Application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone in preparation of medicine for treating or preventing drug-resistant mycobacterium tuberculosis infection

Abstract

The invention provides an application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone in preparation of a medicine for treating or preventing drug-resistant mycobacterium tuberculosis infection, the MIC (minimal inhibitory concentration) of the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone to mycobacterium tuberculosis H37Rv, rifampicin drug-resistant strains, levofloxacin drug-resistant strains and bedaquiline drug-resistant strains is 2g / mL, and the MIC (minimal inhibitory concentration) of the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone to mycobacterium tuberculosis H37Rv, rifampicin drug-resistant strains, levofloxacin drug-resistant strains and bedaquiline drug-resistant strains is The core problem of tuberculosis with multiple drug resistance and wide drug resistance is solved, and an alternative treatment approach is provided.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to the use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection. Background Art

[0002] Tuberculosis (TB) is a highly pathogenic infectious disease that can be treated with a variety of drugs. However, with the emergence of drug-resistant strains of tuberculosis (TB), such as Mycobacterium tuberculosis H37 With the emergence of rifampicin-resistant, levofloxacin-resistant and bedaquiline-resistant strains, the efficacy of traditional tuberculosis treatment drugs is decreasing. And with the wider use of drugs, tuberculosis resistance will become more serious, and tuberculosis treatment faces major challenges; the development of drugs for tuberculosis-resistant strains is imminent. Summary of the invention

[0003] The present application provides an application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of a drug for treating drug-resistant Mycobacterium tuberculosis infection to solve the problems existing in the related technology. The technical solution is as follows: In a first aspect, an embodiment of the present application provides a use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0004] In one embodiment, the drug-resistant Mycobacterium tuberculosis is Mycobacterium tuberculosis H37 , rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains.

[0005] In one embodiment, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against Mycobacterium tuberculosis. H37 , rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains had a MIC of 2 µg / mL.

[0006] In one embodiment, the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one is used alone or in a composition consisting of 0.1%-99.9% by weight and a pharmaceutically acceptable carrier in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0007] In one embodiment, the pharmaceutically acceptable carrier is one of drug nanoparticles, microcapsules, microspheres, liposomes or exosomes.

[0008] In one embodiment, the dosage form of the drug includes an oral dosage form or a non-oral dosage form.

[0009] In one embodiment, the oral dosage form includes tablets, capsules, and granules.

[0010] In one embodiment, the non-oral dosage form comprises an injection solution or a lyophilized powder injection.

[0011] The advantages or beneficial effects of the above technical solution include at least: The present application provides an application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of a drug for treating drug-resistant Mycobacterium tuberculosis infection. (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one has an efficacy of 1.1% to 1.1% on Mycobacterium tuberculosis. H37 The MIC of the drug against rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains was 2µg / mL, which solves the core problem of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis and provides an alternative treatment approach; it can reduce reliance on existing, often toxic, and long-term treatment therapies.

[0012] The above summary is for illustrative purposes only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments and features described above, further aspects, embodiments and features of the present application will be readily apparent by reference to the accompanying drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In the accompanying drawings, unless otherwise specified, the same reference numerals throughout the multiple drawings represent the same or similar parts or elements. These drawings are not necessarily drawn to scale. It should be understood that these drawings only depict some embodiments disclosed in the present application and should not be regarded as limiting the scope of the present application.

[0014] Figure 1 This is the result of MTT test; Figure 2 This is the result of the trypan blue exclusion experiment; Figure 3 This is the result of the crystal violet staining experiment; Figure 4 This is the result of VEGF ELISA test; Figure 5 The effect of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one on Mycobacterium tuberculosis H37 MIC determination of strains; Figure 6 Rifampicin-resistant strains of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one RIF-R MIC determination; Figure 7 The MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against levofloxacin-resistant Mycobacterium tuberculosis strains was determined; Figure 8 The MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against bedaquiline-resistant Mycobacterium tuberculosis strains was determined; Fig. 9 Activity and MIC determination of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against Mycobacterium abscessus strains. DETAILED DESCRIPTION

[0015] In the following, only some exemplary embodiments are briefly described. As those skilled in the art will appreciate, the described embodiments may be modified in various ways without departing from the spirit or scope of the present application. Therefore, the drawings and descriptions are considered to be exemplary and non-restrictive in nature.

