CN111184724A - Application of depazolid (LCB01-0371) in mycobacterium fortuitum infection - Google Patents
Application of depazolid (LCB01-0371) in mycobacterium fortuitum infection Download PDFInfo
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- CN111184724A CN111184724A CN202010069582.4A CN202010069582A CN111184724A CN 111184724 A CN111184724 A CN 111184724A CN 202010069582 A CN202010069582 A CN 202010069582A CN 111184724 A CN111184724 A CN 111184724A
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Abstract
The invention discloses application of multiplazolid (LCB01-0371) in mycobacterium fortuitum infection. According to the invention, the nonpuberculosis mycobacterium medicament linezolid recommended by CLSI is used as a reference, and the multiplazolid anti-mycobacterium fortuitum activity determination is carried out by adopting a microplate double dilution method, and the result shows that the activity of the multiplazolid on clinically separated mycobacterium fortuitum is obviously superior to that of the linezolid, most of the multiplazolid is 2-4 times of the bacteriostatic activity of the linezolid, and the new application of the multiplazolid in treating mycobacterium fortuitum infection diseases is expected to be developed.
Description
Technical Field
The invention relates to application of multiplazolid (LCB01-0371) in treating mycobacterium fortuitum infection.
Background
Nontuberculous Mycobacteria (NTM) refers to Mycobacteria other than Mycobacterium Tuberculosis Complex (MTC) and Mycobacterium leprae. More than 190 species are currently known as opportunistic pathogens. In recent years, with the increasing and widespread of bacterial isolation technology, the occurrence of NTM infection and related diseases has been on the rise due to the change of infectious flora of immunocompromised hosts and the like, and it has been reported in our country that the proportion of NTM isolates in culture positive specimens increases from 4.3% in 1979 to 22.9% in 2010.
NTM has extremely high drug resistance to antituberculosis drugs, has different degrees of drug resistance to common antituberculosis drugs such as isoniazid, sodium aminosalicylate, ethambutol, rifampicin, streptomycin and the like, has the drug resistance rate as high as 97.46 percent, and most strains simultaneously have the drug resistance to various antituberculosis drugs. In recent years, the search for drugs that are effective in treating NTM has received much attention from researchers. The linezolid does not generate cross drug resistance with other antibacterial drugs, so that the generation of the drug resistance of bacteria is not easy to induce, and the clinical curative effect can be improved. Therefore, CLSI recommends linezolid for NTM treatment. Although the linezolid (600 mg per day) containing chemotherapy regimen can be tolerated in NTM patients for 6 months or longer, more than one third of the patients develop adverse events (e.g., peripheral neuropathy and cytopenia). Furthermore, linezolid treatment is also involved in reducing the potential risk of platelet, red blood cell and white blood cell counts (myelosuppression). Thus, there is a need for well-defined indications and appropriate therapy monitoring during the course of therapy. Therefore, a drug with higher safety is strongly desired for the treatment of NTM.
The mycobacterium fortuitum is nontuberculous mycobacterium with high separation rate in China, the separation rate is as high as 6.4%, the mycobacterium fortuitum belongs to a fast growth type in nontuberculous mycobacterium (NTM), exists in natural environment, is an opportunistic pathogen, and can cause nosocomial infection. Mycobacterium fortuitum can cause soft tissue infections during trauma and surgery, and pulmonary disease caused by it also sometimes occurs. It has been reported that there are many outbreaks of skin infections caused by mycobacteria that occur sporadically in pools or swimming pools in the community. Mycobacterium fortuitum often causes infection of soft tissues during surgery, and is also reported in many implant-related infections and endocarditis infections. The drug resistance degree of mycobacterium fortuitum to anti-tuberculosis drugs is continuously increased, the drug resistance rate to common anti-tuberculosis drugs such as rifampicin, isoniazid, streptomycin, ethambutol and the like is about 100%, the drug resistance rate to clarithromycin is also up to 100%, the drug resistance rate to kanamycin is up to 94%, and most strains simultaneously resist multiple anti-tuberculosis drugs.
Disclosure of Invention
The invention aims to provide application of multiplazolid (LCB01-0371) in treating mycobacterium fortuitum infection.
The invention firstly protects the application of the depazolid in the preparation of the mycobacterium fortuitum bacteriostatic agent.
The invention also protects a mycobacterium fortuitum bacteriostatic agent, and the active ingredient of the bacteriostatic agent is depazolid.
The invention also protects the application of the displazolid in preparing products; the product has the application of inhibiting the activity of mycobacterium fortuitum.
The invention also protects a product, and the active ingredient of the product is displazolid; the product has the application of inhibiting the activity of mycobacterium fortuitum.
The invention also protects the application of the displazolid in preparing medicines; the application of the medicine is to prevent and/or treat accidental mycobacterial infection.
