KR102400827B1 - Biomarker for predicting responsiveness to treatment in a patient with nontuberculous mycobacterial infection - Google Patents

Abstract

The present invention relates to a biomarker for predicting treatment responsiveness after infection by non-tuberculous mycobacteria, and a kit or prediction method for the prediction.

Description

Biomarker for predicting responsiveness to treatment in a patient with nontuberculous mycobacterial infection

The present invention relates to a biomarker for predicting treatment responsiveness after infection by non-tuberculous mycobacteria, and a kit or prediction method for the prediction.

The genus Mycobacterium includes not only species that cause serious diseases in humans and animals, such as tuberculosis, tuberculosis bovine, and leprosy, but also fungi called opportunistic pathogens. About 72 species are known, including species and saprophytic species that can be seen in the natural environment, and 25 of them are known to be related to human diseases. These Mycobacterium genus are not easily dyed with commonly used dyeing solutions, but once dyed, they are also called acid-fighting bacteria because they are not easily decolorized even when treated with alcohol or hydrochloric acid.

Nontuberculous mycobacteria (NTM) refers to mycobacteria other than Mycobacterium tuberculosis complex and Mycobacterium leprae. Meanwhile, among non-tuberculous mycobacteria belonging to the Mycobacterium avium complex (MAC), more than 180 strains have been officially identified as strains that commonly cause lung disease in humans. MAC mainly includes M. avium and M. intracellulare, and Mycobacterium abscessus (MAB) mainly contains M. abscessus subspecies Absesu. s (M. abscessus subspecies abscessus) and M. abscessus subspecies massiliense (M. abscessus subspecies massiliense). Recently, although reports of lung infections caused by non-tuberculous mycobacteria have been increasing worldwide, there is a lack of biomarkers or pathophysiology studies for diseases for distinguishing patients with non-tuberculous mycobacteria from a healthy population.

It is an object of the present invention to provide a biomarker composition for predicting treatment responsiveness as a prognosis after infection with non-tuberculous mycobacteria.

Another object of the present invention is to provide a kit for predicting treatment responsiveness as a prognosis after infection with non-tuberculous mycobacteria.

Another object of the present invention is to provide a method for predicting treatment responsiveness as a prognosis after infection with non-tuberculous mycobacteria.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

According to one embodiment of the present invention, it relates to a biomarker composition for predicting treatment responsiveness of a patient infected with non-tuberculous mycobacterium, comprising a metabolite.

In the present invention, the "treatment" refers to an approach for obtaining a beneficial or desirable clinical result, and for the purposes of the present invention, the beneficial or desirable clinical result is, but not limited to, alleviation of symptoms, reduction of the scope of the disease. , stabilization (i.e. not worsening) of the disease state, delaying or reducing the rate of disease progression, amelioration or temporary alleviation and amelioration (partial or total) of the disease state, whether detectable or undetectable and may mean increasing survival compared to the expected survival rate in the absence of treatment. Treatment refers to both therapeutic treatment and prophylactic or prophylactic measures. Such treatments include the treatment required for the disorder being prevented as well as the disorder that has already occurred. "Palliating" a disease means that the extent and/or undesirable clinical signs of the disease state are reduced and/or the time course of progression is delayed or prolonged, compared to no treatment. means to lose

In the present invention, "prediction of therapeutic responsiveness" means predicting whether a patient will respond favorably or unfavorably to a therapeutic agent for the treatment of non-tuberculous mycobacterium infection, or predicting the risk of resistance to the therapeutic agent. It means predicting the prognosis of the patient after treatment, that is, positive outcomes, survival, or disease-free survival. The biomarker for predicting treatment responsiveness according to the present invention may provide information for selecting the most appropriate treatment modality for a non-tuberculous mycobacterium-infected patient.

In the present invention, the treatment may be performed using an antibiotic, wherein the antibiotic may be rifampin, isoniazid, ethambutol, pyrazinamide (PZA), quinolone, or aminoglycoside, but is not limited thereto. it is not Here, the quinolone antibiotic is nalidixic acid, marbofloxacin, oxolinic acid, moxifloxacin, trovafloxacin, gatifloxacin, Flumequine, prulifloxacin, gemifloxacin, ciprofloxacin, sitafloxacin, or clinafloxacin, etc. may be used, but are not limited thereto. In addition, the aminoglycoside antibiotics include streptomycin, neomycin, framycetin, gentamycin, novobiocin, kanamycin, and amica. It may be syn (amikacin), sisomycin (sisomycin) or spectinomycin (spectinomycin), but is not limited thereto.

In the present invention, the metabolite refers to a sample of biological origin, that is, a metabolite obtained from a biological sample, and the biological sample refers to a biological body fluid, tissue or cell, for example, whole blood, leukocytes. (leukocytes), peripheral blood mononuclear cells (buffy coat), plasma (plasma), serum (serum), sputum (tears), mucus (mucus), saliva ( nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid , meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate ( One selected from the group consisting of bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cell, cell extract and cerebrospinal fluid, etc. It may be above, but preferably whole blood, plasma, or serum, and more preferably, serum.

In the present invention, the non-tuberculous mycobacteria are Mycobacterium avium (M. avium), Mycobacterium abscessus (M. abscessus), Mycobacterium flavesense (M. flavescence), Mycobacterium Rum africanum (M. africanum), Mycobacterium bovis (M. bovis), Mycobacterium cellone (M. chelonae), Mycobacterium cellatum (M. celatum), Mycobacterium portuitum (M. fortuitum), Mycobacterium gordonae (M. gordonae), Mycobacterium gastri (M. gastri), Mycobacterium haemophilum (M. haemophilum), Mycobacterium intracellulare (M. intracellulare), Mycobacterium kansasii (M. kansasii), Mycobacterium malmoens (M. malmoense), Mycobacterium marinum (M. marinum), Mycobacterium sulgai (M) . simiae) and Mycobacterium xenopi (M. xenopi) is preferably selected from the group consisting of, but is not limited thereto.

In the present invention, whole blood, plasma or serum may be pretreated to detect the metabolite. For example, it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like. In addition, the metabolite may include a substance produced by metabolism and metabolic processes or a substance generated by chemical metabolism by biological enzymes and molecules.

In the present invention, the metabolite is preferably a metabolite obtained from a liquid sample derived from blood, preferably serum, and specific examples include amino acids, amino acid derivatives, allantoin, N,N- Dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid, 3-hydroxybutyric acid, glycerol 3-phosphate (Glycerol 3) -phosphate), choline (Choline), lactate (Lactate) and may include one or more selected from the group consisting of malic acid (Malic acid).

In the present invention, the 2-hydroxyglutaric acid is preferably in the D-form, but is not limited thereto.

In the present invention, the lactate is preferably in the S-form, but is not limited thereto.

In the present invention, the malic acid is preferably in the L-form, but is not limited thereto.

In the present invention, the amino acids and their derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, and lysine. , tryptophan (Tryptophan), methionine (Methionine), serine (Serine), homoserine (Homoserine) and may include one or more selected from the group consisting of threonine (Threonine).

In the present invention, the amino acid may be in L-form, preferably arginine, phenylalanine, glutamate, aspartate, valine, leucine ( Leucine), isoleucine, lysine, tryptophan, methionine, serine or threonine is preferably in the L-form, but limited thereto not.

In one embodiment of the present invention, the metabolite is an amino acid, an amino acid derivative, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid acid), choline and lactate may include at least one selected from the group consisting of, the amino acid and its derivatives are phenylalanine, glutamate, aspartate, It may include at least one selected from the group consisting of valine, leucine, isoleucine, tryptophan, and methionine, and the metabolite is a patient infected with non-tuberculous mycobacteria It may be to predict treatment responsiveness in patients with nodular bronchiectatic form lung disease.

In another example of the present invention, the metabolite may include at least one of phenylalanine and isoleucine, and the metabolite is, in particular, Mycobacterium avium infection among non-tuberculous mycobacteria. It may be for predicting a patient's responsiveness to treatment.

In another example of the present invention, the metabolite may include at least one of aspartate, allantoin, and hypoxanthine, and the metabolite may include mycobacteria among non-tuberculous mycobacteria. It may be for predicting treatment responsiveness in patients with M. intracellulare infection.

