Composition for preventing, alleviating, or treating nontuberculous mycobacteria infection, comprising thiopeptide compound

Abstract

The present invention relates to a composition for preventing, alleviating, or treating nontuberculous mycobacteria infection, the composition comprising a thiopeptide compound. A composition according to one aspect of the present invention can prevent, alleviate, or treat infections or infectious diseases caused by nontuberculous mycobacteria.

Description

Composition for preventing, improving or treating nontuberculous mycobacterial infections comprising a thiopeptide compound

[0001] The present invention relates to a composition for preventing, improving or treating nontuberculous mycobacterial infections, comprising a thiopeptide compound.

[0002] Mycobacterium species are divided into two groups based on their degree of pathogenicity and infectivity to the host: the tuberculosis group, which includes Mycobacterium tuberculosis and Mycobacterium leprae, which are obligate pathogens, and the nontuberculous mycobacteria (NTM), which are opportunistic pathogens.

[0003] The above nontuberculous mycobacteria are widely distributed in nature, such as soil and water, and the virulence of causing diseases varies depending on the species. To date, more than 200 species have been reported, and specifically, M. kansasii, M. avium complex, and M. abscessus have relatively high virulence, while M. fortuitum has relatively low virulence. Diseases caused by nontuberculous mycobacteria present with four characteristic clinical signs: pulmonary disease, lymphadenitis, skin, soft tissue, and bone infections, and disseminated disease.

[0004] Reports of lung disease caused by nontuberculous mycobacteria have been increasing since 2000, and lung disease caused by M. avium complex is currently the most frequently reported causative agent in most developed countries. Furthermore, while relatively rare overseas, M. abscessus is reported as the second most common causative agent in Korea. In particular, many cases in Korea have been reported to be caused by M. avium complex and M. abscessus (or M. abscessus complex). Lung disease caused by infection with these nontuberculous mycobacteria is common in middle-aged or older nonsmoking women, and presents with symptoms such as cough, fever, hemoptysis, and sputum production.

[0005] For patients with lung disease caused by nontuberculous mycobacteria, treatment is administered for at least 12 months using rifampin (RIF), a tuberculosis treatment, and a macrolide such as clarithromycin (CLR) or azithromycin (AZM), and ethambutol (EMB) in combination according to the ATS / IDSA and BTS guidelines. It is also recommended to administer it for at least 12 months even after successful bacteriological conversion. However, even with long-term treatment, the treatment response is poor, with a treatment success rate of only about 50-60%, and a relapse rate as high as 30% has been reported in patients who were successfully treated. Since the currently used antibiotic treatment drugs spread throughout the body after administration, they are accompanied by side effects such as nephrotoxicity, ototoxicity, gastrointestinal disorders, and optic neuropathy. Even with rifampicin and ethambutol, the efficacy and mechanism of action in controlling bacteria are not clearly known, and resistance to macrolides frequently develops even with triple-drug therapy. Efforts are underway in various research fields to develop new antibiotics.

[0006] One object of the present invention is to provide a pharmaceutical composition for preventing or treating infection or infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound or a pharmaceutically acceptable salt thereof; and an antibiotic; as active ingredients.

[0007] Another object of the present invention is to provide a composition for enhancing the susceptibility of nontuberculous mycobacteria to drugs, comprising a thiopeptide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] Another object of the present invention is to provide a composition for overcoming drug-resistant non-tuberculous mycobacteria resistance, comprising a thiopeptide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Another object of the present invention is to provide a composition for preventing, improving or treating infection or infectious disease caused by nontuberculous mycobacteria, which comprises a thiopeptide compound or a pharmaceutically acceptable salt thereof as an active ingredient and replaces existing combination drugs.

[0010] Another object of the present invention is to provide a composition for preventing, improving or treating infection or infectious disease caused by drug-resistant nontuberculous mycobacteria, comprising a thiopeptide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0012] One aspect of the present invention provides a pharmaceutical composition for preventing or treating infection or infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients.

[0013] [Chemical Formula 1]

[0014]

[0015] In the above chemical formula 1,

[0016] Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene;

[0017] Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-;

[0018] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl;

[0019] A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4;

[0020] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene;

[0021] R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

[0022] The above thiopeptide compound can be represented by the following chemical formula 2.

[0023] [Chemical Formula 2]

[0024]

[0025] A1 is or , R' is C1-C10 alkyl, and p is an integer from 0 to 2;

[0026] R1 is hydrogen or C1-C10 alkyl;

[0027] D1 is CH or N;

[0028] D2 is O, S, SO2, C(R b1 )(R b2 ) or NR c1 and;

[0029] R b1 , R b2and R c1 are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid group, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, haloC6-C20 aryl, HaloC1-C10alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C10alkoxycarbonylC1-C10alkyl or carboxylic acidC1-C10alkyl;

[0030] n is an integer from 0 to 5.

[0031] The above thiopeptide compound may be selected from the following structures.

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] The above nontuberculous mycobacteria are Mycobacterium avium, Mycobacterium aviumcomplex (MAC), Mycobacterium abscessus, Mycobacterium abscessus complex, Mycobacterium flavescence, Mycobacterium chelonae, Mycobacterium celatum, Mycobacterium fortuitum, Mycobacterium gordonae, Mycobacterium gastri, Mycobacterium haemophilum, Mycobacterium intracellulare. intracellulare), Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium massiliense, Mycobacterium marinum, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium scrofulaceum, Mycobacterium ulcerans, Mycobacterium simiae, Mycobacterium osloensis, Mycobacterium phlei, Mycobacterium smegmatis,It may be selected from the group consisting of Mycobacterium mucogenicum, Mycobacterium peregrinum, Mycobacterium wolinskyi and Mycobacterium xenopi.

[0038] The above antibiotics are rifampin, rifapentine, isoniazid, pyrazinamide, ethambutol, streptomycin, fluoroquinolone, kanamycin, cycloserine, prothionamide, levofloxacin, moxifloxacin, ofloxacin, rifabutin, capeomycin, amikacin, tobramycin, imipenem, doxycycline, cefoxitin, ciprofloxacin, protionamide, It may be one or more selected from the group consisting of ethionamide, cycloserine, thioacetazone, clofazimine, amoxicillin / clavulanate, derivatives of dianomidiphenylsulphone, bedaquiline, linezolid, and macrolide antibiotics.

[0039] The above antibiotic may be a macrolide antibiotic.

[0040] The above macrolide antibiotic may be one or more selected from the group consisting of erythromycin, clarithromycin, dirithromycin, roxithromycin, azithromycin, josamycin, midecamycin, rokitamycin, and spiramycin.

[0041] The infectious disease caused by the above nontuberculous mycobacteria may be at least one selected from the group consisting of lung disease, lymphadenitis, skin, soft tissue, and bone infection, and disseminated disease.

[0042] The above pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0043] Another aspect of the present invention provides a composition for enhancing the susceptibility of nontuberculous mycobacteria to drugs, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0044] Another aspect of the present invention provides a composition for overcoming drug-resistant non-tuberculous mycobacteria resistance, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0045] Another aspect of the present invention provides a composition for preventing, improving or treating an infection or infectious disease caused by drug-resistant non-tuberculous mycobacteria, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0046] Another aspect of the present invention provides a pharmaceutical composition for preventing infection or recurrence of an infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients.

