CN111870594B - Application of phenelzine in preparation of drug for resisting mycobacterium fortuitum infection - Google Patents
Application of phenelzine in preparation of drug for resisting mycobacterium fortuitum infection Download PDFInfo
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- CN111870594B CN111870594B CN202010876486.0A CN202010876486A CN111870594B CN 111870594 B CN111870594 B CN 111870594B CN 202010876486 A CN202010876486 A CN 202010876486A CN 111870594 B CN111870594 B CN 111870594B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
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Abstract
The invention discloses a new application of phenelzine. The new application is the application of phenelzine or pharmaceutically acceptable salts thereof in preparing products for resisting mycobacterium fortuitum infection. The invention adopts a microplate double dilution method to carry out the determination of the activity of the phenelzine against mycobacterium fortuitum, and the result shows that the phenelzine has better bacteriostatic activity on clinically separated mycobacterium fortuitum and is expected to develop the new application of the phenelzine in the treatment of mycobacterium fortuitum infection diseases.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of phenelzine in preparation of a medicine for resisting mycobacterium fortuitum infection.
Background
Nontuberculous Mycobacteria (NTM) refer to Mycobacteria other than Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM is often present in the natural environment and is an opportunistic pathogen. In recent years, infections caused by NTM have been on a rising trend, and seriously threaten human health. It is reported in the literature that the proportion of NTM isolates in culture positive specimens in our country increased from 4.3% in 1979 to 22.9% in 2010. The pathogenic strains of NTM are various, the NTM of different strains has different sensitivity to drugs, and the treatment scheme aiming at the NTM caused by different strains has larger difference. And the NTM has extremely high drug resistance to anti-tuberculosis drugs, such as common anti-tuberculosis drugs like isoniazid, rifampin, streptomycin and the like, and has different degrees of drug resistance, so that the search for a drug with better NTM treatment effect is very necessary.
Phenelzine is an irreversible and non-selective monoamine oxidase inhibitor and is currently used mainly in the treatment of depression. The mechanism of action is mainly to inhibit the activity of enzyme by forming a drug-enzyme complex with monoamine oxidase so as to interfere the normal metabolism of the substrate and influence the normal biological action of the substrate.
Mycobacterium fortuitum, belonging to rapidly growing nontuberculous mycobacteria, often causes lesions of skin, soft tissues and bones. In recent years, the drug resistance degree of mycobacterium fortuitum to anti-tuberculosis drugs in China is continuously increased, and the drug resistance rate of the mycobacterium fortuitum to common anti-tuberculosis drugs such as rifampicin, isoniazid, streptomycin, ethambutol and the like is up to more than 70%; the strain also has drug resistance to common drugs for treating NTM, such as clarithromycin, and most strains have drug resistance to various antituberculosis drugs simultaneously.
Disclosure of Invention
An object of the present invention is to provide a novel use of phenelzine or a pharmaceutically acceptable salt thereof.
The new application of the phenelzine or the pharmaceutically acceptable salt thereof provided by the invention is at least one of the following 1) -7):
1) the application in the preparation of mycobacterium fortuitum bacteriostat;
2) the application in preparing products for inhibiting the activity of mycobacterium fortuitum;
3) the application in preparing products for resisting mycobacterium fortuitum infection;
4) the application in the preparation of products for preventing and/or treating diseases caused by mycobacterium fortuitum;
5) the application in inhibiting the activity of mycobacterium fortuitum;
6) use against mycobacterium fortuitum infection;
7) the application in preventing and/or treating diseases caused by mycobacterium fortuitum.
The invention relates to phenelzine, CAS No. 156-51-4. The pharmaceutically acceptable salt of phenelzine can be phenelzine hydrochloride or phenelzine sulfate.
Another object of the present invention is to provide a Mycobacterium fortuitum bacteriostatic agent.
The active component of the mycobacterium fortuitum bacteriostatic agent provided by the invention is phenelzine or pharmaceutically acceptable salt thereof.
