CN113842379B - New application of betaxolol as NDM-1 inhibitor or antibiotic protectant - Google Patents
New application of betaxolol as NDM-1 inhibitor or antibiotic protectant Download PDFInfo
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- CN113842379B CN113842379B CN202111065289.1A CN202111065289A CN113842379B CN 113842379 B CN113842379 B CN 113842379B CN 202111065289 A CN202111065289 A CN 202111065289A CN 113842379 B CN113842379 B CN 113842379B
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- Prior art keywords
- ndm
- betaxolol
- beta
- antibiotic
- inhibitor
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Links
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- 230000003115 biocidal effect Effects 0.000 title claims abstract description 12
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 title claims abstract 8
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 title abstract description 54
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims abstract description 24
- 229960002260 meropenem Drugs 0.000 claims abstract description 23
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- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims 2
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- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
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- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
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- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
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- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 1
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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
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a new application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of new medical application of betaxolol. According to the invention, experiments such as an NDM-1 enzyme inhibition test, a micro chessboard dilution method, a time-sterilization curve and the like are adopted to find that betaxolol can remarkably inhibit the activity of NDM-1 and recover the antibacterial activity of meropenem on NDM-1-producing escherichia coli. The present invention thus identifies that betaxolol can be used as an NDM-1 inhibitor, which, when used in combination with a beta-lactam antibiotic, can reduce or even eliminate the hydrolysis of NDM-1 to the beta-lactam antibiotic and restore the sensitivity of the resistant bacteria to the beta-lactam antibiotic.
Description
Technical Field
The invention relates to a novel pharmacological application of betaxolol, in particular to a novel pharmacological application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of novel pharmacological activity application of betaxolol.
Background
The beta-lactam antibiotics have strong bactericidal activity, low toxicity and wide application, and are important medicaments for treating infectious diseases caused by bacteria at present. Beta-lactam antibiotics include carbapenems, cephalosporins, penicillins, and the like, which have a beta-lactam ring structurally exhibiting antibacterial activity. With the widespread use of beta-lactam antibiotics, more and more bacteria are caused to develop resistance mediated by beta-lactamase.
The production of beta-lactamase, which catalyzes the cleavage of the C-N bond on the beta-lactam ring in beta-lactam antibiotics to open the ring, leads to antibiotic inactivation, is one of the important mechanisms for inducing bacterial resistance. Based on amino acid sequence homology, beta-lactamases can be classified into serine-beta-lactamases and metallo-beta-lactamases, which rely on active center serine for catalysis and can be inhibited by clinically used antibiotics such as clavulanic acid, sulbactam and tazobactam. Metallo beta-lactamases act catalytically by means of zinc ions in the active center, hydrolysing all beta-lactam antibiotics including carbapenems, and there are a wide variety of gram-negative and positive pathogenic bacteria for which no clinically effective inhibitors are yet available.
In month 8 2010, journal of the lancet report that new deli-beta-lactamase-1 (NDM-1) hydrolyses carbapenems, the treatment of infections is very difficult due to the extensive resistance of NDM-1-producing bacteria, known as "superbacteria". The blaNDM-1 gene is located on a plasmid, can autonomously replicate independently of the outside of a chromosome, and can horizontally transfer between different strains, so that the strain which is sensitive to the antibiotics can obtain drug resistance. NDM-1 is the most widely-affected and severely compromised metallo-beta-lactamase discovered in recent years, and shows high resistance to almost all antibiotics, and only tigecycline and polymyxin have certain inhibition effects on it, and the constantly evolving mutant strains make clinical treatment more difficult. NDM-1 hydrolyzes the clinically usual beta-lactam antibiotics, while its inhibitors inhibit the activity of NDM-1 enzyme, thereby protecting the beta-lactam antibiotics and restoring their antibacterial effect, so finding an inhibitor of NDM-1 is the most urgent requirement for suppressing the infection caused by "superbacteria".
Betaxolol is a beta 1 adrenergic receptor blocker, has calcium ion antagonism, no intrinsic sympathomimetic activity and weak membrane stabilization, and is clinically mainly used for treating primary hypertension and open angle glaucoma. Up to now, no report that betaxolol can be used as an NDM-1 inhibitor is found at home and abroad.
Disclosure of Invention
The main purpose of the invention is to provide a new application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent.
In order to achieve the above object, the present invention adopts the technical scheme that:
On the one hand, the invention discloses a novel pharmacological application of betaxolol as an NDM-1 inhibitor, namely, the hydrolysis of the NDM-1 to beta-lactam antibiotics is inhibited, and the antibacterial activity of the beta-lactam antibiotics to NDM-1-carrying positive bacteria is recovered. Thus, betaxolol can be used as an antibiotic protectant, in particular as a protectant for beta-lactam antibiotics.