[0016] The present application provides an application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0017] (5R,6E)-5-Hydroxy-17-diphenyl-6-heptene-3-one is a compound having the following structure, which can be obtained from Fagonia arabica It can be extracted from Fagonia arabica It is a plant with traditional medicinal value. Its use has prompted the present applicant to discover the use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0018] .

[0019] As one embodiment, the drug-resistant Mycobacterium tuberculosis is Mycobacterium tuberculosis H37 , rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains.

[0020] As one embodiment, (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one is effective against Mycobacterium tuberculosis H37 The minimum inhibitory concentration (MIC) of rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains was 2 µg / mL.

[0021] As one embodiment, the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one is used alone or in a composition consisting of 0.1%-99.9% by weight and a pharmaceutically acceptable carrier in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0022] As one embodiment, the pharmaceutically acceptable carrier is one of drug nanoparticles, microcapsules, microspheres, liposomes or exosomes.

[0023] As one embodiment, the dosage form of the drug includes an oral dosage form or a non-oral dosage form.

[0024] As one embodiment, the oral dosage form includes tablets, capsules, and granules.

[0025] As one embodiment, the non-oral dosage form includes an injection or a lyophilized powder injection.

[0026] Verification of the drug activity of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one against drug-resistant Mycobacterium tuberculosis: 1. Pharmacokinetic prediction The SwissADME prediction platform (https: / / www.swissadme.ch / ), which is specifically used in the field of drug discovery and medicinal chemistry, was used to predict some influencing parameters of the pharmacokinetics of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one. The prediction results are shown in Table 1.

[0027] Table 1 Prediction of pharmacokinetics of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one.

[0028]

[0029] *HBD: hydrogen bond donor, HBA: hydrogen bond acceptor, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one: (5R,6E)-5-hydroxy-1,7-diphenyl-6-hepten-3-one, TPSA: topological polar surface area. BBB: blood-brain barrier.

[0030] (5R,6E)-5-Hydroxy-17-diphenyl-6-hepten-3-one is a compound with several promising properties that make it a potential candidate for drug development. As shown in Table 1, (5R,6E)-5-Hydroxy-17-diphenyl-6-hepten-3-one is soluble, which improves its bioavailability, and has a high gastrointestinal (GI) absorption rate, indicating that it can be effectively absorbed when administered orally. Notably, (5R,6E)-5-Hydroxy-17-diphenyl-6-hepten-3-one has the ability to cross the blood-brain barrier (BBB), indicating its potential for central nervous system (CNS) applications. (5R,6E)-5-Hydroxy-17-diphenyl-6-hepten-3-one exhibits drug-like and lead-like properties, making it a favorable candidate for further medicinal chemistry exploration. (5R,6E)-5-Hydroxy-17-diphenyl-6-heptene-3-one consists of 21 heavy atoms, including 7 hydrogen bond acceptors (HBAs) and 2 hydrogen bond donors (HBDs), with a topological polar surface area (TPSA) of 78.79 Å. 2 , which is within a range that is favorable for drug permeability and absorption.

[0031] Therefore, the favorable pharmacokinetic characteristics of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, including high gastrointestinal absorption and the ability to cross the blood-brain barrier, make (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one meet the five-drug rule, supporting its potential as an oral treatment option, which can improve patient compliance and provide an effective treatment for tuberculosis.

[0032] 2. Biocompatibility 2.1 MTT assay 2.1.1 Cell culture HepG2 cells were cryopreserved in cryopreserved vials (Cell Culture Laboratory, University of Lahore) from liquid nitrogen storage and revived in culture flasks containing DMEM-HG medium supplemented with 10% fetal bovine serum (FBS), 100 mg / mL penicillin G (Sigma), and 100 U / mL streptomycin (Sigma). The cultures were maintained at 37°C, 5% CO. 2 The cells were maintained in a humidified incubator. All experiments were repeated three times. When the cultured cells reached 70-80% confluence, subculture was performed.

[0033] When subculturing, cells attached to the wall of the culture flask are washed with 1X phosphate buffered saline (PBS) and incubated with 0.05% trypsin-EDTA until the cells are detached from the surface of the culture flask. After confirming the cell detachment by inverted microscopy, a few drops of FBS are added to the culture flask. The cell suspension is then transferred to a 15 ml centrifuge tube and centrifuged at 2000 rpm for 5 minutes. After centrifugation, the supernatant is carefully removed and the cell pellet is resuspended in a 96-well plate and then subjected to the MTT assay.

