Application of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection

Abstract

This application discloses the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection. (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against Mycobacterium tuberculosis. H37Rv The MIC of rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains is 2 µg / mL, which solves the core problem of multidrug-resistant and extensively drug-resistant tuberculosis and provides an alternative treatment approach.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection. Background Technology

[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 TB, such as Mycobacterium tuberculosis... H37Rv The emergence of rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains is reducing the effectiveness of traditional tuberculosis treatments. Furthermore, with the wider use of these drugs, drug resistance will become even more severe, posing a significant challenge to tuberculosis treatment; therefore, the development of drugs targeting drug-resistant tuberculosis strains is urgently needed. Summary of the Invention

[0003] This application provides an application of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for treating drug-resistant Mycobacterium tuberculosis infection, in order to solve the problems existing in related technologies. The technical solution is as follows:

[0004] In a first aspect, embodiments of this application provide the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0005] In one embodiment, the drug-resistant Mycobacterium tuberculosis is Mycobacterium tuberculosis. H37Rv Any one of the following: rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains.

[0006] In one embodiment, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against Mycobacterium tuberculosis. H37Rv The MICs for rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains were 2 µg / mL.

[0007] In one embodiment, the (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, alone or in 0.1%-99.9% by weight, in combination with a pharmaceutically acceptable carrier, is used in the preparation of a medicament for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection.

[0008] In one embodiment, the pharmaceutically acceptable carrier is one of drug nanoparticles, microcapsules, microspheres, liposomes, or exosomes.

[0009] In one embodiment, the dosage form of the drug includes an oral formulation or a non-oral formulation.

[0010] In one embodiment, the oral dosage form includes tablets, capsules, and granules.

[0011] In one embodiment, the non-oral dosage form includes an injection or a lyophilized powder for injection.

[0012] The advantages or beneficial effects of the above technical solutions include at least the following:

[0013] This application provides the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of a drug for treating drug-resistant Mycobacterium tuberculosis infection. (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against Mycobacterium tuberculosis. H37Rv The MIC of rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains is 2 µg / mL, addressing the core issues of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis and providing an alternative treatment approach; it can reduce reliance on existing, often toxic, and long-term therapies.

[0014] The above overview 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 this application will become readily apparent from the accompanying drawings and the following detailed description. Attached Figure Description

[0015] In the accompanying drawings, unless otherwise specified, the same reference numerals throughout the various drawings denote the same or similar parts or elements. These drawings are not necessarily drawn to scale. It should be understood that these drawings depict only some embodiments disclosed in this application and should not be construed as limiting the scope of this application.

[0016] Figure 1 Image showing the MTT test results;

[0017] Figure 2 The experimental results for excluding Panasonic Blue are shown in the image.

[0018] Figure 3 The image shows the results of the crystal violet staining experiment;

[0019] Figure 4 Image showing VEGF ELISA detection results;

[0020] Figure 5 (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one for Mycobacterium tuberculosis H37Rv MIC determination of the strain;

[0021] Figure 6 (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one rifampicin-resistant strain RIF-R MIC determination;

[0022] Figure 7 MIC determination of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against levofloxacin-resistant Mycobacterium tuberculosis strains;

[0023] Figure 8 MIC determination of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against bedaquiline-resistant Mycobacterium tuberculosis strains;

[0024] Figure 9 The activity and MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against Mycobacterium abscessis strain were determined. Detailed Implementation

[0025] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of this application. Therefore, the drawings and description are considered to be exemplary in nature and not restrictive.

[0026] This application provides the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection.

[0027] (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is a compound having the following structure, capable of […]. Fagonia arabica It was extracted from [the source]. Fagonia arabica It is a plant with traditional medicinal value, and its use led to the discovery in this application of the use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection.

[0028] .

[0029] As one embodiment, the drug-resistant Mycobacterium tuberculosis is Mycobacterium tuberculosis. H37Rv Any one of the following: rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains.

[0030] As one embodiment, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against Mycobacterium tuberculosis. H37Rv The minimum inhibitory concentration (MIC) for rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains is 2 µg / mL.

[0031] As one embodiment, the (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, alone or in 0.1%-99.9% by weight of a pharmaceutically acceptable carrier, is used in the preparation of a medicament for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection.

[0032] As one embodiment, the pharmaceutically acceptable carrier is one of drug nanoparticles, microcapsules, microspheres, liposomes, or exosomes.

[0033] As one embodiment, the dosage form of the drug includes oral formulations or non-oral formulations.

[0034] As one embodiment, the oral dosage form includes tablets, capsules, and granules.

[0035] As one embodiment, the non-oral dosage form includes an injection or a lyophilized powder for injection.

