CN114224898A - Application of fidaxomicin in preparation of product for resisting mycobacterium fortuitum infection - Google Patents
Application of fidaxomicin in preparation of product for resisting mycobacterium fortuitum infection Download PDFInfo
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- CN114224898A CN114224898A CN202010940424.1A CN202010940424A CN114224898A CN 114224898 A CN114224898 A CN 114224898A CN 202010940424 A CN202010940424 A CN 202010940424A CN 114224898 A CN114224898 A CN 114224898A
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Abstract
The invention discloses application of fidaxomicin in preparation of a product for resisting infection of mycobacterium fortuitum. The invention provides an application of fidaxomicin or pharmaceutically acceptable salt thereof or a substance taking fidaxomicin or pharmaceutically acceptable salt thereof as an active ingredient in preparing a mycobacterium fortuitum bacteriostatic agent. The invention adopts a microplate double dilution method to carry out the activity determination of the fidaxomicin against the mycobacterium fortuitum, and the result shows that the fidaxomicin has better bacteriostatic activity on the standard strain of the fidaxomicin and clinically separated mycobacterium fortuitum, and is expected to discover the new application of the fidaxomicin in preventing and treating the infection diseases of the fidaxomicin.
Description
Technical Field
The invention relates to the technical field of biology, in particular to application of fidaxomicin in preparation of a product 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.
Fidaxomicin (fidaxomicin) is a novel narrow-spectrum macrolide antibacterial agent developed by Optimer pharmaceutical company in recent years, is used for treating clostridium difficile infection, and is approved by FDA in 2011, 5 months and 27 days. The mechanism of action is to produce a rapid anti-refractory clostridium infection effect by inhibiting the RNA polymerase of the bacteria. Due to the unique target of sigma subunit, the strain with drug resistance to rifamycin or other antibacterial drugs has no cross-resistance to fidaxomicin.
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 as high as 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
The invention aims to provide a new application of fidaxomicin.
In a first aspect, the invention claims the use of a1) fidaxomicin or a2) a pharmaceutically acceptable salt thereof or a3) a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as active ingredient in any of:
(A1) preparing a mycobacterium fortuitum bacteriostatic agent;
(A2) as a bacteriostatic agent for mycobacterium fortuitum.
In a second aspect, the invention claims the use of a1) fidaxomicin or a2) a pharmaceutically acceptable salt thereof or a3) a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as active ingredient in any of:
(B1) preparing a product for inhibiting the activity of mycobacterium fortuitum;
(B2) inhibiting the activity of Mycobacterium fortuitum.
In a third aspect, the invention claims the use of a1) fidaxomicin or a2) a pharmaceutically acceptable salt thereof or a3) a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(C1) preparing a product for resisting mycobacterium fortuitum infection;
(C2) against mycobacterium fortuitum infection.
In a fourth aspect, the invention claims the use of a1) fidaxomicin or a2) a pharmaceutically acceptable salt thereof or a3) a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(D1) preparing a product for preventing and/or treating diseases caused by accidental mycobacterial infection;
(D2) preventing and/or treating diseases caused by accidental mycobacterial infection.
In a fifth aspect, the invention claims a mycobacterium fortuitum bacteriostatic agent.
The mycobacterium fortuitum bacteriostat claimed by the invention has the active ingredient of fidaxomicin or pharmaceutically acceptable salt thereof.
In a sixth aspect, the invention claims a product.
The invention claims a product, the active ingredient of which is fidaxomicin or a pharmaceutically acceptable salt thereof; the product has any one of the following uses:
(a1) inhibiting mycobacterium fortuitum activity;
(a2) against mycobacterium fortuitum infection;
(a3) preventing and/or treating diseases caused by accidental mycobacterial infection.
In each of the above aspects, 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.
In each of the above aspects, the product may be a pharmaceutical product.
In a seventh aspect, the invention claims a method of inhibiting the activity of mycobacterium fortuitum.
The method for inhibiting the activity of mycobacterium fortuitum, which is claimed by the invention, is to use fidaxomicin or pharmaceutically acceptable salt thereof or a substance taking fidaxomicin or pharmaceutically acceptable salt thereof as an active ingredient to inhibit the activity of mycobacterium fortuitum.
Wherein, the mycobacterium fortuitum can be a mycobacterium fortuitum standard strain or a mycobacterium fortuitum clinical isolate.
In the method, the fidaxomicin or a pharmaceutically acceptable salt thereof or a substance having fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient is used in an amount of not less than its Minimum Inhibitory Concentration (MIC) for the mycobacterium fortuitum to be inhibited.
The method is a non-disease diagnostic treatment method. For example, the positive control is used in the process of developing sensitive drugs for the mycobacterium fortuitum.
In each of the above aspects, the fidaxomicin has the formula C52H74Cl2O18(ii) a The structural formula is shown as formula I.
The invention adopts a microplate double dilution method to carry out the activity determination of the fidaxomicin against the mycobacterium fortuitum, and the result shows that the fidaxomicin has better bacteriostatic activity on the standard strain of the fidaxomicin and clinically separated mycobacterium fortuitum, and is expected to discover the new application of the fidaxomicin in preventing and treating the infection diseases of the fidaxomicin.