In another aspect, the present invention provides a pharmaceutical composition for inhibiting pathogenic bacteria comprising an effective amount of an antibiotic, an antibiotic protectant, and a pharmaceutically acceptable carrier or adjuvant, wherein the antibiotic is preferably a beta-lactam antibiotic; the antibiotic protective agent is betaxolol.
The pharmaceutical composition for inhibiting pathogenic bacteria is prepared into clinically common preparations such as powder, granules, tablets, capsules, injection and the like according to the conventional preparation method in the field, and is introduced into muscle, endothelial, subcutaneous, intravenous and mucosal tissues by injection, oral administration, nasal drops, eye drops, physical or chemical mediation methods, or is mixed or wrapped by other substances and then introduced into a body.
The carrier or auxiliary materials refer to conventional carriers or auxiliary materials in the pharmaceutical field, for example: diluents, disintegrants, lubricants, excipients, binders, glidants, fillers, surfactants, and the like; in addition, other adjuvants such as flavoring agents and sweeteners may be added to the composition.
The diluent may be one or more ingredients that increase the weight and volume of the tablet; common diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, sorbitol, mannitol, inorganic calcium salts and the like. Of these, lactose, starch, microcrystalline cellulose are most commonly used.
The disintegrating agent can be one or a mixture of several of crosslinked polyvinylpyrrolidone (2-6% of the total weight), crosslinked sodium carboxymethyl cellulose (2-6% of the total weight), alginic acid (2-5% of the total weight) and microcrystalline cellulose (5-15% of the total weight). Among them, crosslinked polyvinylpyrrolidone (2 to 7% by weight to the total weight) and crosslinked sodium carboxymethylcellulose (2 to 6% by weight to the total weight) are preferable. Most preferred is crosslinked polyvinylpyrrolidone (2-6% by weight to the total weight).
The lubricant comprises one or a mixture of more of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, talcum powder and hydrogenated vegetable oil. Among them, magnesium stearate is most preferable. The amount of lubricant (based on the total weight) is in the range of 0.10 to 1%, generally 0.25 to 0.75%, and most preferably 0.5 to 0.7%.
The binder may be one or more ingredients that facilitate granulation. Can be starch slurry (10-30% and binder weight ratio), hydroxypropyl methylcellulose (2-5% and binder weight ratio), polyvinylpyrrolidone (2-20% and binder weight ratio), preferably polyvinylpyrrolidone ethanol aqueous solution, and most preferably polyvinylpyrrolidone 50% ethanol aqueous solution.
The glidant can be one or a mixture of a plurality of micropowder silica gel, talcum powder and magnesium trisilicate.
The surfactant may be one or more ingredients capable of improving wettability and increasing dissolution of the drug. Sodium dodecyl sulfate (usually in the range of 0.2-6% by weight to the total weight) is commonly used.
The betaxolol described in the present invention includes its prototype, pharmaceutically acceptable salt or formulation containing betaxolol.
The representative drug of the beta-lactam antibiotics in the invention is meropenem, and the molecular formula is as follows: c 17H25N3O5 S, the molecular weight is: 383.5.
The NDM-1 enzyme is a recombinant NDM-1 enzyme extracted from nature or prepared by using genetically engineered bacteria.
The "pathogenic bacteria" in the present invention are preferably gram-negative or positive pathogenic bacteria, more preferably NDM-1 positive bacteria.
Betaxolol, alias: 1- [4- [2- (cyclopropylmethoxy) ethyl ] phenoxy ] -3- (isopropylamino) propan-2-ol, betaxolol, and betamethadone. The molecular formula is as follows: c 18H29NO3, molecular weight: 307.43. the white crystalline solid has the melting point of 61-63 ℃, strong fat solubility, almost complete absorption after oral administration, high bioavailability and long half life, and has the following structural formula:
According to the invention, the activity of the betaxolol for inhibiting the NDM-1 can be verified by an NDM-1 enzyme inhibition test, enzyme inhibition rate and half inhibition concentration measurement, a chessboard method for measuring the minimum inhibitory concentration, a time-sterilization curve method and the like, and the antibacterial activity of the meropenem on the drug-resistant bacteria carrying the NDM-1 is recovered, so that the betaxolol can be used for treating bacterial infectious diseases and has wide medical application.
Detailed description of the overall technical scheme of the invention
The invention uses the NDM-1 (PDB: 4EY 2) crystal structure in the protein database as target protein, uses computer-aided drug design software GLIDE and MAESTRO, and adopts a molecular docking method to calculate the binding free energy of the binding site of betaxolol and the NDM-1 ligand. The free energy of binding of the docking product is less than-10.0 Kcal/mol, and betaxolol is tightly bound to the active region of NDM-1 centered on zinc ions, so that betaxolol is considered as a candidate compound with potential NDM-1 inhibition.