In another example of the present invention, the metabolite may include at least one selected from the group consisting of amino acids, amino acid derivatives and hypoxanthine, and the amino acids and derivatives thereof are phenylalanine, It may include at least one selected from the group consisting of glutamate, methionine, and threonine, and the metabolite may be for predicting treatment responsiveness of a non-tuberculous mycobacterium-infected male patient.

In another example of the present invention, the metabolite may include at least one of an amino acid and N,N-dimethylglycine, and the amino acid may include phenylalanine. And, the metabolite may be for predicting the treatment responsiveness of a non-tuberculous mycobacterium-infected female patient.

According to another embodiment of the present invention, it relates to a kit for predicting treatment responsiveness of a non-tuberculous mycobacterium-infected patient, comprising a quantitative device for measuring the concentration of a metabolite.

In the present invention, the metabolite refers to a sample of biological origin, that is, a metabolite obtained from a biological sample, and the biological sample refers to a biological body fluid, tissue or cell, for example, whole blood, leukocytes. (leukocytes), peripheral blood mononuclear cells (buffy coat), plasma (plasma), serum (serum), sputum (tears), mucus (mucus), saliva ( nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid , meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate ( One selected from the group consisting of bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cell, cell extract and cerebrospinal fluid, etc. It may be above, but preferably whole blood, plasma, or serum, and more preferably, serum.

In the present invention, whole blood, plasma or serum may be pretreated to detect the metabolite. For example, it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like.

In the present invention, whole blood, plasma or serum may be pretreated to detect the metabolite. For example, it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like. In addition, the metabolite may include a substance produced by metabolism and metabolic processes or a substance generated by chemical metabolism by biological enzymes and molecules.

In the present invention, the metabolite is preferably a metabolite obtained from a liquid sample derived from blood, preferably serum, and specific examples include amino acids, amino acid derivatives, allantoin, N,N- Dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid, 3-hydroxybutyric acid, glycerol 3-phosphate (Glycerol 3) -phosphate), choline (Choline), lactate (Lactate) and may include one or more selected from the group consisting of malic acid (Malic acid).

In the present invention, the 2-hydroxyglutaric acid is preferably in the D-form, but is not limited thereto.

In the present invention, the lactate is preferably in the S-form, but is not limited thereto.

In the present invention, the malic acid is preferably in the L-form, but is not limited thereto.

In the present invention, the amino acids and their derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, and lysine. , tryptophan (Tryptophan), methionine (Methionine), serine (Serine), homoserine (Homoserine) and may include one or more selected from the group consisting of threonine (Threonine).

In the present invention, the amino acid may be in L-form, preferably arginine, phenylalanine, glutamate, aspartate, valine, leucine ( Leucine), isoleucine, lysine, tryptophan, methionine, serine or threonine is preferably in the L-form, but limited thereto not.

In one embodiment of the present invention, the metabolite is an amino acid, an amino acid derivative, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid acid), choline and lactate may include at least one selected from the group consisting of, the amino acid and its derivatives are phenylalanine, glutamate, aspartate, Valine, leucine, isoleucine, tryptophan and methionine may include one or more selected from the group consisting of, the kit may include one or more selected from the group consisting of non-tuberculous mycobacteria. It may be for predicting treatment responsiveness in patients with nodular bronchiectatic form lung disease.

In another example of the present invention, the metabolite may include at least one of phenylalanine and isoleucine, and the kit is a non-tuberculous mycobacterium, particularly Mycobacterium avium infection patient. to predict the therapeutic responsiveness of

In another example of the present invention, the metabolite may include at least one of aspartate, allantoin, and hypoxanthine, and the kit is Mycobacterium among non-tuberculous mycobacteria. It may be for predicting treatment responsiveness in patients with M. intracellulare infection.

In another example of the present invention, the metabolite may include at least one selected from the group consisting of amino acids, amino acid derivatives and hypoxanthine, and the amino acids and derivatives thereof are phenylalanine, It may include one or more selected from the group consisting of glutamate, methionine, and threonine, and the kit may be for predicting treatment responsiveness of a non-tuberculous mycobacterium-infected male patient.

In another example of the present invention, the metabolite may include at least one of an amino acid and N,N-dimethylglycine, and the amino acid may include phenylalanine. In addition, the kit may be for predicting the treatment responsiveness of a non-tuberculous mycobacterium-infected female patient.

In the present invention, the quantitative device may be a nuclear magnetic resonance spectrometer (NMR), chromatography, or mass spectrometer, but is not limited thereto.

Chromatography used in the present invention is high performance liquid chromatography (HPLC), liquid-solid chromatography (Liquid-Solid Chromatography, LSC), paper chromatography (Paper Chromatography, PC), thin layer chromatography (Thin) -Layer Chromatography, TLC), Gas-Solid Chromatography (GSC), Liquid-Liquid Chromatography (LLC), Foam Chromatography (FC), Emulsion Chromatography (Emulsion) Chromatography (EC), Gas-Liquid Chromatography (GLC), Ion Chromatography (IC), Gel Filtration Chromatography (GFC) or Gel Permeation Chromatography (Gel Permeation Chromatography, GPC), but is not limited thereto, and any quantitative chromatography commonly used in the art may be used.

In the present invention, the mass spectrometer may use a conventionally known mass spectrometer without any particular limitation, but specifically, for example, a Fourier transform mass spectrometer (FTMS), a Malditope mass spectrometer (MALDI-TOF MS), It may be Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.

In the kit of the present invention, the definition of non-tuberculous mycobacterium, treatment and therapeutic responsiveness overlaps with those described in the biomarker composition of the present invention, and description thereof will be omitted below to avoid excessive congestion of the specification.

According to another embodiment of the present invention, it relates to a method for providing information for predicting treatment responsiveness of a patient infected with non-tuberculous mycobacterium, comprising measuring the expression level of a metabolite in a biological sample isolated from a target subject will be.

In the present invention, the "target individual" refers to an individual having a high probability of being infected, infected, or diagnosed as infected by a non-tuberculous mycobacterium, and it means an individual whose responsiveness to treatment for the infection is uncertain.

In the present invention, the "biological sample" refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, and includes whole blood, leukocytes, and peripheral blood mononuclear cells. mononuclear cells, buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate , breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint It may be one or more selected from the group consisting of joint aspirate, organ secretions, cells, cell extract, and cerebrospinal fluid, and preferably whole blood (whole blood). ), plasma or serum, and more preferably, serum.

In the present invention, prior to measuring the expression level of the metabolite, the step of pre-treating the biological sample, preferably whole blood, plasma or serum may be performed. In the present invention, the pretreatment may include, for example, filtration, distillation, extraction, separation, concentration, inactivation of interfering components, and addition of reagents, but is not limited thereto.

In the present invention, the metabolite is preferably a metabolite obtained from a liquid sample derived from blood, preferably serum, and specific examples include amino acids, amino acid derivatives, allantoin, N,N- Dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid, 3-hydroxybutyric acid, glycerol 3-phosphate (Glycerol 3) -phosphate), choline (Choline), lactate (Lactate) and may include one or more selected from the group consisting of malic acid (Malic acid).

In the present invention, the 2-hydroxyglutaric acid is preferably in the D-form, but is not limited thereto.

In the present invention, the lactate is preferably in the S-form, but is not limited thereto.

In the present invention, the malic acid is preferably in the L-form, but is not limited thereto.

In the present invention, the amino acids and their derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, and lysine. , tryptophan (Tryptophan), methionine (Methionine), serine (Serine), homoserine (Homoserine) and may include one or more selected from the group consisting of threonine (Threonine).

In the present invention, the amino acid may be in L-form, preferably arginine, phenylalanine, glutamate, aspartate, valine, leucine ( Leucine), isoleucine, lysine, tryptophan, methionine, serine or threonine is preferably in the L-form, but limited thereto not.