Drawings
FIG. 1 is a MIC concentration profile of fidaxomicin against clinically isolated Mycobacterium fortuitum strains.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples provided below serve as a guide for further modifications by a person skilled in the art and do not constitute a limitation of the invention in any way.
The experimental procedures in the following examples, unless otherwise indicated, are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the instructions of the products. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The quantitative tests in the following examples, all set up three replicates and the results averaged.
Fidaxomicin (CAS: 873857-62-6): sigma product, cat #: SML 1750; CAS No.: 873857-62-6; the molecular formula is as follows: c52H74Cl2O18. The structural formula is shown as formula I.
Standard strain of mycobacterium fortuitum: ATCC 6841.
Example 1 detection of bacteriostatic Activity of fidaxomicin against Mycobacterium fortuitum Standard Strain
The drug to be tested: fidaxomicin
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 128 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 hole. 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 column of wells 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
| Number of |
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Drug concentration (μ g/mL) | 0 | 0.0625 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 |
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% Tween80 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 fidaxomicin for Mycobacterium fortuitum standard strain ATCC 6841 was 32. mu.g/mL.
Example 2 detection of bacteriostatic Activity of fidaxomicin against 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: fidaxomicin.
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 bacteriostatic activity of fidaxomicin against clinically isolated mycobacterium fortuitum strains
| Strain numbering | MIC(μg/mL) |
| 1 | 2 |
| 2 | 4 |
| 3 | 4 |
| 4 | 2 |
| 5 | 32 |
| 6 | 8 |
| 7 | 0.25 |
| 8 | 16 |
| 9 | 4 |
| 10 | 16 |
| 11 | 0.25 |
| 12 | 32 |
| 13 | 4 |
| 14 | 16 |
| 15 | 4 |
| 16 | 8 |
| 17 | 1 |
| 18 | 16 |
| 19 | 32 |
| 20 | 1 |
| 21 | 16 |
| 22 | 8 |
| 23 | 32 |
TABLE 3 MIC concentration distribution statistics of fidaxomicin against clinically isolated Mycobacterium fortuitum strains
| Drug concentration (μ g/mL) | 0.0625 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 |
| Fidaxomicin | 0 | 0 | 2 | 0 | 2 | 2 | 5 | 3 | 5 | 4 | 0 |
The result shows that the fidaxomicin has better bacteriostatic activity on clinically separated mycobacterium fortuitum and is expected to develop the new application of the fidaxomicin in treating the 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 (10)
1. The use of fidaxomicin or a pharmaceutically acceptable salt thereof or a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(A1) preparing a mycobacterium fortuitum bacteriostatic agent;
(A2) as a bacteriostatic agent for mycobacterium fortuitum.
2. The use of fidaxomicin or a pharmaceutically acceptable salt thereof or a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(B1) preparing a product for inhibiting the activity of mycobacterium fortuitum;
(B2) inhibiting the activity of Mycobacterium fortuitum.
3. The use of fidaxomicin or a pharmaceutically acceptable salt thereof or a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(C1) preparing a product for resisting mycobacterium fortuitum infection;
(C2) against mycobacterium fortuitum infection.
4. The use of fidaxomicin or a pharmaceutically acceptable salt thereof or a substance with fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient in any of:
(D1) preparing a product for preventing and/or treating diseases caused by accidental mycobacterial infection;
(D2) preventing and/or treating diseases caused by accidental mycobacterial infection.
5. A Mycobacterium fortuitum bacteriostatic agent contains fidaxomicin or its pharmaceutically acceptable salt as active ingredient.
6. A product whose active ingredient is fidaxomicin or a pharmaceutically acceptable salt thereof; the product has any one of the following uses:
(a1) inhibiting mycobacterium fortuitum activity;
(a2) against mycobacterium fortuitum infection;
(a3) preventing and/or treating diseases caused by accidental mycobacterial infection.
7. The use according to any one of claims 1 to 4 or the bacteriostatic agent according to claim 5 or the product according to claim 6, wherein: the mycobacterium fortuitum is a mycobacterium fortuitum standard strain or a mycobacterium fortuitum clinical isolate or mycobacterium fortuitum carried by a patient infected by the mycobacterium fortuitum.
8. Use or product according to any of claims 2 to 7, characterized in that: the product is a medicine.
9. A method for inhibiting activity of Mycobacterium fortuitum comprises using fidaxomicin or a pharmaceutically acceptable salt thereof or a substance containing fidaxomicin or a pharmaceutically acceptable salt thereof as an active ingredient to inhibit activity of Mycobacterium fortuitum.
10. The method of claim 9, wherein: the mycobacterium fortuitum is a mycobacterium fortuitum standard strain or a mycobacterium fortuitum clinical isolate.
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| CN202010940424.1A CN114224898A (en) | 2020-09-09 | 2020-09-09 | Application of fidaxomicin in preparation of product for resisting mycobacterium fortuitum infection |
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| CN202010940424.1A CN114224898A (en) | 2020-09-09 | 2020-09-09 | Application of fidaxomicin in preparation of product for resisting mycobacterium fortuitum infection |
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Non-Patent Citations (2)
| Title |
|---|
| MEKONNEN KURABACHEW ETC: "Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis" * |
| 吴琪茵;黎友伦;: "非结核分枝杆菌病的流行趋势、诊断及治疗" * |
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