[0034] 2.1.2 Treatment of cell lines with (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one The cells were divided into four main groups, and the drug dilution concentrations ranged from 100 μg / ml to 400 μg / ml: one group was untreated and the remaining groups were treated. The cultured cells were treated for 24 h in 96-well plates.

[0035] 2.1.3 MTT assay To compare the proliferation ability and drug toxicity of cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed. First, the cell monolayer was washed with 1x phosphate buffered saline (PBS) (Invitrogen Inc., USA), and then 25 µl of MTT solution (Invitrogen Inc., USA) was added to the wells for staining for 3 h. Subsequently, the cells were lysed by adding dimethyl sulfoxide (DMSO) (Invitrogen Inc., USA) and incubated for 24 h. Finally, the absorbance was measured at a wavelength of 570 nm using an enzyme-linked immunosorbent assay (ELISA) plate reader, and the results are shown in Figure 2. Figure 1 shown.

[0036] The control group exhibited the highest absorbance values, reflecting the maximum viability and metabolic activity of the cells, and served as a baseline for comparison. At 100 µg / ml of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, the absorbance values ​​were comparable to the control group, indicating no significant changes in cell viability (p≥0.05). At 200 µg / ml, there was a slight decrease in absorbance compared to the control group. However, this decrease did not reach statistical significance, indicating that the effect on cell viability was small or negligible (p≥0.05). At 400 µg / ml, there was a slight decrease in absorbance values. Nevertheless, this change did not reach statistical significance, indicating that cell viability was only slightly affected even at the highest concentration tested (p≥0.05).

[0037] 2.2 Trypan Blue Detection To assess cell viability, a trypan blue exclusion assay was performed. HepG2 cells were cultured in 6-well plates at 37°C, 5% CO 2 The cells were incubated at 4 °C until they reached approximately 80% confluence. Subsequently, the cells were treated with different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one (100 µg / ml, 200 µg / ml, and 400 µg / ml) for 24 h. After treatment, the cells were trypsinized and centrifuged at 1000 rpm for 5 min. The resulting cell pellet was resuspended in 1 ml PBS and mixed with 0.4% trypan blue dye in a 1:1 ratio. A hemocytometer was used to count the viable (unstained) and nonviable (stained) cells, and the cell survival percentage was calculated. The results are shown in Table 1. Figure 2 shown.

[0038] Trypan blue exclusion assay showed high cell viability in all treatment groups at 100 µg / ml, 200 µg / ml, and 400 µg / ml. No significant decrease in cell viability was observed compared to the control group, and cell viability was always above 95% at all tested concentrations. These results suggest that even at the highest concentration of 400 µg / ml, the treatment had minimal or no cytotoxic effects on normal cells.

[0039] 2.3 Crystal Violet Detection To evaluate cell viability and adhesion ability, crystal violet assay was performed. HepG2 cells were seeded into 96-well plates and incubated overnight to promote cell adhesion. Subsequently, the cells were treated with different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one (100 µg / ml, 200 µg / ml, and 400 µg / ml) for 24 h. After treatment, the wells were gently washed with PBS to remove non-adherent cells. The remaining adherent cells were fixed with 4% paraformaldehyde for 10 minutes and stained with 0.5% crystal violet solution for 20 minutes. Subsequently, the excess dye was removed by rinsing with distilled water, and the wells were air-dried. The stained dye was dissolved by 33% glacial acetic acid, and the absorbance was measured at 570 nm using a microplate reader to quantify cell viability. The results are shown in Figure 2. Figure 3 shown.

[0040] The results of the crystal violet staining experiment showed that there was no significant decrease in cell viability and adhesion in all treatment groups. At concentrations of 100 µg / ml and 200 µg / ml, the absorbance values ​​were comparable to those of the control group. At a concentration of 400 µg / ml, the absorbance values ​​decreased slightly, but the change was not statistically significant. The results confirmed that even at higher concentrations, these treatments did not adversely affect the adhesion or viability of normal cells.

