mu g/mL; the ratio of the concentrations of disulfiram and polymyxin is 0.97: 1;
composition 2, preparing composition 2 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 31.25 mu g/mL, and the final concentration of polymyxin is 8 mu g/mL; the concentration ratio of disulfiram to polymyxin is 3.90: 1;
composition 3: preparing a composition 3 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 62.5 mu g/mL, and the final concentration of polymyxin is 8 mu g/mL; the concentration ratio of disulfiram to polymyxin is 7.81: 1;
composition 4: preparing a composition 4 according to a disulfiram and polymyxin mother liquor, wherein the final concentration of the disulfiram is 62.5 mu g/mL, and the final concentration of the polymyxin is 4 mu g/mL; the ratio of disulfiram to polymyxin concentration is 15.625: 1;
composition 5: preparing a composition 5 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 125 mug/mL, and the final concentration of polymyxin is 4 mug/mL; the concentration ratio of disulfiram to polymyxin is 31.25: 1;
composition 6: preparing a composition 6 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 125 mug/mL, and the final concentration of polymyxin is 2 mug/mL; the concentration ratio of disulfiram to polymyxin is 62.5: 1;
composition 7: preparing a composition 7 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 250 mug/mL, and the final concentration of polymyxin is 2 mug/mL; the concentration ratio of disulfiram to polymyxin is 125: 1;
composition 8: preparing a composition 8 according to a disulfiram and polymyxin mother liquor, wherein the final concentration of the disulfiram is 250 mug/mL, and the final concentration of the polymyxin is 1 mug/mL; the concentration ratio of disulfiram to polymyxin is 250: 1;
composition 9, preparing composition 9 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 500 mug/mL, and the final concentration of polymyxin is 1 mug/mL; the concentration ratio of disulfiram to polymyxin is 500: 1;
the composition 10 is prepared according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 500 mug/mL, and the final concentration of polymyxin is 0.5 mug/mL; the concentration ratio of disulfiram to polymyxin is 1000: 1;
composition 11: preparing a composition 11 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 1000 mug/mL, and the final concentration of polymyxin is 0.5 mug/mL; the concentration ratio of disulfiram to polymyxin is 2000: 1;
composition 12: preparing a composition 12 according to disulfiram and polymyxin mother liquor, wherein the final concentration of disulfiram is 1000 mug/mL, and the final concentration of polymyxin is 0.25 mug/mL; the ratio of disulfiram to polymyxin concentration was 4000: 1.
Example 2 disulfiram and meropenem composition
Composition 1: preparing a composition 1 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 15.63 mu g/mL, and the final concentration of meropenem is 64 mu g/mL; the concentration ratio of disulfiram to meropenem is 0.24: 1;
composition 2, preparing composition 2 according to the disulfiram and meropenem mother liquor, wherein the final concentration of the disulfiram is 31.25 mu g/mL, and the final concentration of the meropenem is 32 mu g/mL; the concentration ratio of disulfiram to meropenem is 0.97: 1;
composition 3: preparing a composition 3 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 62.5 mu g/mL, and the final concentration of meropenem is 32 mu g/mL; the concentration ratio of disulfiram to meropenem is 1.95: 1;
composition 4: preparing a composition 4 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 62.5 mu g/mL, and the final concentration of meropenem is 16 mu g/mL; the concentration ratio of disulfiram to meropenem is 3.90: 1;
composition 5: preparing a composition 5 according to the disulfiram and meropenem mother liquor, wherein the final concentration of the disulfiram is 125 mu g/mL, and the final concentration of the meropenem is 16 mu g/mL; the concentration ratio of disulfiram to meropenem is 7.81: 1;
composition 6: preparing a composition 6 according to the disulfiram and meropenem mother liquor, wherein the final concentration of the disulfiram is 125 mu g/mL, and the final concentration of the meropenem is 8 mu g/mL; the concentration ratio of disulfiram to meropenem is 15.625: 1;
composition 7: preparing a composition 7 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 250 mug/mL, and the final concentration of meropenem is 8 mug/mL; the concentration ratio of disulfiram to meropenem is 31.25: 1;
composition 8: preparing a composition 8 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 250 mug/mL, and the final concentration of meropenem is 4 mug/mL; the concentration ratio of disulfiram to meropenem is 62.5: 1;
composition 9, preparing composition 9 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 500 mug/mL, and the final concentration of meropenem is 4 mug/mL; the concentration ratio of disulfiram to meropenem is 125: 1;
the composition 10 is prepared according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 500 mug/mL, and the final concentration of meropenem is 2 mug/mL; the concentration ratio of disulfiram to meropenem is 250: 1;
composition 11: preparing a composition 11 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 1000 mug/mL, and the final concentration of meropenem is 2 mug/mL; the concentration ratio of disulfiram to meropenem is 500: 1;
composition 12: preparing a composition 12 according to disulfiram and meropenem mother liquor, wherein the final concentration of disulfiram is 1000 mug/mL, and the final concentration of meropenem is 1 mug/mL; the ratio of the concentrations of disulfiram and meropenem is 1000: 1.
Example 3 synergistic antibacterial Activity of polymyxin or Meropenem and disulfiram
A chessboard analysis method is adopted to further evaluate the synergistic antibacterial activity of disulfiram and antibiotics to drug-resistant bacteria, and the test strain is a multi-drug-resistant Escherichia coli E.coli B2. strain source, reproducing peptidomimetic activity inhibitor of New Delhi metals- β -lactames in Gram-Negativia. ACS infection Diseases,2019.DOI, 10.1021/acetylfecalis.9b00364.
The chessboard analysis method comprises the following specific steps:
1) test strains were suspended in MHB broth to a concentration of 1X 106CFU/mL of bacterial suspension.
2) Disulfiram was taken, dissolved in DMSO and diluted with MHB broth to give a disulfiram solution with a concentration of 8 mg/mL.