In one embodiment of the present invention, the metabolite is an amino acid, an amino acid derivative, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid acid), choline and lactate may include at least one selected from the group consisting of, the amino acid and its derivatives are phenylalanine, glutamate, aspartate, It may include one or more selected from the group consisting of valine, leucine, isoleucine, tryptophan and methionine, and the information providing method determines the expression level of the metabolite By measuring, it is possible to predict the treatment responsiveness of patients with nodular bronchiectatic form lung disease among patients infected with non-tuberculous mycobacteria.

In another example of the present invention, the metabolite may include at least one of phenylalanine and isoleucine, and the method for providing information includes measuring the expression level of the metabolite, particularly mycobacteria among non-tuberculous mycobacteria. It is possible to predict the treatment responsiveness of patients with M. avium infection.

In another example of the present invention, the metabolite may include at least one of aspartate, allantoin, and hypoxanthine, and the information providing method measures the expression level of the metabolite By doing so, it is possible to predict the treatment responsiveness of non-tuberculous mycobacteria, especially M. intracellulare-infected patients.

In another example of the present invention, the metabolite may include at least one selected from the group consisting of amino acids, amino acid derivatives and hypoxanthine, and the amino acids and derivatives thereof are phenylalanine, It may include one or more selected from the group consisting of glutamate, methionine, and threonine, and the method for providing information includes measuring the expression level of the metabolite of a non-tuberculous mycobacterium-infected male patient. Therapeutic responsiveness can be predicted.

In another example of the present invention, the metabolite may include at least one of an amino acid and N,N-dimethylglycine, and the amino acid may include phenylalanine. And, the information providing method can predict the treatment responsiveness of a non-tuberculous mycobacterium-infected female patient by measuring the expression level of the metabolite.

In the present invention, the expression level of the metabolite may be performed using a quantitative device. In the present invention, the quantitative device may be a nuclear magnetic resonance spectrometer (NMR), chromatography, or mass spectrometer, but is not limited thereto.

Chromatography used in the present invention is high performance liquid chromatography (HPLC), liquid-solid chromatography (Liquid-Solid Chromatography, LSC), paper chromatography (Paper Chromatography, PC), thin layer chromatography (Thin) -Layer Chromatography, TLC), Gas-Solid Chromatography (GSC), Liquid-Liquid Chromatography (LLC), Foam Chromatography (FC), Emulsion Chromatography (Emulsion) Chromatography (EC), Gas-Liquid Chromatography (GLC), Ion Chromatography (IC), Gel Filtration Chromatography (GFC) or Gel Permeation Chromatography (Gel Permeation Chromatography, GPC), but is not limited thereto, and any quantitative chromatography commonly used in the art may be used.

In the present invention, the mass spectrometer may use a conventionally known mass spectrometer without any particular limitation, but specifically, for example, a Fourier transform mass spectrometer (FTMS), a Malditope mass spectrometer (MALDI-TOF MS), It may be Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.

In the present invention, the expression level of the metabolite may be measured for a biological sample isolated from a target subject before, at the time of, or after the initiation of treatment for non-tuberculous mycobacterium infection.

In an exemplary embodiment of the present invention, the expression level of the metabolite may be measured in a biological sample isolated from a target subject before or at the start of treatment for non-tuberculous mycobacterium infection.

In one example of the present invention, the expression level of the metabolite is 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month after the start of treatment for non-tuberculous mycobacterium infection. It may be measured with respect to a biological sample isolated from a subject of interest after the lapse of time from 3 months.

In one embodiment of the present invention, the expression level of the metabolite is a biological sample isolated from a target subject before or at the time of initiation of treatment for non-tuberculous mycobacterium infection, and 10 days after initiation of treatment for non-tuberculous mycobacterium infection. It may be measured for a biological sample isolated from a target subject after a time of 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months.

In an example of the present invention, the expression level is the expression level of each metabolite measured in a biological sample isolated from a target subject before treatment for non-tuberculous mycobacterium infection or at the time of initiation of treatment for non-tuberculous mycobacterium infection. The same as measured in a biological sample isolated from a subject of interest after a time period of 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months after initiation of treatment for It may be a ratio of the expression level of the metabolite.

In the present invention, when the expression level of the metabolite measured with respect to the biological sample of the subject of interest is increased or decreased compared to the control, predicting that the treatment responsiveness of the patient infected by the non-tuberculous mycobacterium is high. can do.

In the present invention, the "control group" is a normal control not infected with non-tuberculous mycobacterium, the median value of the patient population (or the average value of the patient) infected with the non-tuberculous mycobacterium, or among patients infected with non-tuberculous mycobacteria. It may be the median value of a patient population with low treatment responsiveness (or the mean value of the patient), or the median value of the patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria (or the mean value of the patient).

As an example of the present invention, arginine, phenylalanine measured in a biological sample of the subject of the present invention, preferably, a biological sample isolated at the time of initiation of treatment or before treatment for non-tuberculous mycobacterium infection ), Valine, Isoleucine, Lysine, Methionine, Homoserine, Threonine, N,N-Dimethylglycine and 3-Hyd When the expression level of one or more selected from the group consisting of 3-hydroxybutyric acid is increased compared to the control group, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is high. Here, the control group may be the median value (or the average value of the patient) of a patient population with low therapeutic responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, arginine and phenylalanine measured in a biological sample of the subject of the present invention, preferably, a biological sample isolated at the time of initiation of treatment or before treatment for non-tuberculous mycobacterium infection. ), Valine, Isoleucine, Lysine, Methionine, Homoserine, Threonine, N,N-Dimethylglycine and 3-Hyd When the expression level of one or more selected from the group consisting of 3-hydroxybutyric acid is decreased compared to the control group, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is low. Here, the control group may be the median value (or the average value of the patient) of a patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, a biological sample of the subject of interest, preferably 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, Arginine, phenylalanine, glutamate, aspartate, valine, measured in a biological sample isolated after a time of 2 to 4 months, or 1 to 3 months, Leucine, isoleucine, methionine, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, glycerol When the expression level of one or more selected from the group consisting of 3-phosphate (Glycerol 3-phosphate), choline, lactate and malic acid is reduced compared to the control group, patients with non-tuberculous mycobacteria infection It may further include the step of predicting that the treatment responsiveness of Here, the control group may be the median value (or the average value of the patient) of a patient population with low therapeutic responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, a biological sample of the subject of interest, preferably 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, Arginine, phenylalanine, glutamate, aspartate, valine, measured in a biological sample isolated after a time of 2 to 4 months, or 1 to 3 months, Leucine, isoleucine, methionine, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, glycerol When the expression level of one or more selected from the group consisting of 3-phosphate (Glycerol 3-phosphate), choline, lactate, and malic acid is increased compared to the control group, patients with non-tuberculous mycobacterium infection It may further include the step of predicting that the therapeutic responsiveness of Here, the control group may be the median value (or the average value of the patient) of a patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine measured with respect to the biological sample of the subject of interest in the present invention (Isoleucine), Tryptophan, Methionine, Threonine, N,N-Dimethylglycine, Hypoxanthine, 2-hydroxyglutaric acid acid), choline, lactate, malic acid, serine, and arginine when the expression level of one or more selected from the group consisting of the control group is reduced compared to the control The method may further include predicting that the treatment responsiveness of the fungal infection patient is high. Here, the expression level is the expression level of each metabolite measured in a biological sample isolated from a target subject before treatment for a non-tuberculous mycobacterium infection or at the time of initiation of treatment for a non-tuberculous mycobacterium infection. Expression level of the same metabolite measured in a biological sample isolated from a subject of interest after a time period of days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months may be a ratio of , and the control group may be the median value (or the average value of the corresponding patients) of a patient population with low treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, when the expression level of allantoin measured with respect to the biological sample of the subject of the present invention is increased compared to the control group, the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is predicted to be high It may further include the step of Here, the expression level is the expression level of each metabolite measured in a biological sample isolated from a target subject before treatment for a non-tuberculous mycobacterium infection or at the time of initiation of treatment for a non-tuberculous mycobacterium infection. Expression level of the same metabolite measured in a biological sample isolated from a subject of interest after a time period of days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months may be a ratio of , and the control group may be the median value (or the average value of the corresponding patients) of a patient population with low treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine measured with respect to the biological sample of the subject of interest in the present invention (Isoleucine), Tryptophan, Methionine, Threonine, N,N-Dimethylglycine, Hypoxanthine, 2-hydroxyglutaric acid acid), choline, lactate, malic acid, serine, and arginine when the expression level of one or more selected from the group consisting of the control group is increased compared to the control group The method may further include predicting that the treatment responsiveness of the fungal infection patient is low. Here, the expression level is the expression level of each metabolite measured in a biological sample isolated from a target subject before treatment for a non-tuberculous mycobacterium infection or at the time of initiation of treatment for a non-tuberculous mycobacterium infection. Expression level of the same metabolite measured in a biological sample isolated from a subject of interest after a time period of days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months may be a ratio of , and the control group may be the median value (or the average value of the corresponding patients) of a patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, when the expression level of allantoin measured with respect to the biological sample of the target subject in the present invention is reduced compared to the control group, the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is predicted to be low It may further include the step of Here, the expression level is the expression level of each metabolite measured in a biological sample isolated from a target subject before treatment for a non-tuberculous mycobacterium infection or at the time of initiation of treatment for a non-tuberculous mycobacterium infection. Expression level of the same metabolite measured in a biological sample isolated from a subject of interest after a time period of days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months may be a ratio of , and the control group may be the median value (or the average value of the corresponding patients) of a patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, but is not limited thereto.