[0041] 2.4 Vascular endothelial growth factor enzyme-linked immunosorbent assay (VEGF ELISA) VEGF levels in treated and untreated HepG2 cells were measured using Zokiyo ELISA kit. After cells were seeded in 6-well plates, they were treated with (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one (100 µg / ml, 200 µg / ml, and 400 µg / ml) for 24 h. After treatment, cell culture supernatants were collected and stored at -20°C until analysis. The experiment was performed according to the manufacturer's instructions. Briefly, 100 µL of standards and samples were added to the pre-coated wells and incubated at 37°C for 2 h. After washing, 100 µL of biotin-labeled antibody was added and incubated at 37°C for 1 h. After washing again, HRP-conjugated streptavidin was added and incubated at 37°C for 30 min. After the final wash, 90 µL of TMB substrate solution was added and incubated in the dark for 15 min. The reaction was stopped by adding 50 µL of stop solution and the absorbance was measured at 450 nm using a microplate reader. The VEGF concentration was calculated based on the standard curve generated in the experiment. Figure 4 shown.

[0042] VEGF ELISA results showed that there was no significant change in VEGF levels in normal cells treated with (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one at 100 µg / ml, 200 µg / ml and 400 µg / ml compared to the control group. VEGF concentrations remained within the normal physiological range, indicating that these treatments did not induce angiogenesis or stress responses in normal cells. This suggests that the tested compounds have good biocompatibility with normal cellular processes.

[0043] 3. In vitro antibacterial experiment Mycobacterium tuberculosis was collected from the National Tuberculosis Control Program H37 (wild type), rifampicin-resistant strains, levofloxacin-resistant strains, bedaquiline-resistant strains and Mycobacterium abscessus strains. Among them, rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains are resistant to rifampicin 0.5µg / mL, levofloxacin 1µg / mL and bedaquiline 1µg / mL, respectively.

[0044] 3.1 Bacterial culture Approximately 800 µl of Mycobacterium Growth Indicator Tube (BBL-MGIT) Growth Supplement and Polymyxin B, Amphotericin B, Nalidixic Acid, Trimethoprim, and Aztreonam (BBL MGIT PANTA) were added to the MGIT tube; in addition, 500 µl of the processed decontaminated sample was added to the tube. The MGIT tube was placed in the MGIT 960 instrument (BD Diagnostic Systems, New Jersey, USA); the instrument automatically senses growth in the tube for the recommended 42 days, and the instrument is checked daily for positive signals. When the machine indicates a positive signal, the tube is placed under light for observation; after shaking the tube, small snowflake-like clumps or rope-like objects can be seen moving to the bottom of the tube, resulting in a positive culture.

[0045] To confirm whether the growth was Mycobacterium tuberculosis (MTB), the BD MGIT MTBc identification test (TBc ID, reference number: 245159, Becton, Dickinson) was performed. The test is a rapid chromatographic immunoassay that detects the MTB complex antigen MPT64 secreted during the MTBc cell culture process. Approximately 100 µl of sample is taken from the MGIT positive tube and added to the test well of the TBc ID device. Within 15 minutes, if MTB is detected in the sample, a pink to red band will appear in the test area "T" and the control area "C" position, indicating the presence of the MPT64 antigen of Mycobacterium tuberculosis in the sample.

[0046] 3.2 Preparation of inoculum For each bacterial strain, suspensions were prepared from MGIT subcultures following the manufacturer's instructions (BACTEC™ MGIT™ 960 System User Manual: Becton Dickinson). To determine the minimum inhibitory concentration (MIC), seven different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one solutions were prepared in DMSO, ranging from 0.5 µg / mL to 32 µg / mL; 0.5 µg / mL, 1 µg / mL, 2 µg / mL, 4 µg / mL, 8 µg / mL, 16 µg / mL, 32 µg / mL, respectively. For inoculation, 0.5 mL of positive culture (day 2) was added to each growth indicator tube, and 0.8 mL of OADC supplement was added. In addition, each test series includes a drug-free control tube. When inoculating the control tube, after adding 0.1 mL of pure DMSO and 0.8 mL of OADC, it is inoculated with 0.5 mL of 10-2 diluted suspension (representing 1% of the bacterial concentration in the drug-containing test tube) and placed in the MGIT 960 fully automatic mycobacterium culture instrument for incubation and detection.

[0047] 3.3MIC reading The MIC was defined as the lowest concentration of compound at which no growth of the strain was detected by the MGIT 960 system. The MGIT system detects growth by fluorescence increase. The MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was determined by comparing the growth of strains in tubes containing drug with that in control tubes without compound.