3) Antibiotics were taken, dissolved in water and diluted with MHB broth to give ciprofloxacin at a concentration of 128. mu.g/mL, a 256. mu.g/mL vancomycin solution, 32. mu.g/mL tigecycline, 64. mu.g/mL doxycycline, 128. mu.g/mL meropenem and 32. mu.g/mL polymyxin.
4) Taking a 96-well plate, adding 100 mu L of MHB broth culture medium into each well, adding 100 mu L of disulfiram solution prepared in the step 2) into each well of the last row, and diluting to the second row from the eighth row in a multiple ratio; adding 100 mu L of the antibiotic solution prepared in the step 3) into each well of the first row, diluting the antibiotic solution to the tenth row in a multiple ratio manner, adding 100 mu L of the bacterial suspension prepared in the step 1) into each well, standing and culturing at 37 ℃ for 16-20 h, and measuring the OD of each culture well600(absorbance at 600 nm), a bacterial quantitation heat map was prepared. And calculating the graded inhibitory concentration (FIC index) of the combined use of the two.
The fractional antibacterial concentration FIC index is calculated according to the following formula:
FIC ═ MIC (a combination)/MIC (a alone) + MIC (B combination)/MIC (B alone); a is tigecycline, B is disulfiram;
FIC index interpretation criteria: when the FIC index is less than 0.5, the two medicines act synergistically; when the FIC index is 0.5-1, the two medicines have an additive effect; when the FIC index is more than l and less than or equal to 2, the two medicines have unrelated effects; when the FIC index is greater than 2, the two drugs are antagonistic.
The test results are shown in FIG. 1. The calculation result shows that FIC values of disulfiram, ciprofloxacin, vancomycin and tigecycline are all 2.0, and are irrelevant effects; the FIC value of disulfiram and doxycycline is 0.75, which is additive effect; the FIC values of disulfiram, meropenem and polymyxin are 0.094 and 0.061 which are both less than 0.5, which shows that the disulfiram, the meropenem and the polymyxin have obvious synergistic antibacterial activity.
Example 4 time sterilization curves for the combination of polymyxin or meropenem and disulfiram
MHA culture medium preparation: 6.0g of beef powder, 1.5g of soluble starch, 17.5g of acid hydrolyzed casein and 17.0g of agar, 900mL of distilled water is added, the pH is adjusted to 7.3, and the volume is adjusted to 1000 mL. Sterilizing at 121 deg.C under high pressure for 15 min, cooling to 50 deg.C, pouring into sterile plate, and air drying.
After 5 hours of culture of e.coli B2 in BHI broth, equal volumes of 0.01mol/LPBS (pH 7.2), polymyxin, meropenem, disulfiram, polymyxin and disulfiram mixture, meropenem and disulfiram mixture were added to give final drug concentrations of polymyxin (2 μ g/mL), meropenem (8 μ g/mL), disulfiram (125 μ g/mL) and mixed concentrations (2 μ g/mL polymyxin +125 μ g/mL disulfiram, 8 μ g/mL meropenem +125 μ g/mL disulfiram), respectively. Then, 100. mu.L of the suspension was applied to MHA medium at 4h, 8h, 12h and 24h, respectively, and cultured overnight before colony counting.
The results of the experiment are shown in FIG. 2. The results show that the addition of polymyxin and disulfiram and of meropenem and disulfiram significantly reduced the number of bacteria compared to polymyxin, meropenem and disulfiram alone by more than 3log after 24 hours10CFU/mL。
Example 5 in vivo efficacy of combination of polymyxin or meropenem and disulfiram
E.coli suspension: resuspending E.coli (Escherichia coli) B2 with PBS buffer to obtain E.coli suspension; in mice, E.coli (Escherichia coli) B2 was present at a concentration of 1.5X 106CFUs/only.
36 BALB/c female mice (about 20g) 6-8 weeks old were selected and randomly divided into Control group, polymyxin-treated group, disulfiram-treated group and co-treated group (6 mice per group). To avoid the effect of mouse autoimmunity on the experiment, pre-administration of cyclophosphamide (150mg/kg and 100mg/kg) to all mice 4 days and 1 day before infection, respectively, resulted in neutropenia and immunodeficiency in the mice.
Control group: injecting 0.1mL of escherichia coli suspension into thigh muscles on the right side of the abdominal cavity of the mouse; after 1 hour, the mice were injected with 200. mu.L of PBS buffer;
polymyxin treatment group: injecting 0.1mL of escherichia coli suspension into thigh muscles on the right side of the abdominal cavity of the mouse; after 1 hour, the mouse is injected with 200 mu L polymyxin liquid medicine (1mg/mL) in the abdominal cavity; dosage: 10 mg/kg;
meropenem treatment group: injecting 0.1mL of escherichia coli suspension into thigh muscles on the right side of the abdominal cavity of the mouse; after 1 hour, the mice are injected with 200 mu L of meropenem liquid medicine (2mg/mL) in the abdominal cavity; dosage: 20 mg/kg;
disulfiram treatment group: injecting 0.1mL of escherichia coli suspension into thigh muscles on the right side of the abdominal cavity of the mouse; after 1 hour, the mice are injected with 200 mu L disulfiram liquid medicine (2mg/mL) in the abdominal cavity; dosage: 20 mg/kg;
the co-treatment group: injecting 0.1mL of escherichia coli suspension into thigh muscles on the right side of the abdominal cavity of the mouse; after 1 hour, the mice were injected intraperitoneally with 200. mu.L of polymyxin (1mg/mL) or a mixed solution of meropenem (2mg/mL) and disulfiram (2 mg/mL). Dosage: polymyxin plus disulfiram, 10mg/kg +20 mg/kg; meropenem and disulfiram are added, 10mg/kg and 20 mg/kg.
24 hours after infection, all mice were euthanized and the right thigh muscle of the mice was placed in 3mL PBS, disrupted by a tissue disruptor, and 100. mu.L of the disruption solution was plated for colony counting.
The results of the experiment are shown in FIG. 3. The strain carrying capacity of the thigh muscle of the mice in the PBS, polymyxin, meropenem and disulfiram single treatment groups is equivalent without significant difference. The results indicate that three drugs alone do not effectively control bacterial infections. Whereas the combined administration of polymyxin and disulfiram significantly reduced the bacterial load compared to the polymyxin group alone (P0.0001); the combined administration of meropenem and disulfiram also significantly reduced bacterial load compared to meropenem alone (P ═ 0.0003). These results indicate that disulfiram can effectively enhance the in vivo effectiveness of polymyxin and meropenem, and provide a new treatment scheme for infectious diseases caused by drug-resistant bacteria.