The invention also protects a medicament, the active ingredient of which is depazolid; the application of the medicine is to prevent and/or treat accidental mycobacterial infection.
The invention also protects the application of the depazolid in susceptibility test of mycobacterium fortuitum infection. The application can increase the selection scope for clinically screening sensitive drugs for screening the mycobacterium fortuitum.
The invention also protects a method for inhibiting the activity of mycobacterium fortuitum, comprising the step of inhibiting the activity of mycobacterium fortuitum by using depazolid.
Any of the above-mentioned Mycobacterium fortuitum may specifically be a standard strain of Mycobacterium fortuitum (ATCC 6841) or a clinically isolated Mycobacterium fortuitum or a Mycobacterium fortuitum carried by a patient infected with Mycobacterium fortuitum.
According to the invention, the nonpuberculosis mycobacterium medicament linezolid recommended by CLSI is used as a reference, and the multiplazolid anti-mycobacterium fortuitum activity determination is carried out by adopting a microplate double dilution method, and the result shows that the activity of the multiplazolid on clinically separated mycobacterium fortuitum is obviously superior to that of the linezolid, most of the multiplazolid is 2-4 times of the bacteriostatic activity of the linezolid, and the new application of the multiplazolid in treating mycobacterium fortuitum infection diseases is expected to be developed.
Drawings
FIG. 1 is a graph of MIC concentration profiles of depazolid and linezolid against clinically isolated strains of Mycobacterium fortuitum.
FIG. 2 is a graph showing the effect of 10. mu.M depazolid and linezolid on U-937 cell viability
FIG. 3 is a graph showing the effect of 20. mu.M depazolid and linezolid on U-937 cell viability.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. 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.
deplazolid (LCB 01-0371): purchased from kyanirui biomedicine limited, cat #: RMX 2001; CAS No. 1219707-39-7; the molecular formula is as follows: c14H17FN4O3. The structural formula is as follows:
linezolid (Linezolid): purchased from Sigma, cat #: PZ 0014. Linezolid (Linezolid) of the formula: c16H20FN3O4CAS No. 165800-03-3. The structural formula is as follows:
standard strain of mycobacterium fortuitum: ATCC 6841.
Example 1 detection of bacteriostatic Activity of depazolid against Mycobacterium fortuitum Standard Strain
The drug to be tested: depazolid (LCB01-0371) and Linezolid (Linezolid, control).
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 μ l of a drug solution to be detected (configured by DMSO) with the concentration of 128 μ g/mL into the first row, sucking 100 μ l after mixing uniformly, adding the drug solution into the second row, sequentially diluting in a gradient manner to the 11 th row, sucking 100 μ l and discarding, and taking the last row without the drug as 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: inoculating the mycobacterium fortuitum standard strain into a neutral Roche medium, culturing in an incubator at 37 ℃ for 3-4 weeks, scraping the strain on the neutral Roche medium in a growth log phase, grinding the strain for turbidimetry, and diluting the strain with Mueller Hinton (MH) medium (containing 5% OADC).
TABLE 1
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 Alamarblue 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 MIC of depazolid for M.bifidus standard was 32. mu.g/mL and MIC of linezolid for M.bifidus standard was > 32. mu.g/mL.
Example 2 detection of bacteriostatic Activity of depazolid on clinically isolated Mycobacterium fortuitum strains
Clinically isolating the strain: 25 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 16SrRNA, hsp65, rpoB and 16-23S rRNA.
The drug to be tested: depazolid (LCB01-0371) and Linezolid (Linezolid, control).
The bacteriostatic activity of the test drug against 25 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
TABLE 3
The results show that the activity of the depazolid on clinically separated mycobacterium fortuitum is obviously superior to that of linezolid, most of the depazolid is 2-4 times of the bacteriostatic activity of linezolid, and the depazolid is expected to be applied to clinically treating mycobacterium fortuitum infection diseases.
EXAMPLE III cytotoxicity test
The drug to be tested: depazolid (LCB01-0371) and Linezolid (Linezolid, control).
1. A96-well plate is taken, 100 mu LU-937 cell (purchased from Beijing Borun Yangzi technology Co., Ltd.) suspension (1 ten thousand per well) is added into each well, and 100nmol/L PMA is added at the same time to induce 24 hours until the cells adhere to the wall.
2. After completion of step 1, the old medium was aspirated, and the plates were incubated for 12h, 24h, 36h and 48h, respectively, with different concentrations (20 μ M and 10 μ M) of test and control drugs, 200 μ l/well, respectively. Both 20. mu.M and 10. mu.M were the final concentrations after addition to the wells.
3. After completion of step 2, the old medium was aspirated, 100. mu.l of 1640 medium and 10. mu.L of CCK-8 solution were added to each well, and the plates were incubated in an incubator for 2 hours.
