CN114129564B - Application of epalrestat or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and/or treating bacterial infection diseases - Google Patents
Application of epalrestat or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and/or treating bacterial infection diseases Download PDFInfo
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- CN114129564B CN114129564B CN202111243742.3A CN202111243742A CN114129564B CN 114129564 B CN114129564 B CN 114129564B CN 202111243742 A CN202111243742 A CN 202111243742A CN 114129564 B CN114129564 B CN 114129564B
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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-lactamase to beta-lactam antibiotics, thereby recovering the sensitivity of drug-resistant microorganisms to the beta-lactam antibiotics and having obvious auxiliary antibacterial infection resistance effect.
Description
Technical Field
The invention belongs to the technical field of biological medicine. 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, however bacteria are rapidly resistant to them, mainly because they can themselves produce beta-lactamase and thus the enzymatic hydrolysis of the beta-lactam antibiotics is disabled. Metallo-beta-lactamase is one of beta-lactamase, common subfamilies are IMP, VIM and NDM, and the metallo-beta-lactamase has stable and efficient carbapenem hydrolytic activity, can catalyze water to remove all beta-lactam antibiotics except single-ring beta-lactam drugs, can produce various metallo-beta-lactamase by common gram-negative bacteria such as klebsiella pneumoniae and escherichia coli clinically, has serious drug resistance, and causes very difficult treatment of infection.
To solve the above problems, those skilled in the art have intensively studied a metallo beta-lactamase inhibitor, for example, chinese application CN101267815a discloses that a maleic acid compound has a metallo beta-lactamase inhibiting effect, but it has an inhibiting effect only on IMP-1 type metallo beta-lactamase of IMP subfamily and VIM-2 type metallo beta-lactamase of VIM subfamily, and does not have an inhibiting effect on IMP-7 type metallo beta-lactamase of IMP subfamily. It can be seen that the existing metal beta-lactamase inhibitors are few in variety, and the selection range of drugs for overcoming the problem of bacterial drug resistance is narrow.
Disclosure of Invention
The invention aims to overcome the defects of few types of existing metal beta-lactamase inhibitors, few clinical bacterial drug resistance, few optional drugs for infection treatment and low safety, and provides application of epalrestat or pharmaceutically acceptable salts thereof in preparing drugs for preventing and/or treating bacterial infection diseases.
It is another object of the present invention to provide a medicament for preventing and/or treating bacterial infection diseases.
It is another object of the present invention to provide the use of epalrestat or a pharmaceutically acceptable salt thereof for the preparation of a metallo beta-lactamase inhibitor drug.
The above object of the present invention is achieved by the following technical solutions:
use of epalrestat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of bacterial infection diseases.
Wherein the structure of epalrestat is as follows:
preferably, the epalrestat or pharmaceutically acceptable salt thereof is used for preventing and/or treating bacterial infection diseases by inhibiting metallo beta-lactamase.
Preferably, the metallo-beta-lactamase is an IMP-7, NDM-1 or VIM-2 metallo-beta-lactamase.
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, the gram-positive bacteria including staphylococcus aureus, enterococcus faecalis, enterococcus faecium, streptococcus, pneumococcus, bacillus anthracis, bacillus diphtheriae or bacillus tetanus.
Preferably, the gram-negative bacteria include escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter baumannii, bacillus dysenteriae, typhoid bacillus, 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 salt thereof can inhibit the hydrolysis of beta-lactam antibiotics by metal beta-lactamase, thereby protecting the antibiotics and effectively improving the sensitivity of drug-resistant microorganisms to beta-lactam drugs. When various preparations of the beta-lactam antibiotics are used together with epalrestat, the hydrolysis of the beta-lactam antibiotics by the metallic beta-lactamase generated by microorganisms can be inhibited, 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 medicine for treating bacterial infection diseases is high in toxicity and cannot be clinically used, the invention creatively applies epalrestat or pharmaceutically acceptable salt thereof to the treatment of bacterial infection diseases, and epalrestat is a clinically used medicine, is low in toxicity, accords with the standard of medicines of food and medicine administration and ensures the safety.