[0047] According to the present invention, a thiopeptide compound having a specific structure can not only increase the susceptibility of nontuberculous mycobacteria to drugs, particularly antibiotics, thereby reducing the dosage of the drugs, but can also replace existing combination drugs that do not have an inhibitory effect on nontuberculous mycobacteria, thereby bringing about a better inhibitory effect on nontuberculous mycobacteria, and further, can effectively inhibit the growth or proliferation of nontuberculous mycobacteria resistant to drugs, thereby preventing, improving, or treating infections or infectious diseases caused by the nontuberculous mycobacteria.

[0048] In one aspect, the thiopeptide compound exhibits a synergistic effect when used in combination with a macrolide antibiotic, and can exhibit excellent therapeutic effects even at a lower dose compared to a high-dose single antibiotic, and can replace existing combination drugs (e.g., rifampicin, ethambutol, etc.).

[0049] Furthermore, the combination composition comprising the thiopeptide compound exhibits tissue protection and inflammation-relieving effects that significantly reduce the area of ​​infectious lesions when used together with a macrolide antibiotic, and can be utilized as an effective means for preventing, improving, treating, or preventing recurrence of infections or infectious diseases caused by nontuberculous mycobacteria.

[0050] Figure 1 shows the results of analyzing the minimum inhibitory concentration (MIC) of two standard strains, two clinical strains, and two nontuberculous mycobacterial clinical strains with a macrolide resistance gene mutation site in Example 1 by treating AJ-099. In this case, clarithromycin (CLR), an antibiotic of the macrolide series, was used as a control.

[0051] Figure 2 shows the results of confirming the degree of inhibition of growth of intracellular nontuberculous mycobacteria when macrolide-based standard antibiotics such as clarithromycin (CLR), rifampin (RIF), or ethambutol (EMB) were treated for 3 days in macrophage cells in Example 2.

[0052] Figure 3A shows the results of confirming the degree of growth inhibition of intracellular nontuberculous mycobacteria after infecting macrophage cells with two standard strains of nontuberculous mycobacteria susceptible to macrolides in Example 3, and treating them with clarithromycin (CLR) or AJ-099 for 3 days to confirm the intracellular effect of AJ-099.

[0053] Figure 3B shows the results of examining the degree of inhibition of growth of intracellular macrolide-resistant non-tuberculous mycobacteria after infecting macrophage cells with two types of macrolide-resistant strains in Example 3 and treating them with clarithromycin (CLR) or AJ-099 for 3 days to confirm the intracellular effect of AJ-099.

[0054] Figure 4 shows the results of Example 4, in which two types of non-tuberculous mycobacterial standard strains were infected into macrophage cells, and then AJ-099 was used in combination with clarithromycin (CLR) for 3 days, and the degree of inhibition of growth of intracellular non-tuberculous mycobacteria was confirmed compared to treatment alone.

[0055] Figure 5 shows the results of confirming the growth inhibition effect of nontuberculous mycobacteria according to the concentration-dependent effect of clarithromycin (CLR) alone and the combined treatment with AJ-099 in large macrophage cells in Example 5.

[0056] Figure 6A schematically illustrates the experimental design of Example 6.

[0057] Figure 6B is a graph showing the results of measuring the number of nontuberculous mycobacteria in the lung and spleen tissues of mice infected with nontuberculous mycobacteria after co-administration of AJ-099 and clarithromycin (CLR) in Example 6.

[0058] Figure 7 shows the results of histopathological analysis of lesions in lung tissue of mice infected with nontuberculous mycobacteria after combined administration of AJ-099 and clarithromycin (CLR) in Example 6, using H&E staining.

[0059] Figure 8 shows the relative ratio of the number of nontuberculous mycobacteria in the lung tissue of mice infected with nontuberculous mycobacteria by combined administration of AJ-099 and clarithromycin (CLR) and administration of clarithromycin (CLR) at different concentrations in Example 7.

[0060] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0061] As used herein, the singular forms may be intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0062] Throughout this specification, the terms "comprises," "includes," "contains," or "has" a component, unless specifically stated to the contrary, do not exclude other components, but rather may include other components, and do not exclude additional unrecited elements, materials, or processes.

[0063] The numerical ranges used herein include the lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of the upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specified herein, values ​​outside the defined range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0064] Unless otherwise specified herein, “about” may be considered a value within 30%, 25%, 20%, 15%, 10% or 5% of the stated value.

[0065] The following terms used in this specification are defined as follows, but are for illustrative purposes only and are not intended to limit the invention, application, or use.

[0066] The terms "subject" and "subject" as used herein are animals (e.g., cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs), preferably mammals such as non-primates and primates (e.g., monkeys and humans), and most preferably humans.

[0067] As used herein, "effective amount" refers to an amount of a compound sufficient to provide a therapeutic benefit in the treatment or management of an infection or infectious disease caused by nontuberculous mycobacteria. An "effective amount" also refers to an amount sufficient to treat and prevent an infection or infectious disease caused by nontuberculous mycobacteria, either in vitro or in vivo. An "effective amount" can be readily determined by one of ordinary skill in the art based on factors including the patient's sex, age, weight, and health status, the type and severity of the infectious disease caused by nontuberculous mycobacteria, the activity and sensitivity of the drug, the method of administration, the time of administration, the route of administration, and the excretion rate, the duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field.

[0068] The term "pharmaceutically acceptable" as used herein means suitable for use in pharmaceutical preparations, generally considered safe for such use, and officially approved by a national regulatory agency for such use or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0069] Below, the present disclosure will be described in detail. However, this is merely exemplary and the present disclosure is not limited to the specific embodiments described as examples.

[0070] One aspect of the present invention provides a pharmaceutical composition for preventing or treating infection or infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients.

[0071] [Chemical Formula 1]

[0072]

[0073] In the above chemical formula 1,

[0074] Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene;

[0075] Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-;

[0076] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl;

[0077] A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4;

[0078] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene;

[0079] R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

[0080] The thiopeptide compound of the above chemical formula 1 is a compound described in WO2022-108354 A1 filed by the present applicant, and is known to inhibit protein synthesis by simultaneously binding to 23S rRNA of the 50S subunit and ribosomal protein L11 and suppressing the function of elongation factor G (EF-G).

[0081] The above thiopeptide compound can effectively prevent, improve or treat nontuberculous mycobacteria.

[0082] In the above chemical formula 1, Ar1 and Ar2 are each independently C3-C20 heteroarylene; Z1 is a single bond or -CONR1-; Z2 is a single bond, -CONR1-, -NR2CO- or -COO-; Z3 is a single bond, -NR2CO-, -NR5COO-, -NR6- or -S-; R1, R2, R5 and R6 are independently hydrogen, hydroxy or C1-C10 alkyl; A1 is or , R' is hydrogen or C1-C10 alkyl, p is an integer from 0 to 2; A2 is a single bond or C1-C10 alkylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; The alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of the above R is halogen, amino, nitro, hydroxy, carboxylic acid group, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, It may be further substituted with one or more selected from the group consisting of haloC6-C20aryl, haloC1-C10alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C10alkoxycarbonylC1-C10alkyl and carboxylic acidC1-C10alkyl.