It is yet another object of the present invention to provide a product.
The active ingredient of the product provided by the invention is phenelzine or pharmaceutically acceptable salt thereof;
the product has at least one of the following effects:
a) inhibiting mycobacterium fortuitum activity;
b) against mycobacterium fortuitum infection;
c) preventing and/or treating diseases caused by mycobacterium fortuitum.
In the present invention, the mycobacterium fortuitum may be a standard strain of mycobacterium fortuitum or a clinical isolate of mycobacterium fortuitum or a mycobacterium fortuitum carried by a patient infected with mycobacterium fortuitum.
In one embodiment of the present invention, the Mycobacterium fortuitum is Mycobacterium fortuitum Standard strain ATCC 6841.
In another embodiment of the present invention, the Mycobacterium fortuitum is a clinical isolate of Mycobacterium fortuitum.
The product of the invention can be specifically a medicine.
When necessary, one or more pharmaceutically acceptable carriers can be added into the medicine; the carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc.; the medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The above medicine can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, and mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
The invention also provides a method for inhibiting the activity of mycobacterium fortuitum.
The method for inhibiting the activity of the mycobacterium fortuitum comprises the following steps: use of a substance containing phenelzine or a pharmaceutically acceptable salt thereof as an active ingredient for inhibiting the activity of Mycobacterium fortuitum.
Wherein, the mycobacterium fortuitum can be a standard strain of mycobacterium fortuitum or a clinical isolate of mycobacterium fortuitum.
In the above method, the Mycobacterium fortuitum may be a standard strain of Mycobacterium fortuitum or a clinical isolate of Mycobacterium fortuitum.
The lowest using concentration of the phenelzine or the pharmaceutically acceptable salt thereof in the substance taking the phenelzine or the pharmaceutically acceptable salt thereof as the active ingredient is not lower than the Minimum Inhibitory Concentration (MIC) of the mycobacterium fortuitum inhibited by the phenelzine or the pharmaceutically acceptable salt thereof.
The method is a non-disease diagnostic treatment method. For example, as a positive control in screening for drugs sensitive to Mycobacterium fortuitum.
The invention uses a microplate double dilution method to carry out the phenyl ethyl hydrazine activity determination of resisting accidental mycobacteria, and the result shows that the phenyl ethyl hydrazine has better bacteriostatic activity to the standard strains of the accidental mycobacteria and clinical isolated accidental mycobacteria, and is expected to find out the new application of the phenyl ethyl hydrazine in treating the accidental mycobacteria infection diseases.
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FIG. 1 is a graph showing MIC concentration profiles of phenelzine against clinically isolated Mycobacterium fortuitum strains.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. The quantitative tests in the following examples, all set up three replicates and the results averaged.
Phenylethylhydrazine sulfate (CAS: 156-51-4): purchased from Sigma, cat #: p6777;
the molecular formula is as follows: c8H12N2·H2SO4The structural formula is as follows:
standard strain of mycobacterium fortuitum: ATCC 6841.
Example 1 detection of bacteriostatic activity of phenelzine against Mycobacterium fortuitum Standard Strain
The drug to be tested: phenylethylhydrazine sulfate
1. Add 100. mu.l Mueller Hinton (MH) medium (containing 5% OADC) to each well of a 96-well plate;
2. after the step 1 is completed, taking the 96-well plate, adding 100 mu l of a drug solution to be detected (prepared by DMSO) with the concentration of 6400 mu g/mL into the 12 th row, sucking 100 mu l after mixing uniformly, adding into the 11 th row, sequentially diluting in a gradient manner to the 2 nd row, sucking 100 mu l and discarding, wherein the 1 st row contains no drug and is a positive control well. 3 multiple wells were set for each concentration.
3. After the step 2 is completed, taking the 96-well plate, adding 100 mul of mycobacterium fortuitum standard strain bacterial suspension into each well, so that the final volume of each well is 200 mul, and the final concentration of the bacterial liquid is 2.5 multiplied by 105CFU/mL；The final drug concentration in each well is detailed in table 1.