As another example of the present invention, in the present invention, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine measured with respect to the biological sample of the subject of interest in the present invention (Isoleucine), tryptophan (Tryptophan), methionine, N,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid (2-hydroxyglutaric acid), choline ( Choline) and lactate (Lactate) when the expression level of one or more selected from the group is reduced compared to the control group, among patients infected with non-tuberculous mycobacteria, the treatment responsiveness of patients with nodular bronchiectatic form lung disease is high It may further include the step of predicting that Wherein the control group is the median value (or the average value of the patient) of patients infected with non-tuberculous mycobacteria, preferably patients with low treatment responsiveness among patients with nodular bronchiectatic form lung disease caused by non-tuberculous mycobacterium infection. However, the present invention is not limited thereto.

As another example of the present invention, in the present invention, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine measured with respect to the biological sample of the subject of interest in the present invention (Isoleucine), tryptophan (Tryptophan), methionine, N,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid (2-hydroxyglutaric acid), choline ( Choline) and lactate (Lactate), when the expression level of one or more selected from the group is increased compared to the control group, the treatment responsiveness of patients with nodular bronchiectatic form lung disease among patients infected with non-tuberculous mycobacteria is low It may further include the step of predicting that Wherein the control group is the median value (or the average value of the patient) of patients infected with non-tuberculous mycobacteria, preferably patients with high treatment responsiveness among patients with nodular bronchiectatic form lung disease caused by non-tuberculous mycobacterium infection. However, the present invention is not limited thereto.

As another example of the present invention, when the expression level of at least one of phenylalanine and isoleucine measured with respect to the biological sample of the subject of the present invention is reduced compared to the control, among non-tuberculous mycobacteria In particular, the method may further include predicting that the treatment responsiveness of the Mycobacterium avium (M. avium) infection patient is high. Here, the control group may be the median value (or the average value of the patient) of a patient population with low therapeutic responsiveness among patients infected with non-tuberculous mycobacteria, preferably M. avium infected patients, but It is not limited.

As another example of the present invention, when the expression level of at least one of phenylalanine and isoleucine measured with respect to the biological sample of the subject of the present invention is increased compared to the control, among non-tuberculous mycobacteria In particular, it may further include the step of predicting that the treatment responsiveness of the Mycobacterium avium (M. avium) infection patient is low. Here, the control group may be the median value (or the average value of the patient) of a patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, preferably M. avium infected patients, but It is not limited.

As another example of the present invention, the expression level of at least one of aspartate and hypoxanthine measured with respect to the biological sample of the target subject in the present invention is reduced compared to the control, or allantoin (Allantoin) ), when the expression level is increased compared to the control, predicting that the treatment responsiveness of the non-tuberculous mycobacteria, especially the M. intracellulare infection patient is high. Here, the control group may be the median value (or the average value of the patient) of a patient population with low therapeutic responsiveness among patients infected with non-tuberculous mycobacteria, preferably M. intracellulare infection, However, the present invention is not limited thereto.

As another example of the present invention, the expression level of at least one of aspartate and hypoxanthine measured with respect to the biological sample of the subject of the present invention is increased compared to the control, or allantoin (Allantoin) ), when the expression level is reduced compared to the control, predicting that the treatment responsiveness of the non-tuberculous mycobacteria, especially Mycobacterium intracellulare (M. intracellulare) infection patient is low. Here, the control group may be the median value (or the average value of the patient) of the patient population with high treatment responsiveness among patients infected with non-tuberculous mycobacteria, preferably M. intracellulare infection, However, the present invention is not limited thereto.

As another example of the present invention, the group consisting of phenylalanine, glutamate, methionine, threonine and hypoxanthine measured with respect to the biological sample of the subject of interest in the present invention When the expression level of at least one selected from the control group is decreased compared to the control group, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected male patient is high. Here, the control group may be the median value (or the average value of the patient) of patients infected with non-tuberculous mycobacteria, preferably male patients with low treatment responsiveness, but is not limited thereto.

As another example of the present invention, the group consisting of phenylalanine, glutamate, methionine, threonine and hypoxanthine measured with respect to the biological sample of the subject of interest in the present invention When the expression level of at least one selected from the control group is increased compared to the control group, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected male patient is low. Here, the control group may be the median value (or the average value of the patient) of patients infected with non-tuberculous mycobacteria, preferably male patients with high treatment responsiveness, but is not limited thereto.

As another example of the present invention, the expression level of at least one of phenylalanine and N,N-dimethylglycine measured with respect to the biological sample of the subject of the present invention compared to the control group If it is reduced, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected female patient is high. Here, the control group may be the median value (or the average value of the corresponding patients) of patients infected with non-tuberculous mycobacteria, preferably female patients with low treatment responsiveness, but is not limited thereto.

As another example of the present invention, the expression level of at least one of phenylalanine and N,N-dimethylglycine measured with respect to the biological sample of the subject of the present invention compared to the control group If increased, the method may further include predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected female patient is low. Here, the control group may be the median value (or the average value of the patient) of patients infected with non-tuberculous mycobacteria, preferably female patients with high treatment responsiveness, but is not limited thereto.

In the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months after the initiation of treatment for the non-tuberculous mycobacterium infection. The expression level of the metabolite measured in the biological sample isolated from the subject is the expression level of the metabolite measured in the biological sample isolated from the subject before initiation of treatment or at the time of initiation of treatment for the non-tuberculous mycobacterium infection. The method may further include predicting that the treatment responsiveness of the patient infected by the non-tuberculous mycobacterium is high when it is increased or decreased compared to the above.

In the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months after the initiation of treatment for the non-tuberculous mycobacterium infection. The expression level of the metabolite measured in the biological sample isolated from the subject is the expression level of the metabolite measured in the biological sample isolated from the subject before initiation of treatment or at the time of initiation of treatment for the non-tuberculous mycobacterium infection. The method may further include predicting that the treatment responsiveness of the patient infected by the non-tuberculous mycobacterium is low when it is increased or decreased compared to the above.

As an example of the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months after the start of treatment for the non-tuberculous mycobacterium infection in the present invention Phenylalanine, Glutamate, Aspartate, Valine, Leucine, Isoleucine, Tryptophan (Phenylalanine, Glutamate, Aspartate), Tryptophan), Methionine, Threonine, N,N-Dimethylglycine, Hypoxanthine, 2-hydroxyglutaric acid, Choline ), lactate (Lactate), malic acid (Malic acid), the expression level of one or more metabolites selected from the group consisting of serine (Serine) and arginine (Arginine) before the start of treatment for the non-tuberculous mycobacteria infection, or When the expression level of the metabolite measured in the biological sample isolated from the target individual at the time of initiation of treatment is decreased, the method may further include predicting that the treatment responsiveness of the patient infected with non-tuberculous mycobacteria is high. have.