[0083] In the above chemical formula 1, Ar1 and Ar2 are independently thiazolilene ( ) and Z1 is -CONH-; Z2 is -CONR1-; Z3 is a single bond; R1 is hydrogen or C1-C10 alkyl; A1 is or , R' is C1-C10 alkyl, p is an integer from 0 to 2; A2 is a single bond or C1-C10 alkylene; R is C3-C10 heterocycloalkyl; The heterocycloalkyl of the above R is halogen, amino, nitro, hydroxy, carboxylic acid group, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, haloC6-C20 aryl, It may be further substituted with one or more selected from the group consisting of haloC1-C10alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C10alkoxycarbonylC1-C10alkyl and carboxylic acidC1-C10alkyl.

[0084] Specifically, the thiopeptide compound can be represented by the following chemical formula 2.

[0085] [Chemical Formula 2]

[0086]

[0087] In the above chemical formula 2,

[0088] A1 is or , R' is C1-C10 alkyl, and p is an integer from 0 to 2;

[0089] R1 is hydrogen or C1-C10 alkyl;

[0090] D1 is CH or N;

[0091] D2 is O, S, SO2, C(R b1 )(R b2 ) or NR c1 and;

[0092] R b1 , R b2 and R c1 are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid group, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, haloC6-C20 aryl, HaloC1-C10alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C10alkoxycarbonylC1-C10alkyl or carboxylic acidC1-C10alkyl;

[0093] n is an integer from 0 to 5.

[0094] Specifically, in the above chemical formula 2, A1 is or , R' is C1-C10 alkyl, p is an integer of 0 or 1; D1 is N; D2 is O, S or NR c1 and R1 is hydrogen; R c1 is hydrogen, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonylC1-C10 alkyl or carboxylic acidC1-C10 alkyl; n can be an integer from 0 to 5.

[0095] More specifically, in the above chemical formula 2, A1 is or , R' is C1-C10 alkyl, p is an integer of 0 or 1; D1 is N; D2 is O, S or NR c1 and R1 is hydrogen; R c1 is hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C3-C10 cycloalkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; n can be an integer from 1 to 3.

[0096] The above thiopeptide compound may be selected from the following structures, but is not necessarily limited thereto.

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] The pharmaceutically acceptable salts may be salts generally considered by those skilled in the art to be suitable for medical applications (e.g., because such salts are not harmful to the subject to be treated with the salts), or salts that cause acceptable side effects within the respective treatment. Typically, the pharmaceutically acceptable salts may be salts considered acceptable by regulatory authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Health, Labour and Welfare of Japan. However, the present invention may also, in principle, include salts of the compounds of the present invention that are not pharmaceutically acceptable in themselves, for example, as intermediates in the preparation of the compounds of the present invention or physiologically functional derivatives thereof, or as intermediates in the preparation of pharmaceutically acceptable salts of the compounds of the present invention or physiologically functional derivatives thereof. The salts may include water-insoluble salts, and in particular, water-soluble salts.

[0103] For example, the salt may be an acid addition salt or a salt with a base, particularly a pharmaceutically acceptable inorganic acid and organic acid addition salt and a salt with a base commonly used in pharmacy, which may be a water-insoluble or particularly a water-soluble acid addition salt. Examples of pharmaceutically acceptable acid addition salts include those derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, ascorbic acid and their analogs, as well as those derived from acids such as hydrogen chloride, hydrogen bromide, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide or Salts derived from phosphorous acid and its analogs are included. Salts of amino acids, such as alginate and its analogs, and analogs of organic acids, such as glucuronic or galactunoric acids and their analogs may also be included. Examples of pharmaceutically acceptable base addition salts may also include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium, and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates, and aryl sulfonates).

[0104] The above nontuberculous mycobacteria (NTM) refers to all mycobacteria other than Mycobacerium tuberculousis complex and Mycobacterium laprae, for example, Mycobacterium avium, Mycobacterium avium complex (MAC), Mycobacterium abscessus, Mycobacterium abscessus complex, Mycobacterium flavescence, Mycobacterium chelonae, Mycobacterium celatum, Mycobacterium fortuitum, Mycobacterium Mycobacterium gordonae, Mycobacterium gastri, Mycobacterium haemophilum, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium massiliense, Mycobacterium marinum, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium scrofulaceum, Mycobacterium ulcerans, Mycobacterium simiae,It may be selected from the group consisting of, but is not limited to, Mycobacterium osloensis, Mycobacterium phlei, Mycobacterium smegmatis, Mycobacterium mucogenicum, Mycobacterium peregrinum, Mycobacterium wolinskyi and Mycobacterium xenopi.

[0105] The above Mycobacterium avium complex is the most common slow-growing mycobacterium causing nontuberculous mycobacterial lung disease, and may include, but is not limited to, Mycobacterium aviumsubsp.Paratuberculosis, Mycobacterium aviumsubsp.Hominisuis, or Mycobacterium intracellulare.

[0106] The above Mycobacterium abscessus or Mycobacterium abscessus complex is a common rapid-growing mycobacterium that causes nontuberculous mycobacterial lung disease, and may include, but is not limited to, Mycobacterium abscessussubsp.abscessus, Mycobacterium abscessussubsp.bolletii, and Mycobacterium abscessussubsp.massiliense.

[0107] The above antibiotics include rifampin, rifapentine, isoniazid, pyrazinamide, ethambutol, streptomycin, fluoroquinolone, kanamycin, cycloserine, prothionamide, levofloxacin, moxifloxacin, ofloxacin, rifabutin, capeomycin, amikacin, ciprofloxacin, protionamide, ethionamide, tobramycin, imipenem, doxycycline, It may be one or more selected from the group consisting of cefoxitin, cycloserine, thioacetazone, clofazimine, amoxicillin / clavulanate, derivatives of dianomidiphenylsulphone, bedaquiline, linezolid, and macrolide antibiotics.

[0108] The above antibiotic may be a macrolide antibiotic, and specifically, one or more selected from the group consisting of erythromycin, clarithromycin, dirithromycin, roxithromycin, azithromycin, josamycin, midecamycin, rokitamycin, and spiramycin may be exemplified, but is not limited thereto.

[0109] The above macrolide antibiotics are representative treatments for respiratory infections, and are called macrolide antibiotics because they contain a macrocyclic lactone ring. Depending on their structure, macrolides are classified into 14-membered (erythromycin, clarithromycin, dirithromycin, roxithromycin), 15-membered (azithromycin), and 16-membered (josamycin, midecamycin, rokitamycin, spiramycin).

[0110] Another aspect of the present invention provides a composition for enhancing the susceptibility of nontuberculous mycobacteria to drugs, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0111] The above drug may be an antibiotic, and the specific type of antibiotic is as described above.