Preferably, the antibiotic comprises a penicillin, cephalosporin, penem, cephalosporin, and thiomycin antibiotic.
Preferably, the antibiotic comprises penicillin, ampicillin, piperacillin, cefuroxime, ceftriaxone, cefaclor, cefdinir, ceftazidime, meropenem, imipenem.
Preferably, the medicament is a capsule, tablet, pill, granule, electuary, injection or spray.
Preferably, the medicament is suitable for use in humans or animals.
The invention also protects the application of epalrestat or pharmaceutically acceptable salts thereof in preparing a metal beta-lactamase inhibitor medicament.
Preferably, the metallo-beta-lactamase is an IMP-7, NDM-1 or VIM-2 metallo-beta-lactamase inhibitor.
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 metal beta-lactamase to beta-lactam antibiotics, 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 beta-lactam drugs, overcoming the problem of bacterial drug resistance and having remarkable anti-bacterial infection effect; meanwhile, the toxicity is low and the safety is ensured.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are not intended to limit the invention in any way. Unless otherwise indicated, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
During the reaction, meropenem is used as a substrate, and 50mM 4-hydroxyethyl piperazine ethane sulfonic acid (HEPES) and 100 mu M ZnCl are used as buffers 2 Bovine Serum Albumin (BSA) at 100 μg/mLWhite (BSA) and 0.01% polyethylene glycol octyl phenyl ether (Trion X-100), wherein the pH=7.0 of the reaction system, the reaction temperature is 25 ℃, the final concentrations of IMP-7, VIM-2 and NDM-1 metallo beta-lactamase are respectively 2nM,4nM and 10nM, the final reaction volume is 100 mu L, and the detection wavelength is 300nM.
EXAMPLE 1 detection of the IMP-7 type Metal beta-lactamase inhibitory Activity of epalrestat
Experimental group:
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 buffer solution in a 96-well plate, and incubating at 25 ℃ for 30min to enable the inhibitor to be fully combined with the enzyme; the method comprises the steps of carrying out a first treatment on the surface of the
S2, meropenem dissolved in buffer solution (the final concentration of IMP-7 and VIM-2 is 50 mu M, the final concentration of NDM-1 is 100 mu M) is taken and added into a 96-well plate, the change of absorbance of the system is measured immediately after uniform mixing, and data are recorded.
Since the absorbance of the substrate meropenem decreases after the substrate meropenem is hydrolyzed by the enzyme, the degree of hydrolysis of the substrate can be characterized by measuring the change in the absorbance of meropenem. The residual activity of the enzyme after inhibition of metallo-beta-lactamase by epalrestat at various concentrations was calculated, IC50 values were calculated by fitting a curve of epalrestat concentration to residual activity, and the known metallo-beta-lactamase inhibitor ML302F (available from cheng duhui jie pharmaceutical technologies ltd) was used as a positive control. The results are shown in Table 1.
TABLE 1 inhibition of metallo beta-lactamase by epalrestat (. Mu.M/L)
Experimental results show that epalrestat has excellent inhibition effect on IMP-7 type metallo beta-lactamase and IC thereof 50 The beta-lactamase is 38.02+/-22.72 mu M, which is obviously superior to the metallo beta-lactamase in NDM-1 and VIM-2, and has excellent selectivity. Furthermore, the inhibition effect (IC) of the positive control ML302F on the metallo beta-lactamase is obviously better than that of the positive control ML302F 50 ＝43.26±15.28μM)。
Example 2 in vitro antibacterial assay of Metal beta-lactamase inhibitor in combination with meropenem
S1, preparation of inoculum
Colonies were picked from fresh cultures (E.coli BL21 (DE 3) expressing metallo-beta-lactamase) grown in plates for 18-24 h, inoculated into 3mL of LB liquid medium containing kanamycin, cultured for 4-6 h, and then adjusted to a colony concentration of 0.5% by weight of a malt-turbidity standard bacterial suspension, and the bacterial suspension was diluted 1:100 with LB broth for later use. In the dilution process, 20mM isopropyl-beta-D-thiogalactoside (IPTG) is added according to the ratio of 1:20, so that the diluted bacterial liquid contains 1mM IPTG.