[0036] Validation of the drug activity of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against drug-resistant Mycobacterium tuberculosis:

[0037] 1. Pharmacokinetic prediction

[0038] The SwissADME prediction platform (https: / / www.swissadme.ch / ), specifically designed for drug discovery and medicinal chemistry, was used to predict some parameters affecting the pharmacokinetics of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one. The prediction results are shown in Table 1.

[0039] Table 1. Pharmacokinetic prediction of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one.

[0040]

[0041] *HBD: Hydrogen bond donor; HBA: Hydrogen bond acceptor; (5R,6E)-5-hydroxy-1,7-diphenyl-6-hepten-3-one; TPSA: Topological polar surface area; BBB: Blood-brain barrier.

[0042] (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is a compound with several promising properties, making 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 efficient absorption upon oral administration. Notably, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one has the ability to cross the blood-brain barrier (BBB), suggesting its potential for central nervous system (CNS) applications. (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one exhibits drug similarity and lead-like properties, making it a promising candidate for further medicinal chemistry exploration. (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one consists of 21 heavy atoms, containing 7 hydrogen bond acceptors (HBA) and 2 hydrogen bond donors (HBD), and has a topological polar surface area (TPSA) of 78.79 Å. 2 It is within a range that is conducive to drug permeability and absorption.

[0043] Therefore, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one exhibits favorable pharmacokinetic characteristics, including high gastrointestinal absorption and the ability to cross the blood-brain barrier. (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one conforms to the five rules of class-specific drugs, supporting its potential as an oral treatment option, which could improve patient adherence and provide an effective treatment for tuberculosis.

[0044] 2. Biocompatibility

[0045] 2.1 MTT Measurement

[0046] 2.1.1 Cell Culture

[0047] HepG2 cell cryopreservation vials (Lahore University Cell Culture Laboratory) were removed from liquid nitrogen storage and revived in culture flasks containing high-glucose DMEM medium (DMEM-HG) supplemented with 10% fetal bovine serum (FBS), 100 mg / mL penicillin G (Sigma), and 100 U / mL streptomycin (Sigma). Cultures were maintained in a humidified incubator at 37°C and 5% CO2. All experiments were repeated three times. Cells were passaged when they reached 70-80% confluence.

[0048] During passage, cells adhering to the culture flask wall were washed with 1X phosphate-buffered saline (PBS) and incubated with 0.05% trypsin-EDTA until the cells detached from the culture flask surface. After confirming cell detachment using an inverted microscope, a few drops of FBS were added to the culture flask. The cell suspension was then transferred to a 15 ml centrifuge tube and centrifuged at 2000 rpm for 5 minutes. After centrifugation, the supernatant was carefully removed, and the cell pellet was resuspended in a 96-well plate for MTT assay.

[0049] 2.1.2 Treatment of cell lines with (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one

[0050] Cells were divided into four main groups, with drug dilutions ranging from 100 μg / ml to 400 μg / ml: one group was untreated, while the remaining groups were treated. The cultured cells were then treated for 24 hours in 96-well plates.

[0051] 2.1.3 MTT Measurement

[0052] To compare cell proliferation and drug toxicity, a 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed. First, cell monolayers were washed with 1x phosphate-buffered saline (PBS) (Invitrogen Inc., USA), and then 25 µl of MTT solution (Invitrogen Inc., USA) was added to each well for staining for 3 h. Subsequently, cells were crystallized by adding dimethyl sulfoxide (DMSO) (Invitrogen Inc., USA) and incubated for 24 h. Finally, absorbance was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader. The results are shown below. Figure 1 As shown.

[0053] The control group exhibited the highest absorbance, reflecting maximum cell viability and metabolic activity, and served as the baseline for comparison. At a concentration of 100 µg / ml (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one, the absorbance was comparable to the control group, indicating no significant change in cell viability (p≥0.05). At a concentration of 200 µg / ml, the absorbance decreased slightly compared to the control group. However, this decrease was not statistically significant, indicating a small or negligible effect on cell viability (p≥0.05). At a concentration of 400 µg / ml, the absorbance decreased slightly. Nevertheless, this change was still not statistically significant, indicating that even at the highest tested concentration, cell viability was only slightly affected (p≥0.05).

[0054] 2.2 Trypan Blue testing

[0055] To assess cell viability, a trypan blue exclusion assay was performed. HepG2 cells were cultured in 6-well plates and incubated at 37°C with 5% CO2 until approximately 80% confluence was achieved. Subsequently, 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, 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 at a 1:1 ratio. Viable (unstained) and non-viable (stained) cells were counted using a hemocytometer, and the cell survival percentage was calculated. The results are shown below. Figure 2 As shown.

[0056] Trypan blue exclusion assays 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 consistently exceeded 95% at all tested concentrations. These results indicate that even at the highest concentration of 400 µg / ml, the treatment has minimal or no cytotoxic effect on normal cells.