[0112] The above "susceptibility" can be used interchangeably with "sensitivity," and is the opposite concept of antibiotic resistance induced by antibiotic use, and refers to a state in which the therapeutic effect of antibiotics can be exerted as intended. As used herein, "enhanced susceptibility" includes a state that can be quantitatively evaluated through indicators such as a decrease in the minimum inhibitory concentration (MIC) in response to an antibiotic or an increase in the duration of antibacterial action. Furthermore, enhanced susceptibility also includes a phenomenon in which the survival rate of pathogens existing within a cell is reduced or the bactericidal effect of an antibiotic within a cell is enhanced.

[0113] When the above thiopeptide compound or a pharmaceutically acceptable salt thereof is used in combination with an existing antibiotic, the susceptibility or sensitivity of nontuberculous mycobacteria causing nontuberculous mycobacterial infections to antibiotics is increased, thereby more effectively inhibiting the proliferation and growth of nontuberculous mycobacteria compared to when used alone. Compared to high doses of existing antibiotics, when the thiopeptide compound or a pharmaceutically acceptable salt thereof is used in combination with a low dose of existing antibiotics, a synergistic effect is exerted in the treatment, which can significantly improve the efficiency of inhibiting the growth and proliferation of nontuberculous mycobacteria. Such combination therapy can also contribute to reducing side effects due to a reduction in antibiotic dosage and improving patient compliance with treatment.

[0114] Another aspect of the present invention provides a composition for overcoming resistance of drug-resistant non-tuberculous mycobacteria, comprising a thiopeptide compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0115] The above "overcoming resistance" refers to the action of increasing the susceptibility of nontuberculous mycobacteria that have acquired resistance to a specific drug to the drug. For the purposes of the present invention, the specific drug may refer to an antibiotic. The increase in susceptibility refers to the degree in which the concentration that exhibits an effect such as growth inhibition on nontuberculous mycobacteria that have acquired resistance is increased to the same or greater extent than the concentration that exhibits an effect such as growth inhibition on nontuberculous mycobacteria that do not have resistance. Synonyms for the above resistance overcoming include "resistance suppression," "resistance release," or "resistance release."

[0116] According to one embodiment, a composition for overcoming resistance can significantly improve the effect of overcoming resistance by further including one or more types of antibiotics. Here, the antibiotics include, for example, rifampin, rifapentine, isoniazid, pyrazinamide, ethambutol, streptomycin, fluoroquinolone, kanamycin, cycloserine, prothionamide, levofloxacin, moxifloxacin, ofloxacin, rifabutin, capeomycin, amikacin, tobramycin, imipenem, doxycycline, cefoxitin, ciprofloxacin, protionamide, It may be ethionamide, cycloserine, thioacetazone, clofazimine, amoxicillin / clavulanate, derivative of dianomidiphenylsulphone, erythromycin, clarithromycin, dirithromycin, roxithromycin, azithromycin, josamycin, midecamycin, rokitamycin, spiramycin, bedaquiline or linezolid, etc., and preferably rifampin, ethambutol,It may be at least one selected from the group consisting of rifapentine, rifabutin, bedaquiline, amikacin, moxifloxacin and clofazimine, and more preferably at least one selected from the group consisting of rifabutin, bedaquiline, amikacin and clofazimine, but is not limited thereto.

[0117] Treatment with the above thiopeptide compound or a pharmaceutically acceptable salt thereof increases susceptibility to drugs, specifically antibiotics, thereby inhibiting or killing the growth of resistant nontuberculous mycobacteria, thereby restoring the effectiveness of the antibiotics. This restoration of susceptibility ultimately enables the overcoming of drug resistance.

[0118] Another aspect of the present invention provides a composition for preventing, improving or treating an infection or infectious disease caused by nontuberculous mycobacteria, which comprises a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and replaces a companion drug used in conventional combination therapy.

[0119] Here, "combination therapy" typically consists of a core drug that exhibits the main therapeutic effect and a companion drug used together to complement the effect or suppress the development of drug resistance. Macrolide antibiotics are representative core drugs used in the treatment of nontuberculous mycobacteria, and "companion drug" in this specification means a concomitant drug other than the core drug, macrolide antibiotic, used in combination with the core drug, i.e., a companion drug administered in combination.

[0120] The above auxiliary drugs may preferably include, but are not limited to, one or more selected from the group consisting of rifampin, ethambutol, rifapentine, rifabutin, bedaquiline, amikacin, moxifloxacin, and clofazimine.

[0121] However, most currently used adjuvants have limitations: their efficacy in inhibiting the growth and proliferation of nontuberculous mycobacteria, or their mechanisms of action, are not clearly understood. Therefore, the thiopeptide compound of the present invention is a novel candidate for combination use that can replace existing adjuvants, and is expected to exhibit excellent therapeutic effects when used in combination with core drugs.

[0122] When the thiopeptide compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof is used in combination with a macrolide series antibiotic, which is a key drug, the efficiency of inhibiting the growth and proliferation of nontuberculous mycobacteria can be significantly improved, and it can be used as a composition for preventing, improving, or treating infection or infectious disease caused by nontuberculous mycobacteria.

[0123] Another aspect of the present invention provides a composition for preventing, improving or treating an infection or infectious disease caused by drug-resistant non-tuberculous mycobacteria, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0124] According to one embodiment, the composition may further comprise one or more antibiotics, thereby enhancing the preventive effect, inhibiting the progression, or significantly improving the therapeutic effect against the infection or infectious disease. Here, the antibiotics include, for example, rifampin, rifapentine, isoniazid, pyrazinamide, ethambutol, streptomycin, fluoroquinolone, kanamycin, cycloserine, prothionamide, levofloxacin, moxifloxacin, ofloxacin, rifabutin, capeomycin, amikacin, tobramycin, imipenem, doxycycline, cefoxitin, ciprofloxacin, protionamide, It may be ethionamide, cycloserine, thioacetazone, clofazimine, amoxicillin / clavulanate, derivatives of dianomidiphenylsulphone, erythromycin, clarithromycin, dirithromycin, roxithromycin, azithromycin, josamycin, midecamycin, rokitamycin, spiramycin, bedaquiline, or linezolid.Preferably, it may be at least one selected from the group consisting of rifampin, ethambutol, rifapentine, rifabutin, bedaquiline, amikacin, moxifloxacin, and clofazimine, and more preferably, it may be at least one selected from the group consisting of rifabutin, bedaquiline, amikacin, and clofazimine, but is not limited thereto.

[0125] The composition according to one aspect shows a superior combined effect compared to antibiotics alone against infections or infectious diseases caused by non-tuberculous mycobacteria showing drug resistance, and the composition can prevent the progression of infection by inhibiting the proliferation of pathogens in the early stage of infection, and in the case of advanced infection, can simultaneously show symptom relief (improvement) and fundamental treatment effects.

[0126] Another aspect of the present invention provides a pharmaceutical composition for preventing infection or recurrence of an infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients.