In another example of the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to 3 months after the start of treatment for the non-tuberculous mycobacterium infection in the present invention The expression level of allantoin (Allantoin) measured in the biological sample isolated from the target subject after the lapse of months is the biological sample isolated from the target subject before the start of treatment for the non-tuberculous mycobacterium infection or at the start of the treatment. When it is increased compared to the expression level of the allantoin measured in , the method may further include predicting that the treatment responsiveness of the patient infected with non-tuberculous mycobacteria is high.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to Phenylalanine, Glutamate, Aspartate, Valine, Leucine, Isoleucine, Tryptophan measured in a biological sample isolated from a subject after 3 months of time has elapsed (Tryptophan), methionine, Threonine, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, choline ( Choline), lactate (Lactate), malic acid (Malic acid), the expression level of one or more metabolites selected from the group consisting of serine (Serine) and arginine (Arginine) before the start of treatment for the non-tuberculous mycobacterium infection Or when the expression level of the metabolite measured in the biological sample isolated from the target individual at the time of initiation of treatment is increased, predicting that the treatment responsiveness of the patient infected by the non-tuberculous mycobacteria is low can

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of allantoin measured in the biological sample isolated from the target subject after the lapse of 3 months, before the start of treatment for the non-tuberculous mycobacterium infection or at the start of treatment, the biological sample isolated from the subject When the expression level of allantoin measured in the sample is decreased, the method may further include predicting that the treatment responsiveness of the patient infected with non-tuberculous mycobacteria is low.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to Phenylalanine, Glutamate, Aspartate, Valine, Leucine, Isoleucine, Tryptophan measured in a biological sample isolated from a subject after 3 months of time has elapsed (Tryptophan), methionine, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, choline and lactate (Lactate), the expression level of one or more selected from the group consisting of, the metabolite expression level measured in a biological sample isolated from the subject before or at the time of initiation of treatment for the non-tuberculous mycobacterium infection. When it is reduced compared to, the method may further include predicting that the treatment responsiveness of a patient infected with a non-tuberculous mycobacterium, preferably a patient with a nodular bronchiectatic form lung disease caused by a non-tuberculous mycobacterium infection is high.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to Phenylalanine, Glutamate, Aspartate, Valine, Leucine, Isoleucine, Tryptophan measured in a biological sample isolated from a subject after 3 months of time has elapsed (Tryptophan), methionine, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, choline and lactate The expression level of one or more selected from the group consisting of (Lactate) is the expression level of the metabolite measured in a biological sample isolated from the subject before or at the time of initiation of treatment for the non-tuberculous mycobacterium infection. When it is increased compared to that, the method may further include predicting that the treatment responsiveness of a patient infected with a non-tuberculous mycobacterium, preferably a patient with a nodular bronchiectatic form lung disease caused by a non-tuberculous mycobacterium infection is low.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of phenylalanine and isoleucine measured in the biological sample isolated from the subject after the lapse of 3 months is, When it is reduced compared to the expression level of the metabolite measured in the biological sample isolated from the subject of interest, the patient infected with non-tuberculous mycobacteria, preferably Mycobacterium avium (M. avium) infection The method may further include predicting that the treatment responsiveness is high.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of phenylalanine and isoleucine measured in the biological sample isolated from the subject after the lapse of 3 months is, When it is increased compared to the expression level of the metabolite measured in the biological sample isolated from the subject of interest, a patient infected with a non-tuberculous mycobacterium, preferably a M. avium-infected patient The method may further include predicting that the treatment responsiveness is low.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of aspartate and hypoxanthine measured in the biological sample isolated from the subject after the lapse of 3 months is, When the expression level of the metabolite measured in the biological sample isolated from the subject of interest at the time of initiation is decreased compared to the expression level of the metabolite, a patient infected with a non-tuberculous mycobacterium, preferably M. intracellulare (M. intracellulare) ) may further include the step of predicting that the treatment responsiveness of the infected patient is high.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of allantoin measured in the biological sample isolated from the target subject after the lapse of 3 months, before the start of treatment for the non-tuberculous mycobacterium infection or at the start of treatment, the biological sample isolated from the subject When it is increased compared to the expression level of the metabolite measured in the sample, it is predicted that the treatment responsiveness of patients infected with non-tuberculous mycobacteria, preferably M. intracellulare infection, is high. It may include further steps.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of aspartate and hypoxanthine measured in the biological sample isolated from the subject after the lapse of 3 months is, When it is increased compared to the expression level of the metabolite measured in a biological sample isolated from the subject of interest at the time of initiation, a patient infected with a non-tuberculous mycobacterium, preferably M. intracellulare (M. intracellulare) ) may further include predicting that the treatment responsiveness of the infected patient is low.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of allantoin measured in the biological sample isolated from the target subject after the lapse of 3 months, before the start of treatment for the non-tuberculous mycobacterium infection or at the start of treatment, the biological sample isolated from the subject When it is decreased compared to the expression level of the metabolite measured in the sample, it is predicted that the treatment responsiveness of patients infected with non-tuberculous mycobacteria, preferably M. intracellulare infection, is low. It may include further steps.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to At least one selected from the group consisting of Phenylalanine, Glutamate, Methionine, Threonine, and Hypoxanthine measured from a biological sample isolated from a subject after 3 months of time has elapsed When the expression level is reduced compared to the expression level of the metabolite measured in a biological sample isolated from the target subject before the start of treatment for the non-tuberculous mycobacterium infection or at the time of initiation of treatment for the non-tuberculous mycobacterium infection, The method may further include predicting that an infected patient, preferably a male patient, is highly responsive to treatment.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to At least one selected from the group consisting of Phenylalanine, Glutamate, Methionine, Threonine, and Hypoxanthine measured from a biological sample isolated from a subject after 3 months of time has elapsed When the expression level is increased compared to the expression level of the metabolite measured in a biological sample isolated from the target subject before initiation of treatment for the non-tuberculous mycobacterium infection or at the time of initiation of treatment for the non-tuberculous mycobacterium infection, It may further comprise the step of predicting that the treatment responsiveness of the infected patient, preferably a male patient, is low.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of N,N-Dimethylglycine and Phenylalanine measured in a biological sample isolated from the subject after 3 months of time has elapsed, When the expression level of the metabolite measured in a biological sample isolated from the subject of interest before initiation of treatment or at the time of initiation of treatment is decreased, the treatment reactivity of a patient infected with non-tuberculous mycobacteria, preferably a female patient It may further include the step of predicting this high.

As another example of the present invention, in the present invention, 10 days to 24 months, 1 month to 12 months, 3 months to 6 months, 2 months to 4 months, or 1 month to The expression level of at least one of N,N-Dimethylglycine and Phenylalanine measured in a biological sample isolated from the subject after 3 months of time has elapsed, When the expression level of the metabolite measured in a biological sample isolated from the subject before the start of treatment or at the time of initiation of treatment is increased, the treatment reactivity of a patient infected with non-tuberculous mycobacteria, preferably a female patient It may further include the step of predicting that this is low.

In the present invention, the term "high therapeutic responsiveness" refers to a favorable response to a therapeutic agent for the treatment of a non-tuberculous mycobacterium infection, a low risk or low risk of resistance to the therapeutic agent, and a negative charge of non-tuberculous mycobacteria after treatment. It may mean that this occurs, or that the survival period increases, but is not limited thereto.

In the present invention, the term "low therapeutic responsiveness" refers to a non-preferential response to a therapeutic agent for the treatment of non-tuberculous mycobacterium infection, a risk or high risk of resistance to the therapeutic agent, and a bacterial negative charge that does not occur even after treatment. It may mean that the positivity persists or the bacteria positivity occurs again after the bacterial negative change, or the survival period is shortened, but is not limited thereto.

