CN108159029B - Pterostilbene is preparing the application in NDM-1 enzyme inhibitor - Google Patents
Pterostilbene is preparing the application in NDM-1 enzyme inhibitor Download PDFInfo
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- CN108159029B CN108159029B CN201810192781.7A CN201810192781A CN108159029B CN 108159029 B CN108159029 B CN 108159029B CN 201810192781 A CN201810192781 A CN 201810192781A CN 108159029 B CN108159029 B CN 108159029B
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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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- 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
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Abstract
The present invention relates to pterostilbenes to prepare the application in NDM-1 enzyme inhibitor, discloses the new medical application of one kind of pterostilbene；Pterostilbene is able to suppress the activity of NDM-1 enzyme, restores Meropenem to the bactericidal activity of NDM-1 Escherichia coli；In experiment in vivo, pterostilbene, which is combined Meropenem, has good therapeutic effect to the bacterial infection of expression NDM-1, the especially infection such as peritonitis caused by NDM-1 Positive E. coli, has extensive medical application.
Description
Technical field
The present invention relates to pterostilbenes to prepare the application in NDM-1 enzyme inhibitor, discloses the new doctor of one kind of pterostilbene
With purposes, it is able to suppress the activity of NDM-1 enzyme, belongs to medicine pharmaceutical technology field.
Background technique
Bacterial drug resistance is continuously increased, and causes the appearance of bacterial infection case more difficult in many treatments,
Wherein the state of an illness caused by the gram positive bacterial infection with Extended-spectrum β-lactamases is more serious, people under regular situation
The gram positive bacterial infection for producing super beta lactamase is treated using carbapenem antibiotic, but it is almost resistance to all
The appearance of the super drug-fast bacteria such as NDM-1 of antibiotic etc., leads to treatment failure and the higher death rate, to treatment nosocomial infection,
Especially treatment ICU infection brings bigger pressure.The bacterium for expressing NDM-1 is equal to clinically used most antibiotic
With drug resistance, such as Meropenem, Imipenem, cefotaxime, cephalo pyrroles, Ciprofloxacin, amikacin.It there is no at present
Therefore the report of effective NDM-1 inhibitor is developed new safely and effectively drug and is had a very important significance.
Pterostilbene is a kind of Polyphenols native compound from red sandalwood, blueberry, blackberry, blueberry etc., is in traditional Chinese medicine dragon's blood
Important component.Pterostilbene has the effect of promoting blood circulation analgesic therapy, removing blood stasis and hemostasis, myogenic sore.As the novel innate efficacy factor,
Pterostilbene has the various biologicals such as antimycotic, anti-oxidant, anti-inflammatory, anticancer activity, has critical role in clinical medicine.Through
Retrieval has no that pterostilbene is preparing the relevant report in NDM-1 inhibitor.
Summary of the invention
The present invention provides a kind of pterostilbenes to prepare the medical application in NDM-1 enzyme inhibitor, discloses pterostilbene energy
The activity for enough inhibiting NDM-1 enzyme restores Meropenem to the bactericidal activity of NDM-1 Escherichia coli.
Pterostilbene of the present invention, molecular formula: C16H16O3, molecular weight: 256.30；
Meropenem of the present invention, molecular formula: C17H25N3O5S·3H2O, molecular weight: 437.51.
The present invention inhibits test, chessboard method and time-kill curve method verifying pterostilbene to be able to suppress NDM-1 enzyme by enzyme
Activity and restore Meropenem to the antibacterial activity of NDM-1 Positive E. coli.Further by establishing mouse peritoneum inflammation sense
Dye model proves that pterostilbene combination Meropenem is infected caused by can generate the Escherichia coli of NDM-1 with good treatment
Effect.
The positive effect of the present invention is:
It provides pterostilbene and is preparing the new medical application in NDM-1 enzyme inhibitor, disclose pterostilbene and be able to suppress
The activity of NDM-1 enzyme restores Meropenem to the bactericidal activity of NDM-1 Escherichia coli.In experiment in vivo, pterostilbene is combined Metro
Training south has the bacterial infection of expression NDM-1, the especially infection such as peritonitis caused by NDM-1 Positive E. coli good
Therapeutic effect, have extensive medical application.
Detailed description of the invention
Fig. 1 is inhibitory effect figure of the pterostilbene of the present invention to NDM-1 enzyme；
Fig. 2 is time-kill curve of the present invention.
Specific embodiment
By following embodiment further illustrate description the present invention, do not limit the invention in any way, without departing substantially from
Under the premise of technical solution of the invention, easy to accomplish any of those of ordinary skill in the art made for the present invention changes
Dynamic or change is fallen within scope of the presently claimed invention.
Embodiment 1
Pterostilbene is used for pharmaceutically acceptable any carrier as NDM-1 enzyme inhibitor.
Embodiment 2
Pterostilbene is used to prepare the drug for the treatment of infectious diseases as NDM-1 enzyme inhibitor.
Embodiment 3
For pterostilbene as NDM-1 enzyme inhibitor for treating infectious diseases caused by bacterium, especially NDM-1 is positive big
Infection caused by enterobacteria.
Test example 1
Enzyme inhibits test
Take 96 hole sterile microplates, by 1 μ L of NDM-1 enzyme of expression and purification, various concentration pterostilbene adding hole in, use
PBS(PBS, pH=7.4 supplement 10mM ZnCl2) mend total volume to 200 μ L, so that the final concentration of pterostilbene divides in every hole
Not Wei 2,4,8 and 16 μ g/mL, separately set up not enzyme negative control group and the positive controls of pterostilbene be not added.It mixes, 37
DEG C be incubated for 10 min, later be added 25 μ L of Nitrocefin, mix, continue 37 DEG C of 30 min of incubations, in 492 nm at measurement suction
Light value calculates pterostilbene to the inhibitory effect (Fig. 1) of NDM-1 enzyme；
Conclusion: pterostilbene can dose-dependently inhibit the activity of NDM-1 enzyme.
