CN108553459A - A kind of MCR-1 inhibitor and its application in preparing inhibition MCR-1 positive drug-fast bacteria drugs - Google Patents
A kind of MCR-1 inhibitor and its application in preparing inhibition MCR-1 positive drug-fast bacteria drugs Download PDFInfo
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- CN108553459A CN108553459A CN201810494825.1A CN201810494825A CN108553459A CN 108553459 A CN108553459 A CN 108553459A CN 201810494825 A CN201810494825 A CN 201810494825A CN 108553459 A CN108553459 A CN 108553459A
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- mcr
- inhibitor
- positive drug
- polymyxins
- fast
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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
- A61K31/415—1,2-Diazoles
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- 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
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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
Abstract
The invention discloses a kind of 1 inhibitor of MCR and its preparing the application in inhibiting the positive drug-fast bacteria drugs of MCR 1, the present invention uses 1 inhibitor screening systems of MCR, it confirms that 1 inhibitor of MCR of the present invention (the methyl carbamide compounds of halogeno-benzyl and pyrazolylmethyl modification) can inhibit the activity of the positive drug-fast bacteria proliferation of MCR 1, causes to inhibit the positive drug-fast bacterias of MCR 1 multiple to polymyxins quick.To be pushed further into the research and development that the positive drug-fast bacterias of MCR 1 carry out treatment new strategy, the strong theoretical foundation and practical basis for promoting the clinical conversion of medicine to provide have important research and development value and development significance.
Description
Technical field
The present invention relates to a kind of new opplications of compound, more particularly to the methyl ureas of halogeno-benzyl and pyrazolylmethyl modification
Application of the compound in inhibiting MCR-1 positive drug-fast bacterias.
Background technology
China is that bacterial resistance problem is serious, multidrug resistant and general drug-fast bacteria force doctor select " last line " drug into
Row treatment.Polymyxins (Polymyxins) be clinical treatment severe drug-fast bacteria infection most effective " last line " drug it
One.Applicant found for the first time in early-stage study plasmid carry mcr-1 genes (mobile colistin resistance,
Moveable polymyxins drug resistant gene) polymyxins drug resistance can be mediated.And plasmid-mediated it can be caused resistance to horizontal transmission
Medicine spread speed faster, range it is wider, be to cause the clinical drug resistance circulation way for endangering most serious at present.It is worth noting that,
Applicant reports MCR-1 in the Local primitive exponent in China and causes infected patient dead for the first time, while reporting nearly 2 years MCR-1
Field planting rate in Guangdong Province inpatient and Healthy People enteron aisle significantly increases.Further, applicant reports MCR-1 and is easy
It coexists to form multidrug resistant and general drug resistance with other " super drug resistant genes ".The above achievement in research prompt MCR-1 tools of applicant
There is potential fashion trend, the harm of more bad clinical is likely to result in if do not contained.Therefore, research is directed to MCR-1 drug resistance machines
The new drug of system just becomes the important means for coping with this great basic research problems and public health challenge.However, currently without
Any information alert or report halogeno-benzyl and pyrazolylmethyl modification methyl carbamide compounds have make MCR-1 positive drug-fast bacterias
To the multiple quick effect of polymyxins.
Invention content
Inhibit MCR-1 positive drug-fast bacteria drugs the purpose of the present invention is to provide a kind of MCR-1 inhibitor and its preparing
In application.
The technical solution used in the present invention is：
MCR-1 inhibitor or its acceptable pharmaceutical salts are in preparing the antibacterials for inhibiting MCR-1 positive drug-fast bacterias
Using the MCR-1 inhibitor is shown in formula I：
In Formulas I：
R1 is the monosubstituted base or multi-substituent of any position on benzene radicals, and substituent group is H or halogen；
R2 is H or methyl.
Further, the acceptable pharmaceutical salts of MCR-1 inhibitor are its Na, K, Ca salt.
Further, the halogen is F, Cl, Br, I.
Further, the MCR-1 inhibitor is
Further, also contain polymyxins in the antibacterials.
A kind of antibacterials inhibiting MCR-1 positive drug-fast bacterias, containing described in any one of the above embodiments in the antibacterials
MCR-1 inhibitor or its acceptable pharmaceutical salts and polymyxins.
Further, in above-mentioned antibacterials, a concentration of 0.5~64mg/l (preferably 14~18mg/ of polymyxins
L), a concentration of 5~50 μM of MCR-1 inhibitor or its acceptable pharmaceutical salts.
