Use of fosmanogepix in mycobacterium kansasii infection

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to application of an anti-invasive fungal infection drug in anti-mycobacterium infection. The Fosmanogepix in the application has obvious strain specificity for mycobacterium, can effectively inhibit the activity of a standard strain of Kansas mycobacterium and a clinically isolated strain of Kansas mycobacterium, the MIC of the standard strain of Kansas mycobacterium (ATCC12478) is 1 ug / mL, and the MIC of the clinically isolated strain of Kansas mycobacterium is 2 ug / mL. 50 The compound can be applied to development of an anti-Kansas mycobacterium infection drug as a candidate drug, and has important significance for preventing and treating Kansas mycobacterium disease, especially drug-resistant Kansas mycobacterium disease.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to application of an anti-invasive fungal infection drug in anti-mycobacterium infection. BACKGROUND

[0002] Non-tuberculous Mycobacteria (NTM) refers to mycobacteria other than mycobacterium tuberculosis complex (MTC) and mycobacterium leprae, is a gram-positive, acid-fast, aerobic bacillus, widely exists in soil, water, dust and other natural environment, most of which are saprophytic bacteria, which can be divided into fast-growing abscess mycobacteria (Mycobacteria abscessum complex, MAB), Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium smegmatis; slow-growing avium mycobacteria (Mycobacteria avium complex, MAC), Mycobacterium kansasii, Mycobacterium gordonae, Mycobacterium marinum, etc. (Li Xiangfang, Ding Shoupeng, Gao Jinghua, et al. Research progress on pathogenic mechanism of non-kansasii mycobacterium [J]. Chinese Journal of Pathogenic Biology, 2022, 17(03): 352-355.). At present, more than 200 non-tuberculous mycobacteria have been isolated, which are conditional pathogenic bacteria. In recent years, with the continuous improvement and popularization of bacterial isolation technology, the change of bacterial flora in immunocompromised hosts, etc., the incidence of NTM infection and related diseases shows an upward trend. Literature reports that the proportion of NTM isolates in mycobacterium isolates in China increased from 4.3% in 1979 to 22.9% in 2010. Among NTM infected patients, Mycobacterium kansasii has a higher clinical relevance, about 60%. At the same time, Mycobacterium kansasii is also the non-tuberculous mycobacterium with the highest isolation rate in China, with an isolation rate of 6.4%. Mycobacterium kansasii is one of the most common pathogenic NTMs, which can cause lung, lymph node, skin, skeletal muscle and other multiple site lesions and systemic disseminated diseases, with lung lesions being the most common. In China, the incidence is the highest in the highly urbanized eastern and southern coastal regions (Liu Zengwei, Chen Pinru, Li Huiru, et al. Clinical and CT imaging features of Mycobacterium kansasii pulmonary disease [J]. Journal of Molecular Imaging, 2024, 47(03): 321-326.).

