Application of L-selenomethionine in preparation of antifungal drugs or synergists

Abstract

The invention discloses a new application of L-selenomethionine as an antifungal drug and an antifungal synergist thereof, L-selenomethionine is screened through a large number of experiments, and the L-selenomethionine can be combined with the antifungal drug itraconazole for use, so that the antibacterial effect of itraconazole on itraconazole-resistant aspergillus fumigatus is remarkably improved. The L-selenomethionine is expected to be developed into a novel medicine or a synergist of an anti-aspergillus fumigatus medicine, and has an important application value.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and in particular relates to the application of L-selenomethionine in the preparation of an antifungal drug synergist. Background Art

[0002] With the widespread use of immunosuppressants, broad-spectrum antibiotics and anticancer drugs, the phenomenon of fungal infection (IFI) is increasing, and it often occurs in organ transplant recipients, hematopoietic stem cell transplant recipients, ICU and surgical patients. Among them, Aspergillus infection is most common in hematology and ICU. There are more than 30 species of Aspergillus associated with human infection, and 90% of aspergillosis is caused by Aspergillus fumigatus, followed by Aspergillus flavus, Aspergillus terreus and Aspergillus niger. Because fungi are evolutionarily close to humans, the drugs used to treat fungal infections are very limited. Azoles (such as itraconazole and voriconazole) are the first-line drugs for the treatment and prevention of Aspergillus infections. In recent years, the emergence of drug-resistant or multidrug-resistant strains of Aspergillus pathogens has seriously endangered people's health. If patients are infected with multidrug-resistant Aspergillus bacteria, it will cause infection treatment failure and recurrence. The development of new anti-resistant bacterial infection drugs or anti-infection strategies has become an urgent requirement in the field of public health.

[0003] Selenium is an indispensable trace element in humans and animals. Its supplementation forms are divided into inorganic and organic forms. The representative of inorganic selenium is sodium selenite, and the organic selenium is mainly yeast selenium, and its main form of selenium is selenomethionine. Compared with inorganic selenium, L-selenomethionine shows low toxicity, high bioavailability, stable properties, significant effects, and high practical value, indicating a broad prospect for promotion and application.

[0004] At present, the application research of selenomethionine mainly focuses on the three major fields of planting, breeding and medicine. In the breeding industry, an appropriate amount of selenomethionine is mainly added to livestock and poultry feed to optimize the growth of livestock and poultry and improve meat quality; in the planting industry, selenomethionine foliar spraying technology is mainly used to promote better plant growth; in the field of medicine, selenomethionine is a key intermediate in immune drugs and anticancer drugs, playing an immune-enhancing and anti-cancer role. So far, there has been no report on the use of L-selenomethionine to fight Aspergillus fumigatus, nor has there been any report on the use of L-selenomethionine to enhance the antifungal effect of itraconazole. Summary of the invention

[0005] The purpose of the present invention is to screen out new clinical uses of L-selenomethionine antifungal drugs through a large number of experiments on the basis of existing itraconazole antifungal drugs.

[0006] The structural formula of L-selenomethionine is:

[0007]

[0008] The present invention has experimentally found that L-selenomethionine and its derivatives have the efficacy of resisting Aspergillus fungi or resisting drug-resistant Aspergillus fungi.

[0009] Preferably, the Aspergillus fungi include Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger and Aspergillus terreus.

[0010] The present application found that L-selenomethionine has an important biological function of significantly inhibiting the growth and development of azole-resistant Aspergillus fumigatus when used in combination with itraconazole. Therefore, the present invention proposes that L-selenomethionine and its derivatives can be used to prepare a synergist for the antifungal drug itraconazole.

[0011] As a preferred embodiment, L-selenomethionine and its derivatives are prepared with a pharmaceutically acceptable carrier into tablets, granules, capsules, pills, powders, oral liquids and injections.

[0012] Beneficial Effects:

[0013] The present invention found that L-selenomethionine alone had a certain effect on the resistance to azole-resistant Aspergillus fumigatus (Table 1, MIC 90 =24μg / ml), and the effect of itraconazole alone on anti-azole-resistant Aspergillus fumigatus was weak (Table 2, MIC>16μg / ml). However, after the two were used in combination, the MIC value of L-selenomethionine decreased from greater than 48μg / ml to 0.375μg / ml, and the MIC value of itraconazole decreased from greater than 16μg / ml to 2-4μg / ml (Table 2). These results show that L-selenomethionine can be used in combination with itraconazole to enhance the ability of itraconazole to resist azole-resistant Aspergillus fumigatus. Azoles-resistant Aspergillus fumigatus is an important pathogen that causes invasive Aspergillus infection and leads to failure of azole drug treatment in clinical practice. Therefore, the present invention has important clinical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 L-Selenomethionine inhibits the growth of azole-resistant Aspergillus fumigatus.

[0015] Figure 2 L-selenomethionine combined with itraconazole inhibits the growth of azole-resistant Aspergillus fumigatus. DETAILED DESCRIPTION

[0016] The present invention has found through a large number of experimental screenings that L-selenomethionine combined with itraconazole can significantly inhibit the growth of azole-resistant Aspergillus fumigatus in vitro. The present invention is further described below in conjunction with specific implementations, but these implementations should not be interpreted as limiting the present invention.