In the present invention, by measuring the expression level of a blood metabolite in a biological sample of a target individual, the most appropriate treatment method for a non-tuberculous mycobacterium-infected patient is provided by simply, easily and accurately predicting the therapeutic response of a non-tuberculous mycobacterium-infected patient. allow you to choose

Figures 1a to 1j in one embodiment of the present invention, among patients infected with Mycobacterium avium complex (MAC), in patients who succeeded in antibacterial treatment through antibiotic treatment and patients who failed, each of the serum samples obtained before the antibiotic treatment It shows a graph comparing the expression level of metabolites.
Figures 2a to 2h in one embodiment of the present invention, among patients infected with Mycobacterium avium complex (MAC), in patients who succeeded in antibiotic treatment through antibiotic treatment and patients who failed, 3 months after the start of the antibiotic treatment A graph comparing the expression level of each metabolite in the serum samples obtained at the time point is shown.
Figures 3a to 3g in one embodiment of the present invention, among patients infected with Mycobacterium avium complex (MAC), in patients who succeeded in antibacterial treatment through antibiotic treatment and patients who failed, 3 months after the start of the antibiotic treatment A graph comparing the expression level of each metabolite in the serum samples obtained at the time point is shown.
Figures 4a to 4n in one embodiment of the present invention in patients with Mycobacterium avium complex (MAC) infection in patients who succeeded and failed in antibiotic treatment through antibiotic treatment, each of the serum samples obtained before antibiotic treatment It shows a graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration (T0).
5a to 5n are each of the serum samples obtained before antibiotic treatment in patients who succeeded in antibiotic treatment and patients who failed in antibiotic treatment among Mycobacterium avium complex (MAC)-infected patients in one embodiment of the present invention. It shows a graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration (T0).
Figures 6a to 6j are in one embodiment of the present invention in patients with successful and unsuccessful antibiotic treatment among patients with nodular bronchiectatic form lung disease caused by Mycobacterium avium complex (MAC) infection. , Median of the percent ratio (%) of each metabolite concentration (T3) in the sample obtained 3 months after the start of antibiotic treatment for each metabolite concentration (T0) in the serum sample obtained before antibiotic treatment A graph comparing them is shown.
7a to 7c show that in an embodiment of the present invention, in patients with nodular bronchiectatic form lung disease caused by Mycobacterium avium complex (MAC) infection, successful and unsuccessful patients with antibiotic treatment , Median of the percent ratio (%) of each metabolite concentration (T3) in the sample obtained 3 months after the start of antibiotic treatment for each metabolite concentration (T0) in the serum sample obtained before antibiotic treatment A graph comparing them is shown.
Figures 8a and 8b in one embodiment of the present invention in patients with M. avium infection in patients who succeeded in antibiotic treatment through antibiotic treatment and patients who failed, in the serum samples obtained before antibiotic treatment. A graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in a sample obtained at 3 months after the start of antibiotic treatment for each metabolite concentration (T0) is shown.
Figures 9a to 9c in one embodiment of the present invention in patients with M. intracellulare infection, in patients who succeeded in antibiotic treatment through antibiotic treatment and patients who failed, in the serum samples obtained before antibiotic treatment. It shows a graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in a sample obtained 3 months after the start of antibiotic treatment for each metabolite concentration (T0) of
Figures 10a to 10e in one embodiment of the present invention in the patients who succeeded and failed in antibiotic treatment among male patients infected with Mycobacterium avium complex (MAC) in the serum samples obtained before antibiotic treatment. A graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in a sample obtained at 3 months after the start of antibiotic treatment for each metabolite concentration (T0) is shown.
Figures 11a and 11b show the results from the serum samples obtained before antibiotic treatment in the patients who succeeded and failed in antibiotic treatment among female patients infected with Mycobacterium avium complex (MAC) in one embodiment of the present invention. A graph comparing the median of the percent ratio (%) of each metabolite concentration (T3) in a sample obtained at 3 months after the start of antibiotic treatment for each metabolite concentration (T0) is shown.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

Example

[Experimental Example 1] Sample collection of MAC-infected patients before antibiotic treatment

Patients infected with Mycobacterium avium complex ( avium : 80, intracellulare : 65, total 145) collected at Samsung Hospital in Seoul for approximately 6 years from January 2012 to August 2016 Serum samples were prepared before the start of antibiotic treatment. Specific information of 145 patients is shown in Table 1 below. Here, for the antibiotic treatment of an infected patient, a macrolide drug, rifampicin or ethambutol, including clarithromycin or azithromycin, was used.

MAC Patient Information Infectious strain Success of Geumeumjeon after antibiotic treatment (=97) After antibiotic treatment, the failure of gyuneumjeon (=48) Total (=145) M. avium 63 17 80 M. intracellulare 34 31 65 Periods ^* x<=30 ^** X<=90 ^*** 90<x ^**** 48 145 n, 28 35 34 lung disease form Nodular bronchiectatic (NB) 82 32 114 Number 26 32 24 Upper lobe cavitary (UC) 15 16 31 n, 2 3 10 age / gender Male Female Male Female <50 2 8 x One >50 11 16 7 6 >60 19 38 19 15 32 65 26 22 145 * periods: Depending on the antibiotic treatment, it refers to the period of time for successful
** X<=30: If antibiotic treatment was successful within 30 days
*** X<=90: If antibiotic treatment was successful within 90 days
**** 90<X: If antibiotic treatment was successful in over 90 days

[Experimental Example 2] Sample collection of MAC-infected patients after 3 months of antibiotic treatment

Lungs infected with Mycobacterium avium complex ( avium : 80, intracellulare : 65, total 145) collected at Samsung Hospital, Seoul for approximately 6 years from January 2012 to August 2016 Serum samples were prepared 3 months after the start of antibiotic treatment of diseased patients. However, out of 145 patients with the Mycobacterium avium complex-infected lung disease, 97 patients succeeded in antibiotic treatment and 48 patients failed to perform the fungal infection. Here, for the antibiotic treatment of an infected patient, a macrolide drug, rifampicin or ethambutol, including clarithromycin or azithromycin, was used.

[Experimental Example 3] Pretreatment of samples

First, 300 μl chloroform and 150 μl methanol (chloroform-methanol, 2:1, v/v, 4 ℃) were added to the serum sample (50 μl) obtained in Experimental Example 1 and mixed for 30 seconds. 150 μl of water was added thereto, mixed for 30 seconds, put in ICE, and left for 10 minutes for extraction. Then, after centrifugation at 13,000 rpm, 4 ℃ for 10 minutes using a centrifugal separator, the supernatant (250 μl) was separated and dried using a speed vacuum (full vacuum, no temp, 5hours) to analyze the following metabolites It was stored at -20 °C until For mass spectrometry analysis, re-dissolve the dried sample in 250 μl acetonitrile-H ₂ O (75:25, v/v), and filter tube to remove any impurities that may be present. (Costar 8169) was used for filtration and analysis was performed. With Machinery Quality Control (MQC), it is a pre-treatment method such as a serum sample to check the condition of MS/MS equipment. Using serum from a healthy person as a sample for machine quality control (MQC), repeat 4 times per batch analyzed. For sample quality control (SQC), 20 μl per sample was collected to compare differences between samples in each batch, and sample quality control was prepared and analyzed 4 times per batch.