[0003] Fosmanogepix (also known as APX001; E1211) is a broad-spectrum oral antifungal drug targeting the highly conserved Gwt1 enzyme. The chemical formula is C 22 H 21N4O6P, Fosmanogepix (APX001 / E1211) is an N-phosphonoxy methyl prodrug, which is rapidly and completely metabolized to the active moiety mannegepix (APX001A) by systemic alkaline phosphatases. This drug targets the fungal-specific enzyme inositol acyltransferase (Gwt1), and achieves the purpose of inhibiting fungi by affecting the maturation and localization of GPI-anchored proteins. It is currently in the clinical phase 2 trial. Fosmanogepix is active against a variety of fungi, including Candida (including C. albicans, C. auris, C. glabrata, but not C. krusei) (ZHAO Y. LEE M H, PADERU P, et al. Significantly improved pharmacokinetics enhances in vivo efficacy of APX001 against echinocandin-and multidrug-resistant Candida isolates in a mouse model of invasive candidiasis [J]. Antimicrob Agents chemother. 2018. 62(10): e00425-00418.), Cryptococcus neoformans, C. gattii, Aspergillus, Coccidioides, Scedosporium and Fusarium, Pseudallescheria boydii, and Rhizopus arrhizus (Song Xiaoting, Zhao Zuotao, Wang Aiping. Research progress of new systemic antifungal drugs [J]. Chinese Journal of Mycology, 2023, 18(04): 370-376.). Fosmanogepix has both oral and intravenous preparations, with a bioavailability of >90% in humans, and can be switched between intravenous and oral preparations without affecting blood levels. In rats and monkeys administered Fosmanogepix orally or intravenously, the drug was observed to be rapidly and widely absorbed into tissues such as the lungs, brain, liver, kidneys, and eyes, and was mainly cleared through the bile (in rats) and feces (in monkeys). In phase I studies, the plasma exposure curve was linear and dose-dependent, with a half-life of about 2.5 days (HODGES M R, OPLE E, SHAWK J, et al. Phase 1 study to assess safety, tolerability and pharmacokinetics of single and multiple oral doses of APX001 and to investigate the effect of food on APX001 bioavailability [J]. Open Forum Infect Dis. 2017 4(suppl 1): S534.).Meanwhile, fosmanogepix has less side effects. In patients with impaired renal function, no drug-related nephrotoxicity occurred, and no dose adjustment was required (BULPAP, RAHAVG, OREN l, et al. Clinical safety, efficacy, and pharmacokinetics of fosmanogepix, a novel first in-class antifungal, in patients with renal insufficiency: subset analysis from a phase 2 candidemia trial [J]. Open Forum Infect Dis, 2020, 7(suppl 1) S605.). Fosmanogepix was well tolerated at all study doses, with mild adverse reactions, the most common being headache (HODGES M R, OPLE E, SHAWK j, et al. Phase 1 study to assess safety, tolerability and pharmacokinetics of single and multiple oral doses of APX001 and to investigate the effect of food on APx001 bioavailability [J]. Open Forum Infect Dis, 2017. 4(Suppl 1): S534.). There have also been several cases of fungal and Mycobacterium kansasii co-infection reported in the clinic (Pan FY, Fan HZ, Zhuang SH, et al. Severe inflammatory disorder in trisomy 8 without myelodysplastic syndrome and response to methylprednisolone: A case report [J]. World J Clin Cases. 2023 Sep 16; 11(26): 6206-6212; Philip T, Sittirat PD, Eickenhorst D, et al. Spontaneous pneumothorax and COVID-19: Precipitants to a complex HIV-AIDS diagnosis [J]. Radiol Case Rep. 2023 Mar; 18(3): 1197-1200.).Currently, there is no report about Fosmanogepix inhibiting Mycobacterium. SUMMARY

[0004] The present application finds that Fosmanogepix has the effect of inhibiting the activity of Mycobacterium kansasii, and accordingly completes the present application.

[0005] In a first aspect, the present application provides a pharmaceutical composition comprising Fosmanogepix and another drug against Mycobacterium kansasii infection, the pharmaceutical composition having at least one of the following effects:

[0006] a) inhibiting the activity of Mycobacterium kansasii;

[0007] b) against Mycobacterium kansasii infection;

[0008] c) preventing and / or treating diseases caused by Mycobacterium kansasii.

[0009] Further, the Mycobacterium kansasii includes Mycobacterium kansasii clinical isolates, Mycobacterium kansasii standard strains, or Mycobacterium kansasii carried by patients infected with Mycobacterium kansasii.

[0010] Further, the other drug against Mycobacterium kansasii infection includes one or more of antibiotics and other drugs that can help inhibit or kill Mycobacterium kansasii or provide resistance to patients.

[0011] Further, the antibiotic includes one or more of rifampicin, ethambutol, isoniazid, clarithromycin, azithromycin, moxifloxacin, clofazimine, and / or linezolid.

[0012] Further, the other drug includes one or more of vitamins, amino acids, proteins, and / or minerals.

[0013] Further, one or more pharmaceutically acceptable carriers can also be added to the pharmaceutical composition.