Claims (10)

1. The disulfiram or the acceptable salt thereof is applied to the preparation of medicines for treating bacterial infectious diseases or antibiotic synergists.
2. The use according to claim 1, wherein the bacterial infectious disease drug or antibiotic synergist is a single component or a combination formulation.
3. A composition comprising disulfiram, or an acceptable salt thereof, and an antibiotic.
4. The composition of claim 3, wherein the antibiotic is one or both of polymyxin or meropenem.
5. The composition of claim 3, wherein the composition is disulfiram and polymyxin; or disulfiram and meropenem.
6. The composition as claimed in any one of claims 3 to 5, wherein the mass ratio of disulfiram or an acceptable salt thereof to polymyxin is 0.97 to 4000: 1; the mass ratio of the disulfiram or the acceptable salt thereof to the meropenem is 0.24-1000: 1.
7. The composition according to any one of claims 3 to 5, wherein the concentration of disulfiram in the disulfiram or an acceptable salt thereof is 15.63 to 1000 μ g/mL.
8. The composition according to any one of claims 3 to 5, wherein the concentration of polymyxin is 0.25 to 16 μ g/mL and the concentration of meropenem is 1 to 64 μ g/mL.
9. Use of the composition of any one of claims 3 to 8 for the preparation of a medicament or antibiotic synergist for bacterial infectious diseases.
10. The use of claim 9, wherein the medicament for treating bacterial infectious diseases or the antibiotic synergist is in the form of tablet, capsule, sustained release tablet, controlled release tablet, oral liquid, syrup, dripping pill, injection, or lyophilized powder for injection.
CN201911248183.8A 2019-12-09 2019-12-09 Potential application of disulfiram in bacterial infection diseases Withdrawn CN110974814A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911248183.8A CN110974814A (en) 2019-12-09 2019-12-09 Potential application of disulfiram in bacterial infection diseases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911248183.8A CN110974814A (en) 2019-12-09 2019-12-09 Potential application of disulfiram in bacterial infection diseases