4. After completion of step 3, the absorbance at 450nm was measured with a microplate reader.
Cell viability (%) ([ a (dosed) -a (blank) ]/[ a (0 dosed) -a (blank) ] × 100
A (dosing): absorbance of wells with cells, CCK-8 solution and drug solution;
a (blank): absorbance of wells with medium and CCK-8 solution without cells;
a (0 dosing): absorbance of wells with cells, CCK-8 solution, but no drug solution.
The results are shown in FIGS. 2 and 3. The results show that the difference between 10 μ M depazolid and 10 μ M linezolid for the cell viability of U-937 is not statistically significant (F0.622, P0.513) and that the difference between 20 μ M depazolid and 20 μ M linezolid for the cell viability of U-937 is not statistically significant (F0.627, P0.517), indicating that the cytotoxicity of depazolid for U-937 is similar to linezolid.
Claims (8)
- The application of deplaszolid in preparing a mycobacterium fortuitum bacteriostatic agent.
- 2. The active component of the mycobacterium fortuitum bacteriostatic agent is displazolid.
- 3, the application of the multiplazolid in preparing products; the product has the application of inhibiting the activity of mycobacterium fortuitum.
- 4. The product contains depazolid as active ingredient; the product has the application of inhibiting the activity of mycobacterium fortuitum.
- 5, the application of the deplazolid in preparing medicines; the application of the medicine is to prevent and/or treat accidental mycobacterial infection.
- 6. A drug, the active ingredient of which is depazolid; the application of the medicine is to prevent and/or treat accidental mycobacterial infection.
- Use of deplazolid in susceptibility testing of mycobacterium fortuitum infection.
- 8. A method of inhibiting mycobacterium fortuitum activity comprising the step of inhibiting mycobacterium fortuitum activity using depazolid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010069582.4A CN111184724A (en) | 2020-01-21 | 2020-01-21 | Application of depazolid (LCB01-0371) in mycobacterium fortuitum infection |
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| CN202010069582.4A CN111184724A (en) | 2020-01-21 | 2020-01-21 | Application of depazolid (LCB01-0371) in mycobacterium fortuitum infection |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111870594A (en) * | 2020-08-27 | 2020-11-03 | 首都医科大学附属北京胸科医院 | Application of phenelzine in preparation of drug for resisting mycobacterium fortuitum infection |
| CN115702900A (en) * | 2021-08-09 | 2023-02-17 | 上海纳为生物技术有限公司 | RMX2001 preparation composition |
Citations (3)
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| KR20080053209A (en) * | 2006-12-08 | 2008-06-12 | 주식회사 레고켐 바이오사이언스 | Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same |
| CN103228282A (en) * | 2010-09-13 | 2013-07-31 | 苏黎世大学 | Treatment of bacterial infectious diseases |
| CN106420679A (en) * | 2015-08-04 | 2017-02-22 | 中国科学院微生物研究所 | Application of fluorine-containing catechol structure compound serving as mycobacterium tuberculosis inhibitor |
-
2020
- 2020-01-21 CN CN202010069582.4A patent/CN111184724A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20080053209A (en) * | 2006-12-08 | 2008-06-12 | 주식회사 레고켐 바이오사이언스 | Novel oxazolidinone derivatives, process for preparing thereof and pharmaceutical composition containing the same |
| CN103228282A (en) * | 2010-09-13 | 2013-07-31 | 苏黎世大学 | Treatment of bacterial infectious diseases |
| CN106420679A (en) * | 2015-08-04 | 2017-02-22 | 中国科学院微生物研究所 | Application of fluorine-containing catechol structure compound serving as mycobacterium tuberculosis inhibitor |
Non-Patent Citations (3)
| Title |
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| MU-LU WU ETAL.: "NTM drug discovery: status, gaps and the way forward", 《DRUG DISCOVERY TODAY》 * |
| TAE SUNG KIMA ETAL.: "Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| 袁小玲等: "利奈唑胺治疗非结核性分枝杆菌肺病１例报道", 《中华医院感染学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111870594A (en) * | 2020-08-27 | 2020-11-03 | 首都医科大学附属北京胸科医院 | Application of phenelzine in preparation of drug for resisting mycobacterium fortuitum infection |
| CN111870594B (en) * | 2020-08-27 | 2022-03-22 | 首都医科大学附属北京胸科医院 | Application of phenelzine in preparation of drug for resisting mycobacterium fortuitum infection |
| CN115702900A (en) * | 2021-08-09 | 2023-02-17 | 上海纳为生物技术有限公司 | RMX2001 preparation composition |
| CN115702900B (en) * | 2021-08-09 | 2024-02-09 | 上海纳为生物技术有限公司 | RMX2001 preparation composition |
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Application publication date: 20200522 |