[0014] Further, the carrier material includes but is not limited to one or more of water-soluble carrier materials, poorly soluble carrier materials, and / or enteric carrier materials.

[0015] Preferably, the carrier material is a water-soluble carrier material.

[0016] Further, the water-soluble carrier material includes but is not limited to one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0017] Further, the poorly soluble carrier material includes but is not limited to one or more of ethyl cellulose and / or cholesteryl stearate.

[0018] Further, the enteric carrier material includes, but is not limited to, one or more of cellulose acetate phthalate and / or carboxymethylcellulose.

[0019] Further, the pharmaceutical composition can be prepared in various dosage forms, including, but not limited to, one or more of tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, buccal tablets, suppositories, and / or lyophilized powder injections.

[0020] Further, the preparation can be one or more of ordinary preparations, sustained-release preparations, controlled-release preparations, and / or various microparticle drug delivery systems.

[0021] Further, the tablet can widely use various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and / or lubricants.

[0022] Further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0023] Further, the wetting agents and binders include, but are not limited to, one or more of water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, sugar syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and / or polyvinylpyrrolidone.

[0024] Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, alginic acid, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium lauryl sulfate, methyl cellulose, and / or ethyl cellulose.

[0025] Further, the disintegration inhibitors include, but are not limited to, one or more of sucrose, glycerol triestearate, cocoa butter, and / or hydrogenated oil, etc.

[0026] Further, the absorption promoters include, but are not limited to, one or more of quaternary ammonium salts and / or sodium lauryl sulfate.

[0027] Further, the lubricants include, but are not limited to, one or more of talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0028] Further, the tablet can be further prepared into coated tablets, including sugar-coated tablets, film-coated tablets, enteric-coated tablets, double-layer tablets, and multi-layer tablets.

[0029] Further, the pill can widely use various carriers known in the art, including diluents and absorbents, binders and / or disintegrants.

[0030] Further, the diluents and absorbents include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin and / or talc.

[0031] Further, the binders include, but are not limited to, one or more of acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste and / or batter.

[0032] Further, the disintegrants include, but are not limited to, one or more of agar powder, dried starch, alginic acid, sodium lauryl sulfate, methyl cellulose and / or ethyl cellulose.

[0033] Further, the suppositories can widely use various carriers known in the art, including but not limited to one or more of polyethylene glycol, lecithin, cocoa butter, higher alcohol, ester of higher alcohol, gelatin and / or semi-synthetic glyceride.

[0034] Further, the injection preparation includes, but is not limited to, one or more of solutions, emulsions, lyophilized powders and / or suspensions.

[0035] Further, the injection preparation can use all diluents commonly used in the art, including but not limited to one or more of water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and / or polyoxyethylene sorbitol fatty acid ester.

[0036] Further, the injection preparation can add one or more of sodium chloride, glucose, glycerol, conventional cosolvents, buffers and / or pH adjusters to the injection preparation in order to prepare an isotonic injection.

[0037] Further, the various preparations can also add coloring agents, preservatives, flavors, flavoring agents, sweeteners or other materials to the pharmaceutical preparation, if necessary.

[0038] Further, the pharmaceutical composition can be administered by injection, cavity administration, respiratory tract administration or mucosal administration.

[0039] Further, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; the respiratory tract administration includes nasal administration.

[0040] In a second aspect, the present application provides use of Fosmanogepix in the preparation of a product for inhibiting Mycobacterium kansasii, wherein the product comprises Fosmanogepix or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof.

[0041] Further, the Mycobacterium kansasii comprises a Mycobacterium kansasii clinical isolate, a Mycobacterium kansasii standard strain, or a Mycobacterium kansasii carried by a patient infected with Mycobacterium kansasii.

[0042] Further, the product for inhibiting Mycobacterium kansasii comprises one or more of a drug and / or a bacteriostatic agent.

[0043] Further, one or more pharmaceutically acceptable carriers or excipients can be added to the product.

