CN114129564A - Application of epalrestat or pharmaceutically acceptable salt thereof in preparing medicine for preventing and/or treating bacterial infection diseases - Google Patents
Application of epalrestat or pharmaceutically acceptable salt thereof in preparing medicine for preventing and/or treating bacterial infection diseases Download PDFInfo
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- CN114129564A CN114129564A CN202111243742.3A CN202111243742A CN114129564A CN 114129564 A CN114129564 A CN 114129564A CN 202111243742 A CN202111243742 A CN 202111243742A CN 114129564 A CN114129564 A CN 114129564A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- 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
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- 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
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of epalrestat or pharmaceutically acceptable salts thereof in preparation of medicines for preventing and/or treating bacterial infection diseases. The epalrestat or the pharmaceutically acceptable salt thereof can inhibit the hydrolysis of beta-lactam antibiotics by metal beta-lactamase, thereby restoring the sensitivity of drug-resistant microorganisms to the beta-lactam antibiotics and having obvious effect of assisting in resisting bacterial infection.
Description
Technical Field
The invention belongs to the technical field of biological medicines. More particularly, relates to the application of epalrestat or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating bacterial infection diseases.
Background
Beta-lactam antibiotics have been widely used in clinical treatment of bacterial infections since their invention, but bacteria quickly develop resistance to them, mainly because they themselves produce beta-lactamases and thus enzymatically inactivate beta-lactam antibiotics. The metallo-beta-lactamase is one of the beta-lactamase, common subfamilies are IMP, VIM and NDM, the anti-metallo-beta-lactamase has stable and efficient carbapenem hydrolytic activity, can catalyze water to remove all beta-lactam antibiotics except monocyclic beta-lactam drugs, and clinically common gram-negative bacteria such as Klebsiella pneumoniae and Escherichia coli can produce various metallo-beta-lactamase, so that the drug resistance is serious, and the infection caused by the metallo-beta-lactamase is very difficult to treat.
In order to solve the above problems, the skilled in the art has intensively studied metallo-beta-lactamase inhibitors, and as disclosed in chinese application CN101267815A, the maleic acid compound has inhibitory effect on metallo-beta-lactamase, but it has inhibitory effect only on IMP-1 type metallo-beta-lactamase of IMP subfamily and on VIM-2 type metallo-beta-lactamase of VIM subfamily, and does not have inhibitory effect on IMP-7 type metallo-beta-lactam enzymes of IMP subfamily. Therefore, the existing metallo-beta-lactamase inhibitors have few varieties, and the selectable range of the drugs for overcoming the problem of bacterial drug resistance is narrow.
Disclosure of Invention
The invention aims to overcome the defects of few varieties of the existing metallo-beta-lactamase inhibitors, clinical bacterial drug resistance, few medicines for treating infection and low safety, and provides the application of epalrestat or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating bacterial infection diseases.
Another object of the present invention is to provide a medicament for preventing and/or treating bacterial infection diseases.
The invention also aims to provide the application of the epalrestat or the pharmaceutically acceptable salt thereof in preparing the metal beta-lactam enzyme inhibitor medicine.
The above object of the present invention is achieved by the following technical solutions:
application of epalrestat or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating bacterial infection diseases.
Wherein the structure of epalrestat is as follows:
preferably, said epalrestat or a pharmaceutically acceptable salt thereof is used for the prophylaxis and/or treatment of bacterial infectious diseases by inhibition of metallo-beta-lactamases.
Preferably, the metallo beta-lactamase is a metallo beta-lactase of the IMP-7, NDM-1 or VIM-2 type.
More preferably, the metallo-beta-lactamase is an IMP-7 type metallo-beta-lactamase.
Preferably, the bacteria are classified into gram-positive bacteria and gram-negative bacteria, and the gram-positive bacteria include staphylococcus aureus, enterococcus faecalis, enterococcus faecium, streptococcus, diplococcus pneumoniae, bacillus anthracis, laryngobacter albicans, or tetanus bacillus.
Preferably, the gram-negative bacteria include escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, shigella dysenteriae, typhoid bacillus, proteus or vibrio cholerae.
The invention also provides a medicament for preventing and/or treating bacterial infection diseases, which comprises epalrestat or pharmaceutically acceptable salts thereof and antibiotics.
Experiments show that epalrestat or pharmaceutically acceptable salts thereof can inhibit the hydrolysis of metal beta-lactam enzyme on beta-lactam antibiotics, so that the metal beta-lactam enzyme can protect the antibiotics, and the sensitivity of drug-resistant microorganisms to the beta-lactam drugs can be effectively improved. When various preparations of the beta-lactam antibiotics are used together with epalrestat, the beta-lactam antibiotics can be inhibited from being hydrolyzed by metal beta-lactamase generated by microorganisms, so that the stability of the beta-lactam antibiotics is improved, and the anti-infection effect of the antibiotics is recovered.