S2, preparation of epalrestat solution and inoculation of bacterial liquid
(1) Dilution of meropenem: preparing 512 mug/mL of meropenem solution as working solution, adding 100 mug of working solution into the first row of a 96-well plate, namely, A1-H1, respectively adding 50 mug of culture medium into the other holes, sucking 50 mug of working solution from the first row to the second row by using an 8-channel micropipette, diluting and uniformly mixing the liquid medicine, sucking 50 mug of liquid from the row to the next row, repeating the operation until the last row contains 100 mug of liquid, discarding 50 mug, and completing the dilution of meropenem;
(2) epalrestat was added: the epalrestat solution with the concentration of 512 mug/mL, 256 mug/mL, 128 mug/mL, 64 mug/mL, 32 mug/mL, 16 mug/mL, 8 mug/mL and 4 mug/mL is prepared, and 50 mug of the solution is sequentially sucked from high concentration to low concentration and added into a 96-well plate, wherein the adding mode is as follows: 512 μg/mL of the drug solution was added to the A1-A12 wells, 256 μg/mL of the drug solution was added to the B1-B12 wells, and so on to the last column;
(3) inoculating: 100. Mu.L of the bacterial suspension was added to each well by using an 8-channel micropipette, and the concentration of the bacterial suspension in each well was about 5X 105CFU/mL, and the concentration was 0.5mM in IPTG.
The inoculated dilution tube is placed in a 37 ℃ incubator for incubation for 18-24 hours, the growth condition of bacteria under different epalrestat concentrations is observed, the Minimum Inhibitory Concentration (MIC) of meropenem or the combination of meropenem and epalrestat is obtained, and the known metal beta-lactamase inhibitor ML302F is used as a positive control. The results are shown in Table 2 below:
TABLE 2 drug sensitivity test results of meropenem and epalrestat combination
It can be seen that when the epalrestat is combined with the meropenem, the MIC of the meropenem on the escherichia coli producing IMP-7 type metal beta-lactamase can be effectively reduced, the effect is better than that of positive control ML302F, and the compound can inhibit the metal beta-lactamase produced by drug-resistant bacteria, so that the killing effect of the meropenem on the drug-resistant bacteria is recovered, and the problem that the bacteria produce the metal beta-lactamase and fail to beta-lactam antibiotics is solved.
The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (5)
1. A medicament for preventing and/or treating bacterial infection diseases by inhibiting metallo beta-lactamase, characterized in that the active ingredients are epalrestat or pharmaceutically acceptable salts thereof and antibiotics;
the antibiotics are beta-lactam antibiotics;
the beta-lactam antibiotics are penicillins, cephalosporins, carbapenems or cephalosporins;
the metallo-beta-lactamase is IMP-7 type metallo-beta-lactamase.
2. The medicament according to claim 1, characterized in that the β -lactam antibiotic is selected from the group consisting of penicillin, ampicillin, piperacillin, cefuroxime, ceftriaxone, cefaclor, cefdinir, ceftazidime, meropenem or imipenem.
3. Use of a medicament according to claim 1 or 2 for the manufacture of a medicament for the prevention and/or treatment of bacterial infection diseases by inhibition of metallo-beta-lactamase, characterized in that the metallo-beta-lactamase is an IMP-7 metallo-beta-lactamase.
4. The use according to claim 3, wherein the bacterium is escherichia coli, pseudomonas aeruginosa or acinetobacter baumannii.
5. The use of epalrestat or a pharmaceutically acceptable salt thereof in the preparation of a metallo beta-lactamase inhibitor, characterized in that the metallo beta-lactamase inhibitor is an IMP-7 metallo beta-lactamase inhibitor.
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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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| GB201417529D0 (en) * | 2014-10-03 | 2014-11-19 | Isis Innovation | 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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| NDM-1型金属-β-内酰胺酶及其抑制剂研究进展;孙影等;《国外医药(抗生素分册)》;第39卷(第2期);1-98 * |
| William Sinko.Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial Drug Leads.《journal of medicinal chemistry》.2014,5693−5701. * |
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