[0044] Further, the carrier material comprises one or more of a water-soluble carrier material, a poorly water-soluble carrier material, and / or an enteric carrier material.

[0045] In a third aspect, the present application provides use of Fosmanogepix in the preparation of a medicament for preventing and / or treating a disease caused by Mycobacterium kansasii infection, wherein the medicament comprises Fosmanogepix or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof.

[0046] wherein Fosmanogepix exerts an effect by:

[0047] 1) Fosmanogepix inhibits Mycobacterium kansasii activity;

[0048] 2) Fosmanogepix kills Mycobacterium kansasii.

[0049] Further, the Mycobacterium kansasii comprises a Mycobacterium kansasii clinical isolate, a Mycobacterium kansasii standard strain, or a Mycobacterium kansasii carried by a patient infected with Mycobacterium kansasii.

[0050] Further, one or more pharmaceutically acceptable carriers or excipients can be added to the medicament for preventing and / or treating a disease caused by Mycobacterium kansasii infection.

[0051] Further, the carrier material comprises one or more of a water-soluble carrier material, a poorly water-soluble carrier material, and / or an enteric carrier material.

[0052] Preferably, the carrier material is a water-soluble carrier material.

[0053] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0054] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0055] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0056] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0057] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0058] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0059] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0060] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0061] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0062] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0063] Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acid.

[0064] Further, the lubricants include, but are not limited to, one or more of talc, silica, corn starch, stearic acid salts, boric acid, liquid paraffin, and / or polyethylene glycol.

[0065] Further, the tablets can be further manufactured into coated tablets, including sugar-coated tablets, film-coated tablets, enteric-coated tablets, double-layer tablets, and multi-layer tablets.

[0066] Further, the pills can be widely used with various carriers known in the art, including diluents and absorbents, binders, and / or disintegrants.

[0067] Further, the diluents and absorbents include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, and / or talc.

[0068] Further, the binders include, but are not limited to, one or more of acacia, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste, and / or wheat paste.

[0069] Further, the disintegrants include, but are not limited to, one or more of agar powder, dried starch, alginic acid, sodium lauryl sulfate, methyl cellulose, and / or ethyl cellulose.

[0070] Further, the suppositories can be widely used with various carriers known in the art, including, but not limited to, one or more of polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and / or semi-synthetic glycerides.

[0071] Further, the injection preparations include, but are not limited to, one or more of solutions, emulsions, lyophilized powders, and / or suspensions.

[0072] Further, the injection preparations can use all diluents commonly used in the art, including, but not limited to, one or more of water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and / or polyoxyethylene sorbitan fatty acid esters.

[0073] Further, the injection preparations can be added with an appropriate amount of one or more of sodium chloride, glucose, glycerol, conventional cosolvents, buffers, and / or pH adjustors to the injection preparations in order to prepare isotonic injection solutions.

[0074] Further, the various preparations can also add coloring agents, preservatives, flavors, flavoring agents, sweeteners, or other materials to the pharmaceutical preparations, if necessary.

[0075] Further, the drugs for preventing and / or treating diseases caused by Mycobacterium kansasii infection can be administered by injection, cavity administration, respiratory tract administration, or mucosal administration.

[0076] Further, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavity injection, etc.; the cavity administration includes rectal or vaginal administration; the respiratory tract administration includes nasal cavity administration.

[0077] Beneficial effects

[0078] 1. The Fosmanogepix in the present application has obvious strain specificity in mycobacterium inhibition effect, and the inhibition effect of low concentration Fosmanogepix on Kansas mycobacterium (ATCC12478) is significantly higher than that of high concentration Fosmanogepix on Mycobacterium tuberculosis (ATCC 27294), abscess mycobacterium (ATCC 19977) and incident mycobacterium (ATCC 6841).