[0048] Test principle: The instrument has a capacity of 960 wells, which are evenly distributed in three relatively independent incubators. Each incubator can vertically place 320 MGIT culture tubes with fluorescent display agents, and each culture tube position has a detector. 2 The concentration changes are used to monitor the growth status of mycobacteria in the culture tube. If mycobacteria grow, the nutrients and oxygen in the tube will be continuously consumed, and the fluorescent indicator at the bottom of the tube will react with the change of oxygen concentration in the tube. The fluorescent indicator will release fluorescence under the stimulation of a specific light source; the growth of mycobacteria can be judged by continuously detecting the changes in the fluorescence intensity displayed by the culture tube of the inoculated specimen.

[0049] When the Growth Control (GC) reaches a Growth Unit (GU) value of 400 or greater, the instrument indicates the test is complete and prints an inventory report as an "S" when the Growth Unit (GU) value is less than 100, or as an "R" when the GU value is greater than 100.

[0050] right Figure 5 The experimental group containing H37Rv strain with different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one was detected using the MGIT 960 system. H37 Growth of strains. At 0.5 µg and 1 µg / mL, Mycobacterium tuberculosis H37 The test tubes of the strain showed growth; however, at concentrations of ≥2 µg / mL of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, H37 The strain did not grow, so it can be judged that (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one is H37 The MIC of the strain was 2 µg / mL; Likewise, Figure 6 Rifampicin-resistant strains were included ( RIF-R MGIT 960 system was used to detect the different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one experimental groups RIF-R When the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one was ≥2 µg / mL, no growth was observed. RIF-RThe growth of the strain can be used to determine whether (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one is resistant to rifampicin ( RIF-R ) has a MIC of 2 µg / mL; right Figure 7 The experimental group containing different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one containing levofloxacin-resistant Mycobacterium tuberculosis was tested using the MGIT 960 system for the growth of levofloxacin-resistant Mycobacterium tuberculosis. When the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one was ≥2 µg / mL, the growth of levofloxacin-resistant Mycobacterium tuberculosis was also not observed. It can be judged that the MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one against levofloxacin-resistant Mycobacterium tuberculosis is 2 µg / mL; right Figure 8 The experimental groups containing bedaquiline-resistant strains with different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one were tested using the MGIT 960 system to detect the growth of bedaquiline-resistant strains. When the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one was ≥2 µg / mL, the growth of bedaquiline-resistant strains was also not observed. It can be judged that the MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one against bedaquiline-resistant strains is 2 µg / mL.

[0051] right Fig. 9 The experimental group containing different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one containing Mycobacterium abscessus was tested using the MGIT 960 system for the growth of Mycobacterium abscessus. Mycobacterium abscessus was able to grow in all concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one. This indicates that Mycobacterium abscessus is resistant to (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one.

[0052] Therefore, the above experiments can determine the effect of MT5R6E on Mycobacterium tuberculosis H37 , rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains, with an MIC of 2 µg / mL. (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one showed no inhibitory activity against Mycobacterium abscessus even at a concentration of 32 µg / mL; although (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one was ineffective against Mycobacterium abscessus, it was effective against various drug-resistant Mycobacterium tuberculosis strains such as Mycobacterium tuberculosis H37, rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains could provide a targeted approach to combat drug-resistant tuberculosis and change the treatment landscape.

[0053] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.

[0054] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include at least one of the features. In the description of this application, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0055] The above is only a specific implementation of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can easily think of various changes or substitutions within the technical scope disclosed in the present application, which should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. Use of (5R,6E)-5-hydroxy-17-diphenyl-6-heptene-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

2. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 1 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The drug-resistant Mycobacterium tuberculosis is Mycobacterium tuberculosis H37 , rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains.

3. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 2 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: Effect of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one on Mycobacterium tuberculosis H37 , rifampicin-resistant strains, levofloxacin-resistant strains and bedaquiline-resistant strains had a MIC of 2 µg / mL.

4. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 1 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The use of the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one alone or in a composition consisting of 0.1%-99.9% by weight and a pharmaceutically acceptable carrier in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

5. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 4 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The pharmaceutically acceptable carrier is one of drug nanoparticles, microcapsules, microspheres, liposomes or exosomes.

6. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 1 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The dosage form of the drug includes an oral preparation form or a non-oral preparation form.

7. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 6 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The oral dosage forms include tablets, capsules, and granules.

8. The use of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-one according to claim 6 in the preparation of a drug for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that: The non-oral dosage form includes injection or lyophilized powder injection.

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