[0057] 2.3 Crystal Violet Detection

[0058] To assess cell viability and adhesion, a crystal violet assay was performed. HepG2 cells were seeded into 96-well plates and incubated overnight to promote cell adhesion. Subsequently, cells were treated for 24 h with different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one (100 µg / ml, 200 µg / ml, and 400 µg / ml). After treatment, the wells were gently washed with PBS to remove unadhered cells. The remaining adherent cells were fixed with 4% paraformaldehyde for 10 min and stained with 0.5% crystal violet solution for 20 min. Excess dye was then removed by rinsing with distilled water, and the wells were air-dried. The stained dye was dissolved in 33% glacial acetic acid, and the absorbance was measured at 570 nm using a microplate reader to quantify cell viability. The results are shown below. Figure 3 As shown.

[0059] Crystal violet staining results showed no significant decrease in cell viability and adhesion in any of the treatment groups. At concentrations of 100 µg / ml and 200 µg / ml, the absorbance values ​​were comparable to the control group. At a concentration of 400 µg / ml, the absorbance value decreased slightly, but this change was not statistically significant. These results confirm that even at higher concentrations, these treatments did not adversely affect the adhesion or viability of normal cells.

[0060] 2.4 Vascular endothelial growth factor enzyme-linked immunosorbent assay (VEGF ELISA)

[0061] VEGF levels in treated and untreated HepG2 cells were measured using the Zokiyo ELISA kit. Cells were seeded into 6-well plates and 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, the cell culture supernatant was collected and stored at -20°C until analysis. Experiments were performed according to the manufacturer's instructions. Briefly, 100 µL of standards and samples were added to 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-bound streptavidin was added and incubated at 37°C for 30 min. After a 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, and the results are as follows. Figure 4 As shown.

[0062] VEGF ELISA results showed that, compared with the control group, VEGF levels in normal cells treated with (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one at concentrations of 100 µg / ml, 200 µg / ml, and 400 µg / ml did not change significantly. The VEGF concentration remained within the normal physiological range, indicating that these treatments did not induce angiogenesis or stress responses in normal cells. This demonstrates that the tested compound has good biocompatibility with normal cellular processes.

[0063] 3. In vitro antibacterial test

[0064] Mycobacterium tuberculosis was collected from the National Tuberculosis Control Project. H37RvWild-type, rifampicin-resistant, levofloxacin-resistant, bedaquiline-resistant, and Mycobacterium abscessii strains were included. Among them, the rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains were resistant to rifampicin 0.5µg / mL, levofloxacin 1µg / mL, and bedaquiline 1µg / mL, respectively.

[0065] 3.1 Bacterial Culture

[0066] Approximately 800 µl of Mycobacterium growth indicator (BBL-MGIT) growth supplement and polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and aztreonam (BBL MGIT PANTA) were added to the MGIT tubes; additionally, 500 µl of the treated decontaminated sample was added to the tubes. The MGIT tubes were placed in an MGIT 960 instrument (BD Diagnostic Systems, New Jersey, USA); this instrument automatically senses the growth within the tubes for the recommended 42 days, and is checked daily for positive signals. When the machine indicates a positive signal, the tubes are placed under light for observation; after shaking the tubes, small snowflake-like clumps or rope-like objects can be seen moving towards the bottom of the tube, indicating a positive culture.

[0067] To confirm whether the growth was Mycobacterium tuberculosis (MTB), the BD MGIT MTBc identification test (TBc ID, reference number: 245159, Becton, Dickinson) was performed. This test is a rapid chromatographic immunoassay that detects the MTB complex antigen MPT64 secreted during MTBc cell culture. Approximately 100 µl of sample was taken from an MGIT positive tube and added to the test well of the TBc ID device. Within 15 minutes, if MTB was detected in the sample, a pink to red band would appear at the test area "T" and control area "C," indicating the presence of Mycobacterium tuberculosis MPT64 antigen in the sample.

[0068] 3.2 Preparation of inoculum

[0069] For each bacterial strain, suspensions were prepared from MGIT subcultures according to 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, and 32 µg / mL. At inoculation, 0.5 mL of positive culture (day 2) and 0.8 mL of OADC supplement were added to each growth indicator tube. 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 automated mycobacterial culture system for incubation and detection.

[0070] 3.3MIC readings

[0071] The MIC was defined as the lowest concentration of compound at which the MGIT 960 system could not detect the growth of the strain. The MGIT system detects growth by increasing fluorescence. The MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was determined by comparing the growth of the strain in tubes containing the drug with that in control tubes without the compound.