Meanwhile, aiming at the defects that the existing medicines for treating bacterial infection diseases have high toxicity and can not be used clinically, the epalrestat or the pharmaceutically acceptable salt thereof is firstly applied to treating the bacterial infection diseases, is a clinically used medicine, has low toxicity, meets the medicine standard of the food and drug administration, and has guaranteed safety.
Preferably, the antibiotic comprises penicillin, cephalosporin, penem, cephamycin and thiomycin antibiotics.
Preferably, the antibiotic comprises penicillin, ampicillin, piperacillin, cefuroxime, ceftriaxone, cefaclor, cefdinir, ceftazidime, meropenem, imipenem.
Preferably, the medicament is a capsule, a tablet, a pill, a granule, a medicinal granule, an injection or a spray.
Preferably, the medicament is suitable for use in humans or animals.
The invention also provides the application of epalrestat or pharmaceutically acceptable salts thereof in preparing a metal beta-lactamase inhibitor drug.
Preferably, the metallo beta-lactamase is a metallo beta-lactam enzyme inhibitor of the type IMP-7, NDM-1 or VIM-2.
Compared with the prior art, the invention has the following beneficial effects:
the epalrestat or the pharmaceutically acceptable salt thereof can inhibit the hydrolysis of beta-lactam antibiotics by metal beta-lactamase, thereby playing a role in protecting the antibiotics, improving the anti-infection effect of the antibiotics, effectively improving the sensitivity of drug-resistant microorganisms to the beta-lactam antibiotics, overcoming the problem of bacterial drug resistance, and having a remarkable anti-bacterial infection effect; meanwhile, the toxicity is low, and the safety is guaranteed.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise specified.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
During the reaction, meropenem is used as a substrate, and the used buffer solution is prepared from 50mM 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES) and 100 mu M ZnCl2100 mu g/mL Bovine Serum Albumin (BSA), 0.01% polyethylene glycol octylphenyl ether (Trion X-100), pH 7.0, reaction temperature 25 ℃, final concentrations of IMP-7, VIM-2 and NDM-1 metallo-beta-lactamase used were 2nM, 4nM and 10nM, final reaction volume 100. mu.L, and detection wavelength 300nM, respectively.
Example 1 detection of inhibitory Activity of Epalrestat against IMP-7 type metallo beta-lactamase
Experimental groups:
s1, firstly, mixing metal beta-lactamase (IMP-7, VIM-2 and NDM-1 with final concentrations of 2nM, 4nM and 10nM respectively) and epalrestat with different concentrations in a 96-well plate in a buffer solution, and incubating for 30min at 25 ℃ to ensure that an inhibitor is fully combined with enzyme; (ii) a
S2, adding meropenem (with IMP-7 and VIM-2 final concentration of 50 mu M and NDM-1 final concentration of 100 mu M) dissolved in buffer solution into a 96-well plate, immediately measuring the change of the absorbance of the system after uniform mixing, and recording data.
Since the absorbance of the meropenem substrate decreases after the meropenem substrate is hydrolyzed by the enzyme, the degree of hydrolysis of the substrate can be characterized by measuring the change in the absorbance of the meropenem substrate. The residual activity of epalrestat at different concentrations to inhibit metallo-beta-lactamase post-enzyme was calculated, a curve was fitted with the concentration of epalrestat against the residual activity, IC50 values were calculated, and the known metallo-beta-lactamase inhibitor ML302F (available from yokojie pharmaceutical technology limited) was used as a positive control. See table 1 for results.
TABLE 1 inhibitory Activity of Epalrestat on metallo beta-lactamase (μ M/L)
The experimental result shows that the epalrestat has excellent inhibition effect on IMP-7 type metal beta-lactamase and IC thereof5038.02 +/-22.72 mu M, is obviously superior to the metallo beta-lactamase in NDM-1 and VIM-2, and has excellent selectivity. Moreover, the inhibition effect (IC) of the positive control ML302F on the metallo-beta-lactamase is obviously better50＝43.26±15.28μM)。
Example 2 metallo-beta-lactamase inhibitor in combination with meropenem in vitro bacteriostatic assay
S1. inoculum preparation
Colonies were picked from a fresh culture (Escherichia coli BL21(DE3) expressing metallo-beta-lactamase) cultured in a plate for 18 to 24 hours, inoculated into 3mL of LB liquid medium containing kanamycin, cultured for 4 to 6 hours, and then adjusted to a bacterial suspension of 0.5 McBt standard, and the bacterial suspension was diluted 1:100 with LB broth for use. During the dilution process, 20mM isopropyl-beta-D-thiogalactoside (IPTG) is added according to the proportion of 1:20, so that the diluted bacterial solution contains 1mM IPTG.