[0127] The above “recurrence” refers to a phenomenon in which infection occurs again by non-tuberculous mycobacteria after a certain period of time has passed since the end of treatment and clinical symptoms have disappeared.

[0128] In one embodiment, the combination of the thiopeptide compound or a pharmaceutically acceptable salt thereof and an antibiotic can effectively prevent reinfection or reactivation of infection by suppressing the possibility of nontuberculous mycobacteria remaining or reproliferating even after the end of treatment. This composition can be useful for long-term maintenance therapy or infection control strategies for high-risk patients.

[0129] In the compositions according to the above-described aspect, the infectious disease caused by the nontuberculous mycobacteria includes all clinical symptoms exhibited by infection with the nontuberculous mycobacteria, and the infectious disease may include lung disease, lymphadenitis, skin / soft tissue / bone infection, or disseminated disease, depending on the site of occurrence and symptoms.

[0130] The infectious lung disease caused by the above nontuberculous mycobacteria may be of the fibrocavitary form, the nodular bronchiectatic form, or a combination thereof. In addition, the infectious lung disease may be accompanied by cough, sputum, bloody sputum, fever, dyspnea, chest pain, or a combination thereof.

[0131] The compositions according to the above-described aspect may further comprise a pharmaceutically acceptable carrier.

[0132] The above “prevention” may include, without limitation, any act of blocking, suppressing or delaying symptoms caused by infection or infectious disease caused by non-tuberculous mycobacteria by using compositions according to the above-described aspect.

[0133] The above “improvement” and “treatment” may include, without limitation, any act of improving or benefiting symptoms caused by infection or infectious disease caused by nontuberculous mycobacteria by using the compositions according to the above-described aspect.

[0134] In the compositions according to the above-described aspect, by treating the thiopeptide compound or a pharmaceutically acceptable salt thereof, not only can drug sensitivity be increased, thereby reducing the dosage of the drug, but also, by replacing existing auxiliary drugs for combined administration, a superior inhibitory effect on nontuberculous mycobacteria can be achieved, and the recurrence of infections or infectious diseases caused by nontuberculous mycobacteria can be prevented. Furthermore, infections or infectious diseases caused by the drug-resistant nontuberculous mycobacteria can be effectively prevented, improved, or treated.

[0135] The composition for each purpose provided in the present invention can be used as a pharmaceutical composition or a food composition, but its form is not particularly limited.

[0136] The pharmaceutical composition may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being intended for humans.

[0137] The pharmaceutical composition may be formulated in the form of an oral dosage form, an external preparation, a suppository, or a sterile injectable solution. The oral dosage form may be in the form of a powder, granules, tablets, capsules, suspensions, emulsions, syrups, inhalants, or aerosols, and the above dosage forms may be manufactured according to conventional methods. The pharmaceutical composition may be formulated as a preparation for oral inhalation or intranasal administration. Preparations for oral inhalation administration may be administered as a liquid or powder composition using an inhalation device such as a metered dose inhaler (MDI), a dry powder inhaler (DPI), a jet nebulizer, a mesh nebulizer, or an ultrasonic nebulizer. Preparations for intranasal administration may be administered as a liquid or powder composition using a pressurized metered dose nebulizer, a dry powder nebulizer, a dropping container, or the like.

[0138] The pharmaceutical composition may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, and fragrances for oral administration, and may include a mixture of buffers, preservatives, analgesics, solubilizers, isotonic agents, and stabilizers for injections. For topical administration, a base, excipients, lubricants, and preservatives may be used, but are not limited thereto. The dosage form of the pharmaceutical composition of the present invention may be prepared in various ways by mixing it with the pharmaceutically acceptable carriers described above. For example, for oral administration, it may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, and for injections, it may be prepared in the form of unit dose ampoules or multiple doses. Others can be formulated as solutions, suspensions, tablets, capsules, sustained-release, spray, and inhalation preparations.

[0139] Examples of carriers, excipients and diluents suitable for the above formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be additionally included.

[0140] The route of administration of the above pharmaceutical composition may include, but is not limited to, oral, inhalational, intrapulmonary, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.

[0141] The above “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0142] For example, the active ingredient of the composition, the thiopeptide compound or a pharmaceutically acceptable salt thereof, and the antibiotic may be contained in a single or separate unit dosage form, and may be administered simultaneously, sequentially at a set time interval, or without a time interval. Accordingly, the two active ingredients may be independently formulated by combining them together or separately with a pharmaceutically acceptable carrier depending on the purpose of administration.

[0143] The pharmaceutical composition may vary depending on various factors including the activity of the active ingredient, age, body weight, general health, sex, dosage form, administration method, administration time, administration route, excretion rate, drug combination, and severity of the disease, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route, and period, but may be appropriately selected by a person skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. The administration may be administered once a day or in several divided doses. For example, the thiopeptide compound or a pharmaceutically acceptable salt thereof may be administered at a daily dose of 0.1 to 10 mg / kg, and the antibiotic may be administered at a daily dose of 0.1 to 10 mg / kg, once or in several divided doses. However, the number of administrations and the dosage do not limit the scope of the present invention in any way, and any level acceptable in the art may be used. The above pharmaceutical composition can be formulated as a pill, a sugar-coated tablet, a capsule, a liquid, a gel, a syrup, a slurry, a suspension, or an inhalant.

[0144] The above food composition can be manufactured in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, etc.

[0145] When the effective ingredient of the above composition is included in a food composition, the amount may be added in a ratio of 0.1 to 50% of the total weight, but is not limited thereto.

[0146] When the above food composition is manufactured in the form of a beverage, there are no special restrictions other than including the food composition in the indicated proportion, and various flavoring agents or natural carbohydrates, etc. may be contained as additional ingredients like a typical beverage. Specifically, the natural carbohydrates may include monosaccharides such as glucose, disaccharides such as fructose, sucrose, and other polysaccharides, dextrin, cyclodextrin, and other typical sugars, and sugar alcohols such as xylitol, sorbitol, and erythritol. The flavoring agents may include natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.).

[0147] The above food composition may further include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0148] The ingredients included in the above food composition may be used independently or in combination. The proportion of the additives is not a key element of the present invention, but may be selected within the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

[0149] Another aspect of the present invention provides a method for treating an infection or infectious disease caused by nontuberculous mycobacteria, comprising administering to a subject in need of treatment for an infection or infectious disease caused by nontuberculous mycobacteria a thiopeptide compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic.

[0150] The specific examples of the above thiopeptide compounds and antibiotics are the same as those described above, so further description is omitted.

[0151] The above thiopeptide compound and antibiotic may be administered simultaneously, sequentially, or non-simultaneously.

[0152] The above thiopeptide compound and antibiotic may be administered simultaneously, in the same dosage form or in separate dosage forms.

[0153] The above thiopeptide compound and antibiotic may be administered non-simultaneously, independently, more than once daily, specifically at the same daily dosing frequency or at different daily dosing frequencies.

[0154] The above thiopeptide compound and antibiotic may be formulated together or separately as described above and administered according to the administration route described above.