[Experimental Example 4] Metabolite analysis by HPLC-Triple Quad-MS

In order to analyze the polar metabolites in the analysis sample treated with serum, the analysis was performed using chromatography-tandem mass spectrometry (HPLC-MS/MS). The equipment used was an Agilent 1200 HPLC and a Sciex API4000 triple quadrupole MS. As chromatography conditions for hydrophilic interaction, polar metabolites were separated using gradient elution in two methods depending on the solvent at 20 °C using a Luna PFPP (2.0 x 150 mm, 3μm, Phenomenex) column. (A) H ₂ O (v/v) and (B) acetonitrile (v/v) were used as the first mobile phase, and (A) H ₂ O (v/v, 0.1% formic acid) as the second mobile phase and (B) acetonitrile (v/v) were used, and the gradient elution of each condition was performed in the same manner as in Table 2 below with a total analysis time of 15 minutes. Ion-Source Gas 1/2 units were 50/50 arbitrary units, and the units of Curtain Gas were 25 arbitrary units. The source temperature was 500 °C, the ion-spray floating voltage was 5.5 kV (negative -4.5 kV), and the mass range was 50 ~ 1000 m/z. Samples were injected by 3 μl using the HTC_PAL system/CTC analytics auto-sampler, and tandem mass spectrometry conditions (Scheduled Multiple Reaction Monitoring, sMRM) were performed as shown in Tables 2 to 5 below. However, in Tables 3 to 6, m/z means mass to charge ratio, RT means retention time, CE means collision energy, (+) means positive ion mode and (-) means negative ion mode. For the results obtained through sMRM analysis, raw data was calculated through Sciex's Quantitative Analysis Software, and MQC data average value was used to calculate metabolites with a relative standard deviation (RSD<20) or less.

hours (minutes) Mobile phase A (%) Mobile phase B (%) Flow rate (mL/min) 0 100 0 0.35 8 73 27 0.35 9 15 85 0.35 10 100 0 0.35 15 100 0 0.35

Water method (+), 21 metabolites Metabolites (Compounds) m/z product ion RT CE Tyrosine (L-Tyrosine) 182 77 2.8 41 Cystathionine (L-Cystathionine) 223 134 0.9 11 Betaine 118 58 1.32 39 Thiamine 127 110 5.43 21 Ornithine 133 70 0.95 25 Guanine 152 110 2.2 27 Histidine 156 110 1.32 12 Acetylornithine (N-Acetylornithine) 175 115 1.14 14 Glucosamine 180 162 1.4 10 Uracil 113 70 1.85 23 Deoxyuridine 229 113 6.21 11 Cytidine 244 112 2.44 12 Deoxyadenosine 252 136 8.5 20 Deoxyinosine 253 137 6.58 12 Adenosine 268 136 7.72 27 Deoxyguanosine 268 152 6.84 15 Inosine 269 137 6.24 14 Guanosine 284 152 6.55 17 Xanthosine 285 153 6.97 20 Cyclic AMP 328 287 0.86 9 SAH 385 136 0.46 19

Water method (-)), 12 metabolites Metabolites (Compounds) m/z product ion RT CE Glucose (D-Glucose) 179 89 0.92 -12 Hydroxybutyrate (3-hydroxybutyric acid) 103 41 0.96 -32 Taurine 124 80 0.9 -16 Anthranilate 136 92 3.68 -16 Hydroxybenzoate (p-Hydroxybenzoate) 137 93 1.6 -21 Citrulline 174 131 1.21 -13 Hydroxyphenylpyruvate (p-Hydroxybenzoate) 179 107 0.97 -11 myo-Inositol 179 161 0.94 -15 Thymidine 241 125 7.02 -10 Uridine 243 111 4.22 -12 Nicotinate 122 78 1.54 -14 Uric acid 167 124 1.35 -22

Formic acid method (+), 32 metabolites Metabolites (Compounds) m/z product ion RT CE Serine (L-Serine) 106 60 0.9 15 Proline (L-Proline) 116 70 1.13 21 L-Valine 118 72 1.41 15 Threonine (L-Threonine) 120 74 0.96 15 Isoleucine (L-isoLeucine) 132 86 1.93 15 Leucine (L-Leucine) 132 86 2.3 15 Asparagine (L-Asparagine) 133 74 0.9 17 Glutamine (L-Glutamine) 147 84 0.95 23 Lysine (L-Lycine) 147 84 0.74 23 Glutamate (L-Glutamate) 148 84 One 23 Methionine (L-Methionine) 150 104 1.8 11 Phenylalanine (L-Phenylalanine) 166 120 6.41 17 Arginine (L-Arginine) 175 70 0.8 35 Tryptophan (L-Tryptophan) 205 188 8.4 13 Dimethylglycine (N,N-Dimethylglycine) 104 58 1.21 27 Choline 104 60 0.9 19 Glycine 76 30 1.06 16 Folate 442 295 9.58 19 Adenine 136 119 1.75 24 Homocysteine 136 90 1.26 15 Hypoxanthine 137 110 2.8 29 Xanthine 153 110 2.5 23 Allantoin 159 99 1.17 13 Cytosine 112 95 0.98 17 Homoserine 120 56 1.03 27 Thiamine 265 122 0.96 17 Cysteine 122 59 1.24 27 CMP 324 112 1.68 16 UMP 325 97 3 49 AMP 348 136 1.99 21 IMP 349 137 5.7 17 Spermine 203 112 0.53 27

Formic acid method (-), 24 metabolites Metabolites (Compounds) m/z product ion RT CE Aspartate (L-Aspartate) 132 88 0.96 -17 Lactate ((S)-Lactate)) 89 43 1.74 -18 Phosphoglycerate (3-Phosphoglycerate) 185 97 2.11 -22 Succinate 117 73 3.88 -18 Malate (L-Malic acid) 133 115 1.78 -16 Citrate 191 111 3.58 -12 Hydroglutarate (D-2-Hydroyglutaric acid) 147 129 1.03 -14 GTP 522 424 1.6 -30 Acetylphosphate 139 79 1.65 -22 Carbamoyl-phosphate 140 79 0.9 -22 Glycerate 105 75 1.24 -15 Phosphoenolpyruvate 167 79 2.3 -16 Dihydroxyacetone phosphate 169 79 1.7 -38 Glycerol 3-Phosphate 171 79 1.5 -22 Shikimate 173 93 1.65 -16 Allontoate 175 132 1.05 -12 Deoxyrebose 1-Phosphate 213 79 1.6 -33 D-Ribulose 5-Phosphate 229 79 1.3 -48 Glucose 6-Phosphate 259 79 1.73 -40 Fructose 1,6-Bisphosphate 339 271 0.98 -18 dGMP 346 79 2.02 -20 PRPP 389 291 1.4 -18 Itaconate 129 85 6.4 -14 Fructose 6-Phosphate 259 79 1.23 -54

[Experimental Example 5] Metabolite analysis results in serum samples according to treatment reactivity in samples before antibiotic treatment

Metaboanalyst (data statistic site) with the following statistical tests to compare the metabolite concentration of the success or failure of bacterial negative electrolysis with the serum sample of a patient infected with Mycobacterium avium complex (MAC) before antibiotic treatment (data statistics site) and SPSS statistical program were used to calculate the data, and the results were used to distinguish between those who succeeded and those who failed due to antibiotic treatment among Mycobacterium avium complex (MAC)-infected patients before antibiotic treatment. A total of 10 related metabolites were selected based on their respective p-values and fold change values, and the results are shown in Table 7 and FIGS. 1A to 1J below. However, in FIGS. 1a to 1j, Success indicates the expression level of each metabolite in the serum samples before antibiotic treatment of 97 patients who succeeded in negative transfer by antibiotic treatment, and Fail is antibiotic treatment of 48 patients who failed to negatively transfer by antibiotic treatment. The expression level of each metabolite in the whole serum sample is shown. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Arginine 0.02 0.81 L-Methionine 0.0327 0.79 L-isoLeucine 0.0146 0.73 N,N-Dimethylglycine (N,N-Dimethylglycine) 0.0683 0.83 L-Valine 0.0546 0.88 L-Threonine 0.0712 0.84 L-Lysine 0.0843 0.84 L-Phenylalanine 0.0556 0.86 Homoserine 0.079 0.84 3-hydroxybutyric acid 0.076 0.49

As shown in Table 7 and FIGS. 1A to 1J, in the serum sample before antibiotic treatment of a patient who succeeded in negative charge with antibiotic treatment among non-tuberculous mycobacterium-infected patients, L-Arginine, L of blood metabolites -Methionine, L-Isoleucine, N,N-Dimethylglycine, L-Valine, L-Threonine, L -L-Lysine, L-Phenylalanine, Homoserine and 3-hydroxybutyric acid were significantly increased in expression level compared to patients who failed could confirm that

[Experimental Example 6] Metabolite analysis results in serum samples according to treatment reactivity in samples after initiation of antibiotic treatment