The preparation method of the mycobacterium fortuitum standard strain bacterial suspension comprises the following steps: the Mycobacterium fortuitum standard strain is inoculated in a neutral Roche medium, cultured in an incubator at 37 ℃ for 1 week, scraped from the neutral Roche medium in the logarithmic phase of growth, ground and diluted with Mueller Hinton (MH) medium (containing 5% OADC).
TABLE 1 Final drug concentration in each well column
4. After completion of step 3, the 96-well plate was placed in a 37 ℃ incubator and cultured for 9 days.
5. After completion of step 4, the 96-well plate was taken, and 20. mu.l of Alamar blue and 50. mu.l of 5% Tween 80 were added to each well, followed by further incubation in an incubator at 37 ℃ for 24 hours.
6. After step 5, the 96-well plate was taken, the Minimum Inhibitory Concentration (MIC) was read, and the inhibition rate was calculated.
Minimum Inhibitory Concentration (MIC) reading method: the Minimum Inhibitory Concentration (MIC) is the concentration of drug that can inhibit the growth of 90% of colonies. Minimum drug concentration that inhibits > 90% production of reduced Alamar blue by fluorescence detection (Ex/Em,530nm/600 nm).
Inhibition rate%.
The background fluorescence value is the fluorescence value of the negative control, and the fluorescence value of the growth control hole is the fluorescence value of the positive control.
The negative control is a culture medium without the addition of medicines and bacteria liquid, and the positive control is a bacteria-containing culture medium without the addition of medicines.
The results showed that the MIC of phenelzine to the standard strain of Mycobacterium fortuitum was 400. mu.g/mL.
Example 2 detection of bacteriostatic activity of Phenylethylhydrazine on clinically isolated Mycobacterium fortuitum strains
Clinically isolating the strain: 23 strains are separated and cultured from sputum specimens of patients infected by mycobacterium fortuitum, and are identified as mycobacterium fortuitum by sequencing of regions among 16S rRNA, hsp65, rpoB and 16-23S rRNA.
The drug to be tested: phenylethylhydrazine sulfate
The bacteriostatic activity of the test drug against 23 clinically isolated mycobacterium fortuitum strains was tested as in example 1.
The MIC results are shown in table 2. The MIC concentration profile statistics are shown in table 3 and figure 1.
TABLE 2 MIC of phenelzine for clinical isolation of Mycobacterium fortuitum strains
TABLE 3 MIC concentration distribution statistics of phenelzine for clinical isolation of Mycobacterium fortuitum strains
The result shows that the phenelzine has better bacteriostatic activity on clinically separated mycobacterium fortuitum, and is expected to find out the new application of the phenelzine in treating mycobacterium fortuitum infection diseases.
The present invention has been described in detail above. It will be apparent to those skilled in the art that the invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with reference to specific embodiments, it will be appreciated that the invention can be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. The use of some of the essential features is possible within the scope of the claims attached below.
Claims (2)
1. Use of phenelzine or a pharmaceutically acceptable salt thereof in at least one of:
1) the application in the preparation of mycobacterium fortuitum bacteriostat;
2) the application in preparing products for inhibiting the activity of mycobacterium fortuitum.
2. Use according to claim 1, characterized in that: the mycobacterium fortuitum is a standard strain of mycobacterium fortuitum, or a clinical isolate of mycobacterium fortuitum, or mycobacterium fortuitum carried by a patient infected by mycobacterium fortuitum;
the product is a medicine.
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| CN114469914B (en) * | 2020-11-13 | 2023-06-23 | 山东大学 | Application of phenelzine in preparation of coronavirus papain-like protease inhibitor |
| CN112386588B (en) * | 2020-11-17 | 2022-08-23 | 首都医科大学附属北京胸科医院 | Application of phenelzine in preparation of drugs for resisting mycobacterium avium infection |
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