[0155] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0156] Example

[0157] [Preparation Example 1] Method for culturing strains

[0158] The standard strains M. avium ATCC 700898 and M. intracellulare ATCC 13950 were used, and four clinical strains including macrolide-resistant strains were provided by Samsung Medical Center in Seoul and the following experiments were conducted. Before conducting the drug susceptibility test, the liquid medium for culturing the standard strain and clinical strains was Middlebrook 7H9 medium containing 10% OADC, and the strains were cultured at 37℃ with shaking after inoculation into the medium. The culture of nontuberculous mycobacteria was cultured until the absorbance at 600 nm reached 0.3 to 0.5, and the drug susceptibility test was conducted when the absorbance at 600 nm was 0.01 (approximately 5 × 10 5 It was diluted to 10 CFU / ml and used.

[0159] [Preparation Example 2] Differentiation into bone marrow-derived macrophages

[0160] After isolating bone marrow cells from the mouse bone marrow, differentiation medium was prepared by adding 10% L929 cell line culture medium to high glucose DMEM (Biowest, France) culture medium containing 10% fetal bovine serum (Biowest, France) and 1% penicillin / streptomycin (Biowest, France). Then, 10 ml of the differentiation medium was placed in a 90 × 15 mm petri dish (SPL life science, Korea) and cultured for 3 days in an incubator under 5% CO2 and 37 °C conditions. Macrophage cells were obtained by adding an additional 10 ml of the differentiation medium to the petri dish and further culturing for 6 or 7 days. When using the macrophage cells obtained in this way in the following experiments, the macrophage cells were detached using trypsin-EDTA (Biowest, France) and then 1.5 × 10 were seeded into each well of a 48-well cell culture plate. 5 The cells were seeded in the appropriate number and cultured for 24 hours to ensure sufficient attachment of the macrophage cells to the plate.

[0161] [Preparation Example 3] Preparation of 7H10 solid medium for strain cultivation

[0162] In a 1 L Erlenmeyer flask, 9.5 g of DifcoTM Middlebrook 7H10 agar powder (BD bioscience, USA) was added, 450 mL of distilled water was added, and mixed well. After sterilization using an autoclave at 121 °C for 15 minutes, the mixture was cooled sufficiently to 60 °C, 50 mL of OADC (Oleic Acid + Albumin + Dextrose + Catalase; BD bioscience, USA) was added, and 23 mL was poured into a 90 × 15 mm petri dish (SPL life science, Korea). The mixture was left at room temperature for one day to solidify sufficiently, and then refrigerated until used in future experiments.

[0163] [Example 1] Determination of the Minimum Inhibitory Concentration of a Thiopeptide Compound in Nontuberculous Mycobacteria through Drug Susceptibility Testing

[0164] For drug sensitivity testing, a compound having the following structure (hereinafter referred to as 'AJ-099') was used as a thiopeptide compound.

[0165] (AJ-099)

[0166] In order to confirm the minimum inhibitory concentration of AJ-099 of the strains prepared according to the above Preparation Example 1, AJ-099 was treated and the liquid dilution method was performed based on the CLSI (Clinical and laboratory standards institute) guidelines and the liquid medium colorimetric method (Resazurin microtiter assay: REMA). Specifically, the antibiotic susceptibility test of nontuberculous mycobacteria was performed using the liquid dilution method using 7H9 liquid medium, and the macrolide antibiotic clarithromycin (CLR) was used as a control group and the experiment was conducted with clarithromycin (CLR) and AJ-099 in a concentration range of 0.125 to 64 ug / ml. Clarithromycin (CLR) and AJ-099 were prepared in 2x and dispensed into each well of a 96-well plate at 100 ul, and the absorbance at 600 nm was 0.01 (approximately 5 × 10 5 The strains diluted to 10 CFU / ml were additionally inoculated at 100 μl per well and cultured for one week at 37°C. At this time, a group in which only the medium without inoculation of nontuberculous mycobacteria and drugs was cultured (Negative Control group; N) as a negative control group, a group in which only nontuberculous mycobacteria were cultured (Postive Control group; P) as a positive control group, and a group in which clarithromycin (CLR) was administered to nontuberculous mycobacteria (Drug-Treat group) as a drug control group were cultured together. After one week of culture, 22 μl of a color-developing solution (0.02% resazurin solution) was added to each well and cultured again at 37°C for 24 hours. After 24 hours, the antibacterial activity of clarithromycin (CLR) and AJ-099 was compared with the negative control group, positive control group, and drug control group, and the results are shown in Figure 1.

[0167] As shown in Fig. 1, the minimum inhibitory concentration of AJ-099 was confirmed through drug susceptibility testing of the six nontuberculous mycobacterial strains mentioned above. Regardless of the presence or absence of macrolide resistance, it was confirmed that AJ-099 had a lower minimum inhibitory concentration compared to clarithromycin (CLR).

[0168] [Example 2] Confirmation of the growth inhibition effect of nontuberculous mycobacteria according to treatment with existing antibiotics.

[0169] In order to confirm the growth inhibition effect of nontuberculous mycobacteria according to the single treatment of existing antibiotics, M. aviumSMC#7 was inoculated at a multiplicity of infection (MOI) of 1:3 into each well of macrophage cells attached to a 48-well plate in Preparation Example 2, and the culture medium containing the strain was removed after culturing for 4 hours. Then, DMEM culture medium with high glucose content containing 5% fetal bovine serum containing 10 ug / ml clarithromycin (CLR), 10 ug / ml rifampin (RIF), or 10 ug / ml ethambutol (EMB) was treated to each well and cultured for 72 hours. After the culture was completed, each well of the plate was washed with 1X PBS (phosphate buffered saline), and 200 μl of 0.05% Triton X-100 was added to each well and cultured for 10 minutes to sufficiently dissolve the membranes of the macrophages. Thereafter, the lysate released from the macrophages was diluted by a factor of 1 / 1000, and 50 μl of the diluted lysate was dispensed onto each petri dish of the 7H10 solid medium of Preparation Example 3, and then cultured in a microbial incubator for 10 days. After the culture was completed, the number of bacteria (CFU) generated in the petri dish was measured, and the results are shown in Fig. 2.

[0170] As shown in Figure 2, when macrophages infected with nontuberculous mycobacteria were treated with 10 ug / ml of CLR, the growth of nontuberculous mycobacteria in macrophages was significantly reduced compared to the control group (CTL). This demonstrates that macrolide antibiotics are effective in inhibiting the intracellular growth of nontuberculous mycobacteria. However, when treated with 10 ug / ml of RIF or EMB, the bacteria grew in the same manner as the control group (CTL), confirming that RIF and EMB do not inhibit the growth of nontuberculous mycobacteria.

[0171] The above results indicate that existing combination drugs such as RIF and EMB, excluding macrolide antibiotics, cannot inhibit the growth and proliferation of nontuberculous mycobacteria.

[0172] [Example 3] Confirmation of the growth inhibitory effect of AJ-099 on nontuberculous mycobacteria in macrophage cells.