[0079] 2. The MIC of Fosmanogepix on Kansas mycobacterium standard strain (ATCC12478) is 1 μg / mL; the MIC of Fosmanogepix on clinical isolated Kansas mycobacterium strain is 2 μg / mL, and the MIC of Fosmanogepix on Kansas mycobacterium standard strain is 4 μg / mL. 50 90

[0080] 3. The present application first finds that Fosmanogepix alone acting on Kansas mycobacterium has good bacteriostatic effect, which indicates that the compound can be used as a candidate drug for the development of anti-Kansas mycobacterium infection drugs, and has important significance for preventing and treating Kansas mycobacterium disease, especially drug-resistant Kansas mycobacterium disease. DETAILED DESCRIPTION

[0081] The present application will be further described in detail below in combination with specific embodiments. The examples provided below are only for illustrating the present application, and are not intended to limit the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not constitute any limitation on the present application in any way.

[0082] In the following examples, the experimental methods are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0083] Material description:

[0084] Bacteria: Kansas mycobacterium standard strain (ATCC12478), Mycobacterium tuberculosis H37Rv (ATCC 27294), abscess mycobacterium standard strain (ATCC 19977) and incident mycobacterium standard strain (ATCC 6841) are all purchased from the American ATCC strain preservation center.

[0085] ​​Dimethyl sulfoxide (DMSO) was purchased from Solabio, item number D8371; 7H9 medium was purchased from BD, item number 212322; Alamar blue was purchased from Biorad, item number BUF012B; Tween-80 was purchased from Sigma, item number P4780-500ML.

[0086] Manogepix: purchased from MedchemExpress, item number HY-18233. Molecular formula is C 21 H 18 N4O2, molecular weight is 358.39, CAS number is 936339-60-5, and its structural formula is as follows:

[0087]

[0088] Example 1 Fosmanogepix inhibitory activity detection on standard strain of Mycobacterium kansasii

[0089] Fosmanogepix is an N-phosphoxy methyl prodrug, which is converted into an active ingredient in vivo to exert its effect. Clinical trials have shown that Fosmanogepix has a high bioavailability of more than 90%, which indicates that its conversion efficiency is very high (Shaw KJ, Ibrahim AS. Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections [J]. J Fungi (Basel). 2020 Oct 22; 6(4): 239.). Therefore, the in vitro inhibitory activity detection of Fosmanogepix selects its active ingredient Manogepix.

[0090] 1. Preparation of Manogepix solution: Manogepix was dissolved in dimethyl sulfoxide (DMSO) to prepare an 8 mg / ml Manogepix stock solution, which was filtered to remove bacteria and stored at -20°C. The Manogepix stock solution was diluted with 7H9 medium to prepare Manogepix solutions with concentrations of 64 μg / mL and 200 μg / mL, respectively. In the first column of the 96-well plate, 200 μl of Manogepix solution with a concentration of 64 μg / mL or 200 μg / mL was added, and after mixing by blowing, 100 μl was removed from the first column and added to the second column, and then sequentially diluted by gradient to the tenth column, and 100 μl was removed and discarded; 100 μl and 200 μl of 7H9 medium were added to the eleventh and twelfth columns, respectively, as control wells. Two replicate wells were set for each concentration, and three repeated experiments were performed.

[0091] 2. Preparation of bacterial suspension: Mycobacterium tuberculosis (ATCC 27294), Mycobacterium abscessus (ATCC 19977), Mycobacterium fortuitum (ATCC 6841) and Mycobacterium kansasii (ATCC 12478) were cultured in neutral Middlebrook medium to logarithmic phase, and the logarithmic phase strains were scraped and ground in a grinding bottle. The bacterial suspension was diluted with 7H9 medium and turbidimetrically to 1 McFarland, and then added to 7H9 medium at a ratio of 1:20 to mix to obtain a Mycobacterium kansasii suspension.