On the basis, the invention carries out a test of the inhibition activity of the betaxolol on the NDM-1 enzyme, and the test result shows that the betaxolol can inhibit the activity of the NDM-1 enzyme in a dose-dependent manner, the maximum inhibition rate is 93.2%, and the IC50 is 19.3+/-0.9 mu M.
The minimum inhibitory concentration test result shows that the betaxolol alone has no inhibitory effect, and the combined use of the betaxolol and meropenem can reduce the MIC value of the meropenem on NDM-1 positive escherichia coli by 32 times. FIC index shows that the combination of betaxolol and meropenem has obvious synergistic effect on inhibiting the strain producing NDM-1.
According to the test results of the time-sterilization curve, the combined use of betaxolol and meropenem can completely kill NDM-1 positive escherichia coli in 5 hours.
Drawings
FIG. 1 is a graph showing the binding pattern of the active region of betaxolol-NDM-1 complex system.
FIG. 2 is a time sterilization curve of combination of betaxolol and meropenem against NDM-1 positive E.coli.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions can be made in the details and form of the invention without departing from the spirit and scope of the invention, but these modifications and substitutions are intended to be within the scope of the invention.
Test example 1 molecular docking test of betaxolol with target protein NDM-1
The test uses the NDM-1 (PDB: 4EY 2) crystal structure in the protein database as target protein, uses computer-aided drug design software GLIDE and MAESTRO, and adopts a molecular docking method to calculate the binding free energy of the binding site of betaxolol and the NDM-1 ligand. Molecular docking results found that the free energy of binding of the docking product was less than-10.0 Kcal/mol and that betaxolol was tightly bound to the active region of NDM-1 centered on zinc ions (fig. 1), thus betaxolol was considered as a candidate compound with potential NDM-1 inhibition.
Test example 2 NDM-1 protein expression, separation and purification
The gene sequence of blaNDM-1 is inserted into pET32 (alpha) plasmid through EcoRI and XhoI cleavage sites to construct pET32 (alpha) -NDM-1 recombinant plasmid, and DNA sequencing verifies that the blaNDM-1 gene has no mutation in the connection process.
Transferring the recombinant plasmid into competent cells of escherichia coli BL21 (DE 3), screening by an ampicillin plate, selecting a monoclonal colony, inoculating to 5mL of LB liquid medium, oscillating overnight at 180rpm at 37 ℃, mixing 50% glycerol with bacterial liquid according to a ratio of 1:1, and preserving engineering bacteria E.coli BL21 (DE 3) -pET32 (alpha) -NDM-1 at-80 ℃.
Culturing engineering bacteria in LB culture medium containing ampicillin at 37deg.C and 180rpm to OD 0.6-0.8 in logarithmic growth phase, inducing with isopropyl-beta-D-thiogalactoside (IPTG) with final concentration of 1mM at 37deg.C for 4.5 hr, and centrifuging at 4deg.C to collect bacteria.
The collected bacteria are resuspended by phosphate buffer (PBS, pH=8.0), the bacterial lysate is crushed by an ultrasonic cytoclasis instrument in an ice bath, the bacterial lysate is centrifuged, the supernatant is collected and subjected to Ni-NTA His tag affinity chromatography column, and NDM-1 protein is separated and purified by gradient elution with imidazole at 0, 10, 20, 40 and 250mM concentration. And finally, dialyzing the NDM-1 protein for 36h by using a dialysis bag with a molecular cut-off of 10KD, concentrating by using a ultrafiltration tube with a molecular cut-off of 10KD, and detecting the expression and purification result of the NDM-1 protein by using SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) marks to obtain the NDM-1 recombinant protein with the purity of more than 90%.
Test example 3 test of inhibition of NDM-1 enzyme by betaxolol
The enzyme inhibition reaction system comprises 120 mu M meropenem as a substrate, 10mM 4-hydroxyethyl piperazine ethane sulfonic acid (HEPES, pH=8.0) as a buffer solution, 3.0U of NDM-1 enzyme and betaxolol solutions with different concentration gradients. Incubating for 15min at 30 ℃, and detecting enzyme activity by using a 295nm wavelength of an enzyme-labeled instrument. Meanwhile, EDTA is used as a positive control, DMSO is used as a negative control, and a blank control group contains neither inhibitor nor enzyme and is used as a bottom value of the system. Reactions were performed in 96-well plates, with 3 multiplex wells per reaction.