[0173] In order to confirm the growth inhibition effect of nontuberculous mycobacteria according to treatment with AJ-099, macrophage cells infected with M. avium ATCC 700898, M. intracellulare ATCC 13950, macrolide-resistant clinical strain M. avium SMC#417, and macrolide-resistant clinical strain M. intracellulare SMC#104 were treated with 10 ug / ml of clarithromycin (CLR) and 10 ug / ml of AJ-099, respectively, incubated for 3 days, and the number of bacteria (CFU) generated in the petri dish was measured, and the results are shown in Fig. 3.

[0174] As shown in Fig. 3, when AJ-099 was treated on macrophage cells, it was confirmed that the growth of all four types of macrolide antibiotic-sensitive or -resistant nontuberculous mycobacteria in macrophage cells was significantly reduced compared to the control group (CTL).

[0175] Through the above results, it was found that AJ-099 according to the present invention can very effectively inhibit the growth and proliferation of macrolide antibiotic-sensitive and -resistant nontuberculous mycobacteria infected with large macrophage cells.

[0176] [Example 4] Confirmation of the growth inhibition effect of nontuberculous mycobacteria according to combined treatment.

[0177] In order to confirm the synergistic effect of co-administration of AJ-099 and macrolide antibiotics on the growth inhibition of nontuberculous mycobacteria, macrophage cells infected with M. avium ATCC 700898 and M. intracellulare ATCC 13950 were treated with 10 ug / ml clarithromycin (CLR) alone or in combination with 10 ug / ml clarithromycin (CLR) and 10 ug / ml AJ-099 in the same manner as in Example 2, and then cultured for 3 days, and the number of bacteria (CFU) generated in the petri dish was measured, and the results are shown in Fig. 4.

[0178] As shown in Fig. 4, the combined treatment group of AJ-099 and clarithromycin (CLR) (099 + CLR) showed a significant decrease in the number of bacteria compared to the clarithromycin (CLR) treatment group alone, and consistent results were observed in both strains (M. avium, M. intracellulare). These results suggest that AJ-099 enhances the antibacterial activity of clarithromycin (CLR) to more effectively inhibit the growth of nontuberculous mycobacteria in macrophages, and experimentally demonstrate that the thiopeptide compound of the present invention is an effective combination drug candidate that can exhibit a synergistic effect through combination with existing core drugs.

[0179] [Example 5] Confirmation of the growth inhibition effect of nontuberculous mycobacteria according to the combined administration of AJ-099 and macrolide antibiotics and the concentration of macrolide antibiotics.

[0180] In order to compare the effect of co-administration of AJ-099 and macrolide antibiotics and the growth inhibition of nontuberculous mycobacteria according to the concentration of macrolide antibiotics, macrophage cells infected with M. aviumSMC#7 were treated with 10 ug / ml of AJ-099 alone, or with clarithromycin (CLR) in the concentration range of 1 to 30 ug / ml alone, or with 10 ug / ml of clarithromycin (CLR) and 10 ug / ml of AJ-099 in combination, and then cultured for 3 days, and the number of bacteria (CFU) generated in the petri dish was measured, and the results are shown in Fig. 5.

[0181] As shown in Fig. 5, compared to the control group (CTL), the growth of all nontuberculous mycobacteria in macrophages was significantly reduced. Clarithromycin (CLR) showed an almost identical growth inhibitory effect on nontuberculous mycobacteria regardless of concentration. On the other hand, when AJ-099 and clarithromycin (CLR) were combined, the growth of nontuberculous mycobacteria was significantly reduced compared to when clarithromycin (CLR) was treated alone at a high dose of 30 ug / ml in macrophages.

[0182] The above results show that the combined administration of AJ-099 and macrolide antibiotics according to the present invention can very effectively inhibit the growth and proliferation of nontuberculous mycobacteria infected with macrophages, and that the combined treatment with AJ-099 using a low dose of macrolide antibiotics can more effectively inhibit the growth and proliferation of nontuberculous mycobacteria than the treatment with a high dose of macrolide antibiotics alone.

[0183] [Example 6] Evaluation of the efficacy of AJ-099 as a composition for the treatment of nontuberculous mycobacteria.

[0184] To verify the efficacy of AJ-099 as a composition for the treatment of nontuberculous mycobacteria, animal experiments were conducted. The specific experimental design is illustrated in Figure 6A. As experimental animals, 6-week-old BALB / c mice without specific pathogens were inhaled and infected with the M. avium SMC#7 strain. Five weeks after infection, 50 mpk of clarithromycin (CLR) was administered orally or 20 mpk of AJ-099 was administered intranasally five times per week, either alone or in combination. Two weeks after administration, the mice were sacrificed, along with the control group (7w), and lung and spleen tissues were removed and the number of nontuberculous mycobacteria was measured. The number of viable nontuberculous mycobacteria in lung and spleen tissues was measured by plating serially diluted whole organ homogenates on petri dishes of 7H10 solid medium in Preparation Example 3, culturing them at 37°C for 3-4 weeks, and counting colonies. The results were expressed as the average log per whole lung and spleen tissues. 10 It was expressed as CFU±standard deviation and is shown in Figure 6B.

[0185] As a result, as shown in Fig. 6B, the group administered with AJ-099 and clarithromycin (CLR) in combination showed the greatest decrease in the number of nontuberculous mycobacteria in lung and spleen tissues compared to the control group (7w). In addition, compared to the group administered with AJ-099 or clarithromycin (CLR) alone, the group administered with AJ-099 and clarithromycin (CLR) in combination showed a significant decrease in the number of nontuberculous mycobacteria in lung and spleen tissues.

[0186] Additionally, lung tissue from mice infected 7 weeks after treatment was removed, preserved in 10% formalin, and fixed in paraffin. The fixed tissue was sectioned into 4-5 mm sections and stained with hematoxylin and eosin (H&E), and the results are shown in Figure 7.

[0187] As a result, as shown in Fig. 7, the group administered with AJ-099 and clarithromycin (CLR) in combination showed the greatest relative reduction in lesions compared to the control group (7w). In addition, when the area of ​​lesions showing inflammation in lung tissue was analyzed using the ImageJ program (National Institutes of Health, MD, USA), it was confirmed that the group administered with AJ-099 and clarithromycin (CLR) in combination showed a significant reduction in the area of ​​inflammation compared to the control group (7w).

[0188] Therefore, through this, it was found that AJ-099 acts as an effective ingredient of a combination treatment composition that can effectively control nontuberculous mycobacteria and significantly reduce infectious lesions when used in combination with macrolide antibiotics.

[0189] [Example 7] Comparison of the efficacy of AJ-099 as a therapeutic composition for nontuberculous mycobacteria in combination with conventional antibiotics.