[0092] 3. 100 μl of bacterial suspension was added to each well of columns 1-11 and column 12 A-D, so that the final volume in each well was 200 μl, and the final concentration of the bacterial suspension was 4 x 10 5 CFU / mL. For Mycobacterium kansasii and its clinical isolates, 200 μl of Manogepixe solution with a concentration of 64 μg / mL was added to column 1 of the 96-well plate, and the final drug concentration in each well of columns 1-10 was 32 μg / mL, 16 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL, 0.5 μg / mL, 0.25 μg / mL, 0.125 μg / mL, 0.0625 μg / mL, 0.03125 μg / mL, respectively. For Mycobacterium tuberculosis, Mycobacterium abscessus and Mycobacterium fortuitum, 200 μl of Manogepixe solution with a concentration of 200 μg / mL was added to column 1 of the 96-well plate, and the final drug concentration in each well of columns 1-11 was 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL, 6.25 μg / mL, 3.125 μg / mL, 1.5625 μg / mL, 0.78125 μg / mL, 0.390625 μg / mL, 0.1953125 μg / mL, 0.09765625 μg / mL, respectively. Positive control wells (columns 12 A-D, without drug) and negative control wells (columns 12 E-H, without bacterial suspension and drug) were set up, 2 replicates were set up for each concentration, and 3 repeated experiments were performed.

[0093] 4. The 96-well plate was placed in a 37°C incubator for culture, and slow-growing Mycobacterium was cultured for 7 days, and fast-growing Mycobacterium was cultured for 3 days.

[0094] 5. 20 μL of Alamar Blue and 50 μl of 5% Tween-80 premixed color developing solution were added to the microwell plate, and the color change of the 96-well plate was observed after 24 h of continued culture at 37°C.

[0095] 6. Criteria: Blue wells = no growth, pink wells = growth, the lowest drug concentration that prevents the color change from blue to pink is the minimum inhibitory concentration (MIC) that inhibits the growth of M. tuberculosis (ATCC 27294), M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841), and M. kansasii (ATCC 12478).

[0096] The results show that Manogepix has a good inhibitory effect on M. kansasii (ATCC 27294), but has a poor inhibitory effect on the same genus of mycobacteria, M. tuberculosis (ATCC 27294), M. abscessus (ATCC 19977), and M. fortuitum (ATCC 6841). The MIC of Manogepix at a concentration of 64 μg / mL for M. kansasii (ATCC 27294) is only 1 μg / mL, but the MIC of Manogepix at a concentration of 200 μg / mL for M. fortuitum (ATCC 6841) is as high as 25 μg / mL, and for M. tuberculosis (ATCC 27294) and M. abscessus (ATCC 19977) is even 100 μg / mL. This shows that Fosmanogepix has strain specificity for mycobacterial inhibition, and has a good in vitro inhibitory effect on M. kansasii.

[0097] Table 1 MIC of Manogepix against standard mycobacteria commonly associated with disease

[0098] Strain No. Strain Name Manogepix MIC (pg / mL) ATCC 27294 Mycobacterium tuberculosis 100 ATCC 12478 Mycobacterium kansasii 1 ATCC 19977 Mycobacterium abscessus >100 ATCC 6841 Mycobacterium fortuitum 25

[0099] Example 2 Inhibitory activity of Fosmanogepix against clinical isolates of M. kansasii

[0100] According to the method in Example 1, the inhibitory activity of the test drug against 31 clinical isolates of M. kansasii was detected.

[0101] The MIC of Manogepix against the 31 clinical isolates of M. kansasii ranged from 0.0625 to 4 μg / mL, the MIC 50 = 2 μg / mL, and the MIC 90 = 4 μg / mL. This further proves that Fosmanogepix has good in vitro inhibitory activity against M. kansasii. The MIC results are shown in Table 2.

[0102] Table 2

[0103]

[0104]

Claims

1. Use of Fosmanogepix in the manufacture of a product for inhibiting Mycobacterium kansasii, said product comprising Fosmanogepix or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof.

2. Use according to claim 1, said product for inhibiting Mycobacterium kansasii comprising one or more of a medicament and / or a bacteriostatic agent.

3. Use of Fosmanogepix, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease caused by a M. kansasii infection; wherein, Fosmanogepix exerts its effect by: 1) fosmanogepix inhibiting Mycobacterium kansasii activity; 2) fosmanogepix killing Mycobacterium kansasii.

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