[0072] Test Principle: The instrument has a capacity of 960 wells, evenly distributed across three relatively independent incubators. Each incubator can vertically hold 320 MGIT culture tubes containing fluorescent indicators, with a detector at each culture tube position. The instrument measures changes in O2 concentration caused by mycobacterial growth to monitor the growth status of mycobacteria within the culture tubes. If mycobacteria are growing, nutrients and oxygen in the tube will be continuously consumed. The fluorescent indicator at the bottom of the tube reacts with changes in oxygen concentration, releasing fluorescence under the stimulation of a specific light source. The presence of mycobacterial growth is determined by continuously monitoring changes in fluorescence intensity displayed on the culture tubes containing inoculated specimens.

[0073] When the growth control (GC) reaches a growth unit (GU) value of 400 or higher, the instrument will indicate that the test is complete and print an inventory report as "S" if the growth unit (GU) value is less than 100, or as "R" if the GU value is greater than 100.

[0074] right Figure 5Experimental groups containing different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one from strain H37Rv were detected using the MGIT 960 system. H37Rv Growth of the strain. Mycobacterium tuberculosis at 0.5 µg and 1 µg / mL. H37Rv The strain showed growth in test tubes; however, under concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one ≥2 µg / mL, H37Rv The strain did not grow, indicating that (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one is effective against [the virus / disease]. H37Rv The MIC of this strain is 2 µg / mL;

[0075] Similarly, for Figure 6 Contains rifampicin-resistant strains ( RIF-R Different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one were detected using the MGIT 960 system. RIF-R Growth of the strain. No growth was observed when the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was ≥2 µg / mL. RIF-R The growth of the strain can be used to determine the resistance of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one to rifampicin-resistant strains. RIF-R The MIC for ) is 2 µg / mL;

[0076] right Figure 7 Different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one were used in experimental groups containing levofloxacin-resistant Mycobacterium tuberculosis to detect the growth of levofloxacin-resistant Mycobacterium tuberculosis. When the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was ≥2 µg / mL, no growth of levofloxacin-resistant Mycobacterium tuberculosis was observed. Therefore, the MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against levofloxacin-resistant Mycobacterium tuberculosis was determined to be 2 µg / mL.

[0077] right Figure 8The growth of bedaquiline-resistant strains was detected using the MGIT 960 system in experimental groups containing different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one. When the concentration of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was ≥2 µg / mL, no growth of bedaquiline-resistant strains was observed. Therefore, the MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against bedaquiline-resistant strains was determined to be 2 µg / mL.

[0078] right Figure 9 The growth of *Mycobacterium abscessus* was detected in experimental groups containing different concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one using the MGIT 960 system. *Mycobacterium abscessus* grew in all concentrations of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one. This indicates that *Mycobacterium abscessus* exhibits resistance to (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one.

[0079] Therefore, the above experiments confirm that MT5R6E is effective against Mycobacterium tuberculosis. H37Rv It showed inhibitory activity against rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains, with a MIC of 2 µg / mL. Even at a concentration of 32 µg / mL, (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one did not show inhibitory activity against *Mycobacterium abscessus*; although (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one was ineffective against *Mycobacterium abscessus*, it was effective against various drug-resistant *Mycobacterium tuberculosis* strains, such as *Mycobacterium tuberculosis*. H37Rv The targeted activity of rifampicin-resistant, levofloxacin-resistant, and bedaquiline-resistant strains could provide a targeted approach to combat drug-resistant tuberculosis and change the treatment landscape.

[0080] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of those different embodiments or examples.

[0081] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this application, "a plurality of" means two or more, unless otherwise explicitly specified.

[0082] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any person skilled in the art can easily conceive of various variations or substitutions within the technical scope disclosed in this application, and these should all be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. The use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection; characterized in that, The drug-resistant Mycobacterium tuberculosis is any one of the following: rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains; The MIC of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one against rifampicin-resistant strains, levofloxacin-resistant strains, and bedaquiline-resistant strains was 2 µg / mL.

2. The use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one according to claim 1 in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that, The use of the (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one alone or in 0.1% to 99.9% by weight of a pharmaceutically acceptable carrier in the preparation of medicaments for the treatment or prevention of drug-resistant Mycobacterium tuberculosis infection.

3. The use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one according to claim 1 in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that, The pharmaceutically acceptable carrier is one of the following: drug nanoparticles, microcapsules, microspheres, liposomes, or exosomes.

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

5. The use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one according to claim 4 in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that, The oral dosage forms include tablets, capsules, and granules.

6. The use of (5R,6E)-5-hydroxy-17-diphenyl-6-hepten-3-one according to claim 4 in the preparation of drugs for treating or preventing drug-resistant Mycobacterium tuberculosis infection, characterized in that, The non-oral dosage forms include injections or lyophilized powder injections.

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