The beneficial effects of the invention are as follows：
(1) present invention uses MCR-1 inhibitor screening systems, it was confirmed that halogeno-benzyl and pyrazolylmethyl modification of the present invention
Methyl carbamide compounds (Formulas I), the activity that MCR-1 positive drug-fast bacterias can be inhibited to be proliferated cause to inhibit MCR-1 positive drug-fast bacterias
It is multiple to polymyxins quick.
R1 is the monosubstituted base or multi-substituent of any position on benzene radicals, and substituent group is H or halogen；R2 is H or methyl.
(2) present invention is by the minimum inhibitory concentration of more plants of MCR-1 positive drug-fast bacterias experiment (MIC), having found this hair
Bright MCR-1 inhibitor can make MCR-1 positives drug-fast bacteria multiple to polymyxins quick, be opened to be pushed further into MCR-1 positive drug-fast bacterias
The research and development of exhibition treatment new strategy, the strong theoretical foundation for promoting the clinical conversion of medicine to provide and practical basis, tool
There are important research and development value and development significance.
Description of the drawings
Fig. 1 is that chessboard analytic approach (checkerboard assay) studies setting for MCR-1 inhibitor antibacterial activity of the present invention
Count schematic diagram.
Specific implementation mode
With reference to specific embodiment, the present invention is further illustrated.
Influence of the 1 MCR-1 inhibitor of embodiment to bacterial growth
1) Bacteria Culture：4 plants of MCR-1 positive drug-fast bacterias are chosen to make with Escherichia coli type strain ATCC25922 as experiment.
After the recovery of solid LB tablets, picking individual colonies, are incubated overnight with MH culture mediums respectively, increase bacterium.
2) prepared by bacteria suspension：By 0.5 Maxwell turbidity bacteria suspension of normal saline, with MH culture solutions 1:100 dilutions, make
Its bacterial content is 1.5 × 106Cfu/ml is inoculated with 50 μ l in 96 orifice plates per hole.
3) a concentration of 100 μM of various MCR-1 inhibitor (as shown in table 1) of 50 μ l volumes are added in 96 orifice plates, respectively
4 plants of MCR-1 positives drug-fast bacterias and ATCC25922 are inoculated into 96 holes, every plant of bacterium is inoculated with 50 μ l bacterium solutions, makes every hole total volume be
100 μ l, each MCR-1 inhibitor concentrations are 50 μM.Positive control is the tested bacterium for being not added with compound in equal volume, and negative control is
100 μ l MH culture mediums.
4) after 37 DEG C of 16~20h of culture, visually observe in the hole of 96 orifice plates that whether there is or not bacterial growths.
The structural formula of 1 part representativeness MCR-1 inhibitor of table
Experimental result is shown, when each MCR-1 inhibitor concentrations of the present invention are 50 μM, each group bacterium can normal growth, increasing
It grows.Illustrate that MCR-1 inhibitor of the present invention has no toxic action to bacterium normal growth.
2 high concentration MCR-1 inhibitor of embodiment enhances effect of the bacterium to polymyxins sensibility
1) Bacteria Culture：It chooses 4 plants of MCR-1 positive drug-fast bacterias and is used as experimental strain, Escherichia coli type strain
ATCC25922 is as Quality Control bacterium.After the recovery of solid LB tablets, picking individual colonies, are incubated overnight with MH culture mediums respectively, increase bacterium.
2) prepared by bacteria suspension：By 0.5 Maxwell turbidity bacteria suspension of normal saline, with MH culture solutions 1:100 dilutions, make
Its bacterial content is 1.5 × 106Cfu/ml is inoculated with 50 μ l in 96 orifice plates per hole.
3) polymyxins of a concentration of 64mg/ml of 25 μ l volumes is added in 96 orifice plates.It then proceedes to add into 96 orifice plates
Enter the various MCR-1 inhibitor (being shown in Table 1) of a concentration of 200 μM of 25 μ l volumes, respectively 4 plants of MCR-1 positives drug-fast bacterias and
ATCC25922 is inoculated into 96 holes, and every plant of bacterium is inoculated with 50 μ l bacterium solutions, and it is 100 μ l to make every hole total volume, and polymyxins is a concentration of
16mg/l, each MCR-1 inhibitor concentrations are 50 μM.Simultaneously control is set, in equal volume only add colistin liquid hole (for
The holes MIC when independent medication) every plant of bacterium is parallel is repeated 3 times.Positive control is the tested bacterium for being not added with compound in equal volume, negative
Control is 100 μ l MH culture mediums.
4) after 37 DEG C of 16~20h of culture, visually observe in the hole of 96 orifice plates that whether there is or not bacterial growths.