Test example 2
Minimal inhibitory concentration test
In carrying out in 96 hole sterile microplates by chessboard method, pterostilbene, Meropenem are applied alone and the two is combined anti-production NDM-1
The bacteriostatic activity test of Escherichia coli, determining the two is used alone and use in conjunction MIC value, calculating section Mlc index
(FICI).(pterostilbene is single by FICI=MIC (Meropenem joint)/MIC (Meropenem is applied alone)+MIC (pterostilbene joint)/MIC
With), it the results are shown in Table 1:
1 pterostilbene of table is combined Meropenem to MIC the and FIC value of NDM-1 Positive E. coli separation strains
Conclusion: pterostilbene, which is used alone, does not have fungistatic effect, can reduce Meropenem pair with Meropenem combination
4 times of the MIC value of NDM-1 Positive E. coli, FICI numerical value show that the two has synergistic effect.
Test example 3
Time-kill curve test
NDM-1 Positive E. coli separation strains overnight culture is taken, is adjusted to 107CFUs/mL, it is spare.Take sterile test tube
3 groups (antibiotic-free control group, 8 μ g/mL Meropenem groups and 32 μ g/mL pterostilbenes are combined 8 μ g/mL Meropenem groups), often
Group echo is 1,3,5,7 h, and the autoclaved LB culture medium of 1 mL is added in all test tubes and is added 10 in every pipe later
μ L bacterium solution adjusted makes each invisible spectro bacterial concentration 105CFUs/mL.Wherein 8 μ g/mL Meropenem groups and 32
μ g/mL pterostilbene is combined 8 μ g/mL Meropenem groups and is separately added into antibiotic and inhibitor to application amount, after mixing immediately
The bacterium solution of antibiotic-free control group is subjected to coated plate counting, the clump count as 0 h.Later, the h of every 1,3,5 and 7 takes pair respectively
Invisible spectro bacterium solution is answered, coated plate counts, and draws time-kill curve (Fig. 2).
Conclusion: pterostilbene combination Meropenem of the present invention can thoroughly kill NDM-1 Positive E. coli in 7 h.
Test example 4
The experimental therapeutic of mouse peritoneum inflammation is studied
Mouse Escherichia coli peritonitis model
Behind the Baoding BALB/C mice (female, about 20g), through NDM-1 Positive E. coli suspension (1 × 10 is injected intraperitoneally8
CFUs), the model of mouse peritoneum inflammation is established.
Protective rate test
Mouse peritoneal be inoculated with NDM-1 Positive E. coli after, 10 mg/kg(50 μ l are subcutaneously injected respectively immediately) dissolution
In aqua sterilisa Meropenem, intraperitoneal injection 50 mg/kg(50 μ l) pterostilbene nano-emulsion and Meropenem (10 mg/kg)
It is combined pterostilbene (50 mg/kg), every 8 h is administered once, is administered three times altogether.The nano-emulsion that positive controls give 50 μ l is empty
White solvent is not given any drug and is treated；The solvent control group for being uninfected by mouse is individually separately set up, 50 μ l's given in abdominal cavity
Nano-emulsion blank solvent is to investigate the safety of nano-emulsion solvent used.After Dosage Regimens Dosage, mouse infection is recorded respectively
The death rate (every 12 hour records) after NDM-1 Positive E. coli 5 days, the results are shown in Table 2.
The pterostilbene of the present invention of table 2. is combined influence of the Meropenem to the mouse Escherichia coli peritonitis death rate
Conclusion: after pterostilbene combination Meropenem treatment, the death rate of mouse peritoneum inflammation, red sandalwood of the present invention are significantly reduced
Stilbene or Meropenem monotherapy group do not have significant protecting effect.
Claims (1)
- Infectious disease medicament caused by 1. the composition of pterostilbene and Meropenem treats NDM-1 Positive E. coli in preparation In purposes, wherein the NDM-1 Positive E. coli is the drug-fast bacteria of Meropenem, and pterostilbene is the suppression as NDM-1 enzyme Preparation.
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| CN201810192781.7A CN108159029B (en) | 2018-03-09 | 2018-03-09 | Pterostilbene is preparing the application in NDM-1 enzyme inhibitor |
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| CN108159029B true CN108159029B (en) | 2019-10-11 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107714678A (en) * | 2017-10-23 | 2018-02-23 | 吉林大学 | Application of the pterostilbene in the enzyme inhibitors of MCR 1 are prepared |
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| FR2841436B1 (en) * | 2002-07-01 | 2006-01-27 | Univ Bourgogne | MEANS FOR BIOLOGICAL CONTROL OF CRYPTOGAMIC DISEASES IN PLANT VEGETABLES |
| WO2012078798A1 (en) * | 2010-12-07 | 2012-06-14 | Bananalogix, Inc. | Methods of processing organic matter and compositions thereof |
| US20170290853A1 (en) * | 2016-04-12 | 2017-10-12 | Kemin Industries, Inc. | Methods to facilitate the solubilization of beta-1,3-glucan and enhance immune function and other related uses |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107714678A (en) * | 2017-10-23 | 2018-02-23 | 吉林大学 | Application of the pterostilbene in the enzyme inhibitors of MCR 1 are prepared |
Non-Patent Citations (1)
| Title |
|---|
| Coexistence of MCR-1 and NDM-1 in Clinical Escherichia coli Isolates;Beiwen Zheng et al;《Clinical Infectious Diseases》;20160809;第1393-1395页 * |
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