The specific process is as follows:
firstly, preparing an NDM-1 enzyme solution into a solution with the concentration of 3.0U by using a buffer solution, and placing the solution at the temperature of 30 ℃ for incubation for 10min so that Zn 2+ fully occupies an active center; dissolving betaxolol in buffer solution to prepare mother solution with the concentration of 100mM, then carrying out gradient dilution on the mother solution, adding the mother solution into NDM-1 enzyme, and incubating for 10min at 30 ℃ to fully combine the betaxolol with the enzyme; 50 mu L of meropenem is added into a 96-well plate reaction system, and the mixture is placed into an enzyme-labeled instrument for shaking and mixing, and is incubated at 30 ℃ for 15min to detect 295nm ultraviolet absorption change. The inhibition rate of the betaxolol with different concentrations on the NDM-1 enzyme hydrolysis substrate is calculated according to the following calculation formula:
inhibition (%) = (enzyme reaction rate of 1-betaxolol sample/average enzyme reaction rate of negative control wells) ×100%
The result of calculating the semi-inhibitory concentration IC50 value of betaxolol on NDM-1 shows that the betaxolol can inhibit the activity of NDM-1 enzyme in a dose-dependent manner, the maximum inhibition rate is 93.2%, and the IC50 is 19.3+/-0.9 mu M.
Test example 4 minimum inhibitory concentration test
Mu.L of NDM-1 positive E.coli was inoculated into 5mL of LB medium, and the culture was performed at 37℃and 180rpm for about 12 hours until the bacteria were in the late logarithmic phase of growth. Taking bacterial liquid into MH broth culture medium, regulating bacterial liquid concentration to 5×10 6 CFU/mL, adopting micro broth dilution method to make drug sensitivity test of betaxolol and meropenem respectively (concentration gradient is 1-2048 mug/mL), at the same time setting bacterial suspension without meropenem as positive control, MH broth as negative control. After incubation of the 96-well plate at 37 ℃ for 24h, MIC results were read, all performed 3 times in parallel, and the MIC value of the drug was the concentration of drug in the clear well preceding the turbid well in the 96-well plate.
Taking the bacterial liquid of the activation culture, preparing a 96-pore plate by adopting a chessboard method, simultaneously detecting 77 possible concentration combinations, adding betaxolol and meropenem with different concentration combinations, placing the 96-pore plate in a biochemical incubator with constant temperature of 37 ℃ for 24 hours, carrying out an antibacterial activity experiment of combining the betaxolol and the meropenem with NDM-1 positive bacteria, and determining the MIC value of the combined application of the two. Simultaneously setting a negative control group and a positive control group, performing parallel operation for 3 times, and calculating partial antibacterial concentration index FIC value according to the MIC value, wherein the calculation method is as follows:
fic=mic (meropenem combination)/MIC (meropenem alone) +mic (betaxolol combination)/MIC (betaxolol alone)
When FICI is less than or equal to 0.5, the FICI and the FICI are synergistic; FICI is less than or equal to 4 and is 0.5 and has no relation with the FICI; FICI >4, both are antagonism.
TABLE 1 MIC and FIC values of meropenem combined betaxolol for NDM-1 expressing positive E.coli
The minimum inhibitory concentration test result shows that the betaxolol alone has no inhibitory effect, and the combined use of the betaxolol and meropenem can reduce the MIC value of the meropenem on NDM-1 positive escherichia coli by 32 times. FIC index shows that the combination of betaxolol and meropenem has obvious synergistic effect on inhibiting the strain producing NDM-1.
Test example 5 time-sterilization Curve test
Single colony is selected from a pure culture plate of NDM-1 positive escherichia coli, inoculated in MH broth culture medium for 6-8 hours at 37 ℃, bacterial culture is taken, bacteria liquid concentration is adjusted to 5X 10 7 CFU/mL by using a Mitsubishi turbidimeter with sterile physiological saline, and then the bacteria liquid is diluted by 10 times of the sterile MH broth to make the final concentration 10 6 CFU/mL.
A drug-free blank group, a 2 μg/mL meropenem group, a combination group of 2 μg/mL meropenem and 64 μg/mL betaxolol were set. The test group and the control group were cultured at 37℃under the same bacterial liquid concentration, quantitative culture liquids were taken out from each group at 0,1, 3,5, 7, 9 and 11 hours and transferred to the corresponding agar medium, and after culturing at 37℃for 18-24 hours, colony counts were made, the logarithm of the colony numbers was taken as the ordinate, and the culturing time was taken as the abscissa, and a time-sterilization curve was drawn (FIG. 2).
From the time-sterilization curve of fig. 2, it can be seen that betaxolol in combination with meropenem is able to completely kill NDM-1 positive e.coli at 5 h.
Claims (2)
1. Use of betaxolol in combination with the antibiotic meropenem for the preparation of a medicament for inhibiting NDM-1 positive escherichia coli.
2. Use according to claim 1, characterized in that: the betaxolol includes a pharmaceutically acceptable salt.
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| CN101137369A (en) * | 2005-02-09 | 2008-03-05 | 马库赛特公司 | Formulations for ocular treatment |
| CN101522174A (en) * | 2006-05-10 | 2009-09-02 | 赢创德固赛有限责任公司 | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
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