S2, preparing epalrestat solution and inoculating bacterial solution
Dilution of meropenem: preparing 512 mu g/mL meropenem solution as a working solution, adding 100 mu L of the working solution into a first row of a 96-well plate, namely A1-H1 wells, respectively adding 50 mu L of culture medium into the other wells, sucking 50 mu L of the working solution from the first row to a second row by using an 8-channel micropipette, diluting and uniformly mixing the liquid medicine, sucking 50 mu L of the liquid from the row to the next row, repeating the operation until the last row contains 100 mu L of the liquid, discarding 50 mu L, and finishing the dilution of the meropenem;
adding epalrestat: preparing epalrestat solutions with the concentration of 512 mu g/mL, 256 mu g/mL, 128 mu g/mL, 64 mu g/mL, 32 mu g/mL, 16 mu g/mL, 8 mu g/mL and 4 mu g/mL respectively, sucking 50 mu L of the solution of the liquid medicine from high concentration to low concentration in turn, adding the solution into a 96-well plate, wherein the adding mode is as follows: adding 512 mug/mL liquid medicine into the hole A1-A12, adding 256 mug/mL liquid medicine into the hole B1-B12, and the like until the last row;
inoculating: using an 8-channel micropipette, 100. mu.L of the inoculum was added to each well, at a concentration of approximately 5X 105CFU/mL in each well, containing 0.5mM IPTG.
And placing the inoculated dilution tube in an incubator at 37 ℃ for incubation for 18-24 h, observing the growth conditions of bacteria under different epalrestat concentrations to obtain the Minimum Inhibitory Concentration (MIC) of meropenem or the meropenem combined with the epalrestat, and taking a known metallo-beta-lactamase inhibitor ML302F as a positive control. The results are shown in table 2 below:
TABLE 2 drug sensitivity test results for meropenem in combination with epalrestat
It can be seen that the combined use of epalrestat and meropenem can effectively reduce the MIC of meropenem to Escherichia coli generating IMP-7 type metallo-beta-lactamase, and the effect is superior to that of positive control ML302F, which shows that the compound of the invention can inhibit the metallo-beta-lactamase generated by drug-resistant bacteria, and further recover the killing effect of meropenem to drug-resistant bacteria, thereby overcoming the problem that the bacteria generate the metallo-beta-lactamase and lose efficacy to beta-lactam antibiotics.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. Application of epalrestat or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating bacterial infection diseases.
2. The use of claim 1, wherein epalrestat or a pharmaceutically acceptable salt thereof is used for the prevention and/or treatment of bacterial infectious diseases by inhibiting metallo-beta-lactamase.
3. The use of claim 2, wherein the metallo-beta-lactamase is an IMP-7, NDM-1 or VIM-2 type metallo-beta-lactamase.
4. The use according to any one of claims 1 to 3, wherein the bacteria are classified into gram-positive bacteria and gram-negative bacteria, and the gram-positive bacteria include Staphylococcus aureus, enterococcus faecalis, enterococcus faecium, Streptococcus, Diplococcus pneumoniae, Bacillus anthracis, Bacillus diphtheriae, and Bacillus tetani.
5. The use according to claim 4, wherein the gram-negative bacteria comprise Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Bacillus dysenteriae, Salmonella typhi, Bacillus proteus and Vibrio cholerae.
6. A medicament for preventing and/or treating bacterial infectious diseases, which comprises epalrestat or a pharmaceutically acceptable salt thereof and an antibiotic.
7. The medicament of claim 6, wherein the antibiotics comprise penicillin, cephalosporin, carbapenem, cephamycin and thiomycin antibiotics.
8. The medicament of claim 7, wherein the antibiotic comprises penicillin, ampicillin, piperacillin, cefuroxime, ceftriaxone, cefaclor, cefdinir, ceftazidime, meropenem, and imipenem.
9. Use of epalrestat or a pharmaceutically acceptable salt thereof in the preparation of a metallo-beta-lactamase inhibitor.
10. The use of claim 9, wherein the beta-lactamase inhibitor is a metallo beta-lactamase inhibitor of the type IMP-7, NDM-1 or VIM-2.
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| CN202111243742.3A CN114129564B (en) | 2021-10-25 | 2021-10-25 | Application of epalrestat or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and/or treating bacterial infection diseases |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170369433A1 (en) * | 2014-10-03 | 2017-12-28 | Oxford University Innovation Limited | Beta Lactamase Inhibitors |
| US20180015153A1 (en) * | 2016-07-16 | 2018-01-18 | Florida State University Research Foundation, Inc. | Compounds and methods for treatment and prevention of flavivirus infection |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170369433A1 (en) * | 2014-10-03 | 2017-12-28 | Oxford University Innovation Limited | Beta Lactamase Inhibitors |
| US20180015153A1 (en) * | 2016-07-16 | 2018-01-18 | Florida State University Research Foundation, Inc. | Compounds and methods for treatment and prevention of flavivirus infection |
Non-Patent Citations (2)
| Title |
|---|
| WILLIAM SINKO: "Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial Drug Leads", pages 5693 * |
| 孙影等: "NDM-1型金属-β-内酰胺酶及其抑制剂研究进展", 《国外医药(抗生素分册)》, vol. 39, no. 2, pages 1 - 98 * |
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