[0017] Experiment 1: MIC of L-selenomethionine against azole-resistant Aspergillus fumigatus 90 .

[0018] Compounds tested: L-selenomethionine.

[0019] Assay method: The experiment was carried out in a sterile 96-well plate according to CLSI standards. A series of L-selenomethionine solutions (two times the working concentration) were added to the 96-well plate (100 μl was added to each well). The final concentration of L-selenomethionine was 0.375 to 48 μg / ml. 100 ml of bacterial solution (final concentration: 2×10 4 / mL), add 100μL bacterial suspension and 100μL culture medium to the growth control wells, and the last column of wells is the negative control well (blank control), which only has culture medium. After the configuration is completed, place it in a constant temperature incubator and observe the results after culturing at 37℃ for 48 hours. Compare with the growth control wells to conduct experimental results MIC 90 (the lowest drug concentration that inhibits 90% strain growth) determination.

[0020] Table 1 Effect of L-selenomethionine on itraconazole-resistant Aspergillus fumigatus

[0021] Itraconazole-resistant bacteria <![CDATA[MIC 90 (μg / ml)]]> <![CDATA[1160-331(cyp51A G54W )]]> 24 <![CDATA[1160-353(cyp51A M220I )]]> 24 <![CDATA[1160-185(cyp51A G54E )]]> 24 Experiment 2: MICs of L-selenomethionine and itraconazole alone and in combination against azole-resistant Aspergillus fumigatus.

[0022] Compounds tested: L-selenomethionine, itraconazole.

[0023] Assay method: This experiment was performed in a sterile 96-well plate using the chessboard method. A series of L-selenomethionine (four times the working concentration) solutions were added to the 96-well plate (50 μl was added to each well), and a series of itraconazole (four times the working concentration) solutions were added to the 96-well plate (50 μl was added to each well). The final concentration of L-selenomethionine was 0.375 to 48 μg / ml, and the final concentration of itraconazole was 1 to 16 μg / ml. 100 ml of bacterial solution (final concentration: 2×10 4 / mL), add 100μL bacterial suspension and 100μL culture medium to the growth control wells, and the last column of wells is the negative control well (blank control), with only culture medium. After the configuration is completed, place it in a constant temperature incubator and observe the results after culturing at 37℃ for 48 hours. The experimental results are interpreted in accordance with CLSI standards, and compared with the growth control wells during interpretation. The complete clarity of the bacterial solution (the lowest drug concentration that inhibits 100% strain growth) is used as the MIC interpretation standard. The experiment was repeated three times independently.

[0024] The experimental results are shown in Table 2. The effects of L-selenomethionine or itraconazole alone on azole-resistant Aspergillus fumigatus are average. However, after the two are used in combination, the MIC value of L-selenomethionine is reduced from more than 48μg / ml to 0.375μg / ml, and the MIC value of itraconazole is reduced from more than 16μg / ml to 2-4μg / ml. These results show that L-selenomethionine can increase the activity of itraconazole against azole-resistant Aspergillus fumigatus, and play a good synergistic antibacterial effect.

[0025] Table 2 Effect of L-selenomethionine combined with itraconazole against itraconazole-resistant Aspergillus fumigatus

[0026]

[0027] FICI: Inhibitory concentration index (FICI≤0.5 represents synergistic effect; 0.5<FICI≤4 represents no interaction; when FICI>4 represents antagonism).

[0028] The above description is only a preferred embodiment of the present invention and should not be regarded as limiting the scope of the present invention. For ordinary technicians in this technical field, various possible equivalent changes or modifications can be made based on the technical solution of the present invention and the description of its preferred embodiments without departing from the principle of the present invention, and these changes and modifications should also be regarded as the protection scope of the present invention.

Claims

1. Application of L-selenomethionine and its derivatives in the preparation of antifungal drugs.

2. Application of L-selenomethionine and its derivatives in the preparation of drugs against Aspergillus fungi.

3. Application of L-selenomethionine and its derivatives in the preparation of drugs against drug-resistant Aspergillus fungi.

4. Application of L-selenomethionine and its derivatives in the preparation of anti-Aspergillus drug enhancers.

5. Application of L-selenomethionine and its derivatives with itraconazole in the preparation of pharmaceutical preparations against Aspergillus fungi.

6. Application of L-selenomethionine and its derivatives with itraconazole in the preparation of pharmaceutical preparations against drug-resistant Aspergillus fungi.

7. The use according to any one of claims 1 to 6, characterized in that: The Aspergillus fungus includes Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger or Aspergillus terreus.

8. The use according to claim 3 or 6, characterized in that: The drug-resistant Aspergillus fungi include itraconazole-resistant Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger or Aspergillus terreus.

9. The use according to any one of claims 1 to 8, characterized in that: L-selenomethionine and its derivatives are prepared with pharmaceutically acceptable carriers into tablets, granules, capsules, pills, powders, oral liquids or injections.

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