Experimental result is shown, is only added the control group of colistin and is not added in the positive controls of compound, 96 orifice plates
There are a large amount of bacterial growths by Kong Zhongjun；And simultaneously added with the experimental group of 50 μM of present invention each MCR-1 inhibitor and polymyxins,
The Kong Zhongjun of 96 orifice plates is without bacterial growth.The result illustrates that each MCR-1 inhibitor of the present invention all has energy at a concentration of 50 μM
Make MCR-1 positives drug-fast bacteria multiple to polymyxins quick, i.e., it is thin that each MCR-1 inhibitor of the invention can enhance MCR-1 positive drug resistances
Bacterium is to the sensibility of polymyxins, and polymyxins collective effect, realizes and inhibits the growth of MCR-1 positive drug-resistant bacterias and proliferation
Effect.
3 low concentration MCR-1 inhibitor of embodiment enhances effect of the bacterium to polymyxins sensibility
1) Bacteria Culture：4 plants of MCR-1 positive drug-fast bacterias are chosen to make (to be free of mcr- with Escherichia coli type strain ATCC25922
1 gene) it is used as experimental strain, after being recovered with solid LB tablets, picking individual colonies, are incubated overnight with MH culture mediums respectively, are increased
Bacterium.
2) prepared by bacteria suspension：By 0.5 Maxwell turbidity bacteria suspension of normal saline, with MH culture solutions 1:100 dilutions, make
Its bacterial content is 1.5 × 106Cfu/ml is inoculated with 50 μ l in 96 orifice plates per hole.
3) respectively dilution each MCR-1 inhibitor of the present invention and polymyxins (6 dilutions, 2 times of MIC value, 1 times, 1/
2,1/4,1/8,1/16 concentration dilution).It is laterally that gradient direction drops in antibiotic, is longitudinally the drop gradient direction of compound, from
And form the various concentration gradient combination of two kinds of substances.Compound be proved in embodiment 2 can allow MCR- under 50 μM of concentration
1 positive drug-fast bacteria is to the multiple quick compound of polymyxins.It is separately added into MCR-1 inhibitor and each 25 μ L of polymyxins, bacterium per hole
50 μ L of liquid, 100 μ L of total volume.Control is set simultaneously, " 0 row " is isometric only to add MCR-1 inhibitor or only add colistin
Liquid hole (for independent medication when the holes MIC).Positive control is the isometric tested bacterium for being not added with liquid, and negative control is etc.
The MH culture mediums (such as Fig. 1) of volume.
4) after 37 DEG C of 16~20h of culture, statistical result.Inhibitor is evaluated according to inhibition.
Experimental result further displays, compound 1：At a concentration of 16 μM, i.e.,
It is multiple to polymyxins quick that example MCR-1 positives drug-fast bacteria can be achieved.When illustrating 16 μM of compound 1 with polymyxins collective effect,
It can have the function that inhibit the growth of MCR-1 positive drug-resistant bacterias and proliferation.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (7)
1.MCR-1 inhibitor or its acceptable pharmaceutical salts answering in preparing the antibacterials for inhibiting MCR-1 positive drug-fast bacterias
With the MCR-1 inhibitor is shown in formula I：
In Formulas I：
R1 is the monosubstituted base or multi-substituent of any position on benzene radicals, and substituent group is H or halogen；
R2 is H or methyl.
2. application according to claim 1, which is characterized in that the acceptable pharmaceutical salts of MCR-1 inhibitor be its Na, K,
Ca salt.
3. application according to claim 1, which is characterized in that the halogen is F, Cl, Br, I.
4. application according to claim 1, which is characterized in that the MCR-1 inhibitor is
5. application according to claim 1, which is characterized in that also contain polymyxins in the antibacterials.
6. a kind of antibacterials inhibiting MCR-1 positive drug-fast bacterias, which is characterized in that contain claim in the antibacterials
MCR-1 inhibitor or its acceptable pharmaceutical salts described in any one of 1~4 and polymyxins.
7. a kind of antibacterials inhibiting MCR-1 positive drug-fast bacterias according to claim 4, which is characterized in that described anti-
In bacterium drug, a concentration of 0.5~64mg/l of polymyxins, MCR-1 inhibitor according to any one of claims 1 to 4 or
A concentration of 5~50 μM of its acceptable pharmaceutical salts.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109464439A (en) * | 2019-01-10 | 2019-03-15 | 吉林大学 | Osthole is preparing the application in MCR-1 enzyme inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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- 2018-05-22 CN CN201810494825.1A patent/CN108553459B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109464439A (en) * | 2019-01-10 | 2019-03-15 | 吉林大学 | Osthole is preparing the application in MCR-1 enzyme inhibitor |
| CN109464439B (en) * | 2019-01-10 | 2020-10-09 | 吉林大学 | Application of osthole in preparation of MCR-1 enzyme inhibitor |
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