Publications (1)

Publication Number Publication Date
CN110974814A true CN110974814A (en) 2020-04-10

Family

ID=70091143

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911248183.8A Withdrawn CN110974814A (en) 2019-12-09 2019-12-09 Potential application of disulfiram in bacterial infection diseases

Country Status (1)

Country Link
CN (1) CN110974814A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114209682A (en) * 2021-12-31 2022-03-22 山东省妇幼保健院 Application of disulfiram and antibiotic combination in preparation of antibacterial drugs
CN116407557A (en) * 2023-05-29 2023-07-11 四川大学华西医院 Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114209682A (en) * 2021-12-31 2022-03-22 山东省妇幼保健院 Application of disulfiram and antibiotic combination in preparation of antibacterial drugs
CN116407557A (en) * 2023-05-29 2023-07-11 四川大学华西医院 Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof

Similar Documents

Publication Publication Date Title
AU2011373911B2 (en) Pharmaceutical compositions comprising sulbactam and beta-lactamase inhibitor
JP5782615B2 (en) Methods of treatment using a single dose of oritavancin
BRPI0612447A2 (en) fixed dose antibiotic composition, process for the preparation of a fixed dose antibiotic combination product, process for the preparation of a liquid injection and uses of dry powder for injection and liquid injection
TW201806604A (en) 9-aminomethyl minocycline compounds and methods of use thereof in urinary tract infection (UTI) treatment
CN109999027B (en) Use of melatonin
CN110974814A (en) Potential application of disulfiram in bacterial infection diseases
CN110368396B (en) New application of azidothymidine
CN115192593B (en) Application of daunorubicin in treating multi-drug resistant bacteria infection diseases
WO2019178954A1 (en) Application of succinic acid in improving sensitivity of bacteria on antibiotic
RU2327453C2 (en) Composition applied for animals&#39; infectious diseases prevention
US5658887A (en) Pharmaceutical formulations comprising a clavulanic acid salt and erithromycin derivatite
CN107847502A (en) Bactericidal composition
CN113209058A (en) Application of nordihydroguaiaretic acid in preparation of MCR-1 enzyme inhibitor
US11534438B2 (en) Composition containing piperacillin, pharmaceutical formulation thereof and use thereof
CN111569079B (en) Antibody and antibiotic combined preparation for resisting staphylococcus infection
RU2814246C1 (en) Method of treating experimental staphylococcosis in chickens
CN110141569B (en) Pharmaceutical composition for resisting pasteurella multocida
CN107835686A (en) Bactericidal composition
CN105456281A (en) Medicine composition for livestock and preparation method and application thereof
RU2395278C1 (en) Method of obtaining complex medication for prevention and treatment of metabolism pathology and malfunctions of immune system in animals
US20230364065A1 (en) Antibiotic combination therapies
EA017028B1 (en) Antibacterial composition
Aronin Current pharmacotherapy of pneumococcal meningitis
RU2560667C2 (en) Method for preventing pneumonia in piglets
CN118001290A (en) Use of compound 0407-0013 as NDM-1 inhibitor in antibiosis

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication

Application publication date: 20200410

WW01 Invention patent application withdrawn after publication