[0190] In order to verify whether the combined administration of AJ-099 and clarithromycin (CLR) has superior therapeutic efficacy compared to the combination of existing antibiotics or high-dose clarithromycin (CLR), the relative ratio of the number of nontuberculous mycobacteria in lung tissue measured in an independently performed animal experiment was measured compared to the control group (CTL). The number of nontuberculous mycobacteria in lung tissue of the 20 mpk AJ-099, 50 mpk CLR, and 20 mpk AJ-099 and 50 mpk CLR combination treatment groups measured in Example 6 was log 10After expressing it as CFU, the control group (CTL) was set as 100% and the relative ratio was calculated. Other treatment groups, 100 mpk CLR, 200 mpk CLR, CER (standard treatment group consisting of 100 mpk CLR + 100 mpk EMB + 10 mpk RIF), were each performed as independent animal experiments. BALB / c mice without specific pathogens, 6 weeks old, were infected by inhalation with the M. avium SMC#7 strain, and then, starting from the 10th week of infection, they were orally administered 5 times a week under each condition for 4 weeks, and the number of nontuberculous mycobacteria in the lung tissue was measured in the same way as in Example 6. This was calculated in the same way as shown above, and the relative ratio of the number of nontuberculous mycobacteria in the lung tissue according to each treatment condition is shown in Figure 8.

[0191] As a result, as shown in Fig. 8, it was confirmed that the group treated with a combination of 50 mpk of clarithromycin (CLR) and 20 mpk of AJ-099 showed a relatively lower number of nontuberculous mycobacteria in the lung tissue than the group treated with a high dose of 200 mpk of clarithromycin (CLR). This suggests that co-administration of AJ-099 can provide an equivalent or higher level of therapeutic effect while reducing the dose of clarithromycin (CLR). In addition, when comparing the CER treatment group consisting of standard treatment and the group treated with a combination of 50mpk of clarithromycin (CLR) and 20mpk of AJ-099, it was confirmed that the relative number of nontuberculous mycobacteria was significantly reduced in the combination treatment group of CLR and AJ-099, and it was found that treatment by replacing rifampicin (RIF) and ethambutol (EMB) with AJ-099 was more effective in suppressing the growth and proliferation of nontuberculous mycobacteria.

[0192] In addition, when comparing the 100-mpk clarithromycin (CLR) monotherapy group and the CER group with rifampicin (RIF) and ethambutol (EMB), they showed similar nontuberculous mycobacterial inhibition efficacy, which shows that the existing combination drugs RIF and EMB do not have a real therapeutic effect in the lungs.

[0193] Therefore, through this, it was found that AJ-099 acts as an active ingredient of an effective combination treatment composition that, when used in combination with macrolide antibiotics, replaces existing antibiotics (RIF, EMB, etc.) or reduces the dosage of macrolide antibiotics while exhibiting excellent therapeutic effects.

[0194] As described above, the present invention has been described by limited embodiments, but these are provided only to help a more general understanding of the present invention, and the present invention is not limited to the above embodiments, and those skilled in the art to which the present invention pertains can make various modifications and variations based on this description.

[0195] Therefore, the idea of ​​the present invention should not be limited to the described embodiments, and all things that are equivalent or equivalent to the following claims as well as the claims are considered to fall within the scope of the idea of ​​the present invention.

Claims

1. A pharmaceutical composition for preventing or treating infection or infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients. [Chemical Formula 1] In the above chemical formula 1, Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene; Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-; R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4; A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

2. In paragraph 1, A pharmaceutical composition wherein the above thiopeptide compound is represented by the following chemical formula 2. [Chemical Formula 2] In the above chemical formula 2, A1 is or , R' is C1-C10 alkyl, and p is an integer from 0 to 2; R1 is hydrogen or C1-C10 alkyl; D1 is CH or N; D2 is O, S, SO2, C(R b1 )(R b2 ) or NR c1 and; R b1 , R b2 and R c1 are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid group, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, haloC1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, haloC6-C20 aryl, HaloC1-C10alkylC6-C20aryl, C6-C20aryl, C3-C10cycloalkyl, C3-C10cycloalkylcarbonyl, C1-C10alkoxycarbonylC1-C10alkyl or carboxylic acidC1-C10alkyl; n is an integer from 0 to 5.

3. In paragraph 1, A pharmaceutical composition wherein the thiopeptide compound is selected from the following structures.

4. In paragraph 1, The above nontuberculous mycobacteria are Mycobacterium avium, Mycobacterium aviumcomplex (MAC), Mycobacterium abscessus, Mycobacterium abscessus complex, Mycobacterium flavescence, Mycobacterium chelonae, Mycobacterium celatum, Mycobacterium fortuitum, Mycobacterium gordonae, Mycobacterium gastri, Mycobacterium haemophilum, Mycobacterium intracellulare. intracellulare), Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium massiliense, Mycobacterium marinum, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium scrofulaceum, Mycobacterium ulcerans, Mycobacterium simiae, Mycobacterium osloensis, Mycobacterium phlei, Mycobacterium smegmatis,A pharmaceutical composition selected from the group consisting of Mycobacterium mucogenicum, Mycobacterium peregrinum, Mycobacterium wolinskyi and Mycobacterium xenopi.

5. In paragraph 1, The above antibiotics are rifampin, rifapentine, isoniazid, pyrazinamide, ethambutol, streptomycin, fluoroquinolone, kanamycin, cycloserine, prothionamide, levofloxacin, moxifloxacin, ofloxacin, rifabutin, capeomycin, amikacin, tobramycin, imipenem, doxycycline, cefoxitin, ciprofloxacin, protionamide, A pharmaceutical composition comprising one or more selected from the group consisting of ethionamide, cycloserine, thioacetazone, clofazimine, amoxicillin / clavulanate, a derivative of dianomidiphenylsulphone, bedaquiline, linezolid, and macrolide antibiotics.

6. In paragraph 5, A pharmaceutical composition wherein the above antibiotic is a macrolide antibiotic.

7. In paragraph 6, A pharmaceutical composition wherein the macrolide antibiotic is one or more selected from the group consisting of erythromycin, clarithromycin, dirithromycin, roxithromycin, azithromycin, josamycin, midecamycin, rokitamycin, and spiramycin.

8. In paragraph 1, A pharmaceutical composition, wherein the infectious disease caused by the above nontuberculous mycobacteria is at least one selected from the group consisting of lung disease, lymphadenitis, skin, soft tissue, and bone infection, and disseminated disease.

9. In paragraph 1, A pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

10. A composition for enhancing the drug susceptibility of nontuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] In the above chemical formula 1, Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene; Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-; R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4; A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

11. A composition for overcoming drug-resistant non-tuberculous mycobacteria resistance, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] In the above chemical formula 1, Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene; Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-; R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4; A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

12. A composition for preventing, improving or treating infection or infectious disease caused by drug-resistant non-tuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] In the above chemical formula 1, Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene; Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-; R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4; A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

13. A pharmaceutical composition for preventing infection or recurrence of an infectious disease caused by nontuberculous mycobacteria, comprising a thiopeptide compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic as active ingredients. [Chemical Formula 1] In the above chemical formula 1, Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene, or a substituted or unsubstituted C3-C20 heteroarylene; Z1 to Z3 are each independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2- or -OCONR7-; R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxylC1-C10 alkyl or C1-C10 alkoxycarbonylC1-C10 alkyl; A1 is or , R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl or C1-C10 alkoxyC1-C10 alkyl, and p is an integer from 0 to 4; A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene or C6-C20 heteroarylene; R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted haloC1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.

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