Serum samples from Mycobacterium avium complex (MAC)-infected patients obtained 3 months after the start of antibiotic treatment. Data were calculated using Metaboanalyst (data statistics site) and SPSS statistical program in two ways, and using the results, antibiotic treatment among patients with Mycobacterium avium complex (MAC) infection after antibiotic treatment A total of 15 disease-related metabolites that can distinguish successful and unsuccessful people were selected based on their respective p-values and fold change values, and the results are shown in Table 8 and FIGS. 2A to 2H and 3A to 3G shown in However, in FIGS. 2a to 2h and 3a to 3g, Success is the expression level of each metabolite in the serum sample obtained 3 months after the start of antibiotic treatment of 97 patients who succeeded in antibiotic treatment with antibiotic treatment, Fail indicates the expression level of each metabolite in the serum samples obtained 3 months after the start of antibiotic treatment of 48 patients who failed antibiotic treatment with antibiotic treatment. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Valine 0.0069 1.22 L-Methionine 0.0309 1.24 L-Arginine 0.0279 1.24 N,N-Dimethylglycine (N,N-Dimethylglycine) 0.0044 1.24 Choline 0.0356 1.15 Hypoxanthine 0.0009 1.39 Glycerol 3-phosphate 0.0421 1.44 L-isoLeucine 0.0103 1.6 L-Leucine 0.0081 1.46 L-Glutamate 0.0011 1.61 L-Phenylalanine 0.0007 1.37 L-Aspartate 0.0002 2.22 S-Lactate 0.0013 1.4 L-Malic acid 0.0068 2.13 D-2-Hydroxyglutaric acid 0.0003 2.01

As shown in Table 8 and FIGS. 2A to 2H and 3A to 3G, the serum samples obtained at the time point 3 months after the start of antibiotic treatment of non-tuberculous mycobacterium-infected patients who succeeded in antibiotic treatment with antibiotic treatment , L-Valine, L-Methionine, L-Arginine, N,N-Dimethylglycine, Choline among blood metabolites , Hypoxanthine, glycerol 3-phosphate (Glycerol 3-phosphate), L-isoleucine (L-isoLeucine), leucine (Leucine), L-glutamate (L-Glutamate), L-phenylalanine (L-Phenylalanine), L-Aspartate, S-Lactate, L-Malic acid and D-2-Hydroxyglutaric acid are It was confirmed that the expression level was significantly reduced compared to the patients who failed negative charge.

[Experimental Example 7] Metabolite analysis results in serum samples according to treatment reactivity in samples before and after antibiotic treatment

In order to predict the success of antibiotic treatment in patients with Mycobacterium avium complex (MAC) infection, the metabolite concentration in the serum sample before antibiotic treatment was obtained at the time point 3 months after the start of antibiotic treatment. The ratio of metabolite concentration in one sample was calculated as data using Metaboanalyst (data statistics site) and SPSS statistical program with the following two methods of statistical test, and disease that can predict success or failure of bacterial negative charge using the result A total of 14 related metabolites were selected based on their respective p-values and fold change values, and are shown in Tables 9 to 11, and FIGS. 4A to 4N and 5A to 5N. However, Table 9 shows that, in the patient group who succeeded in negative charge with antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained at the time point 3 months after the start of antibiotic treatment. shows the median of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 11 shows the ratio of the median value of Table 10 to the median value of Table 9 for each metabolite. In addition, in FIGS. 4a to 4n and 5a to 5n, Success is obtained at a time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who has succeeded in antibiotic treatment. It shows the percentage ratio (%) of the metabolite concentration in one sample, and Fail is the antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment 3 months after the start of antibiotic treatment Shows the percent ratio (%) of the metabolite concentration in the sample obtained at one time point. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 85.6 N,N-Dimethylglycine (N,N-Dimethylglycine) 86.9 Hypoxanthine 84.7 L-Glutamate 68.6 D-2-Hydroxyglutaric acid 66.6 L-Aspartate 58.2 L-Valine 87.9 L-Leucine 83.7 Choline 95.3 L-isoLeucine 95.2 S-Lactate 79.7 L-Malic acid 79.7 L-Serine 86.7 L-Arginine 75.6

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 115.5 N,N-Dimethylglycine (N,N-Dimethylglycine) 127.5 Hypoxanthine 107 L-Glutamate 168.5 D-2-Hydroxyglutaric acid 152 L-Aspartate 139.5 L-Valine 122.5 L-Leucine 117.5 Choline 129 L-isoLeucine 140.5 S-Lactate 124 L-Malic acid 215 L-Serine 93.0 L-Arginine 120.6

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Phenylalanine 0.0009 1.35 N,N-Dimethylglycine (N,N-Dimethylglycine) 0.005 1.47 Hypoxanthine 0.011 1.26 L-Glutamate 0.011 2.46 D-2-Hydroxyglutaric acid 0.014 2.28 L-Aspartate 0.020 2.40 L-Valine 0.020 1.39 L-Leucine 0.021 1.40 Choline 0.032 1.35 L-isoLeucine 0.037 1.48 S-Lactate 0.0678 1.56 L-Malic acid 0.0793 2.70 L-Serine 0.4838 1.07 L-Arginine 0.1484 1.60

As shown in Table 9 above, when antibiotic treatment succeeded in negative transduction among non-tuberculous mycobacteria-infected patients, L among blood metabolites in the serum sample obtained 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment -Phenylalanine (L-Phenylalanine), N,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), L-glutamate (L-Glutamate), D-2-hydroxyglutaric acid (D-2) -Hydroxyglutaric acid), L-Aspartate, L-Valine, L-Leucine, Choline, L-Isoleucine, S- It was confirmed that the expression levels of lactate (S-Lactate), L-malic acid (L-Malic acid), serine (L-Serine) and L- arginine (L-Arginine) were significantly reduced.

As shown in Table 10 above, when antibiotic treatment failed to negatively affect non-tuberculous mycobacterium infection, in the serum sample obtained 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment, L among blood metabolites -Phenylalanine (L-Phenylalanine), N,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), L-glutamate (L-Glutamate), D-2-hydroxyglutaric acid (D-2) -Hydroxyglutaric acid), L-Aspartate, L-Valine, L-Leucine, Choline, L-Isoleucine, S- The expression levels of lactate (S-Lactate), L-malic acid (L-Malic acid) and L-arginine (L-Arginine) were significantly increased, and the expression level of serine (L-Serine) was significantly decreased. could confirm that

In addition, as shown in Table 11 and FIGS. 4a to 4n and 5a to 5n, among the blood metabolites, L-phenylalanine (L-Phenylalanine), N,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), L-glutamate (L-Glutamate), D-2-hydroxyglutaric acid (D-2-Hydroxyglutaric acid), L-aspartate (L-Aspartate), L-valine (L-Valine) , L-Leucine, Choline, L-isoLeucine, S-Lactate, L-Malic acid, L-Serine And for L-Arginine, the ratio of the expression level in the serum sample obtained 3 months after the start of antibiotic treatment to the expression level in the serum sample obtained before the antibiotic treatment is, non-tuberculosis It was confirmed that among the mycobacteria-infected patients, the number of successful antibiotic treatment was significantly reduced compared to the unsuccessful case.

[Experimental Example 8] Results of analysis of metabolites in serum samples according to treatment reactivity in samples before and after antibiotic treatment of patients with nodular bronchiectatic form lung disease among patients infected with non-tuberculous mycobacteria

In order to predict the success of antibacterial antibiotic treatment in patients with mycobacterium avium complex (MAC) infection, particularly in patients with nodular bronchiectatic form lung disease, the same analysis as in Experimental Example 7 was performed, and as a result, A total of 13 disease-related metabolites that can predict the success or failure of bacterial negative charge using to 7c. However, Table 12 shows that, in the patient group who succeeded in negative charge by antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained at the time point 3 months after the start of antibiotic treatment. shows the median value of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 14 shows the ratio of the median value of Table 13 to the median value of Table 12 for each metabolite. In addition, in FIGS. 6a to 6j and 7a to 7c, Success is obtained at a time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who has succeeded in antibiotic treatment. It shows the percentage ratio (%) of the metabolite concentration in one sample, and Fail is the antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment 3 months after the start of antibiotic treatment Shows the percent ratio (%) of the metabolite concentration in the sample obtained at one time point. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 80.75 L-Valine 83.35 N,N-Dimethylglycine (N,N-Dimethylglycine) 81.55 L-Leucine 81.6 Choline 93.55 D-2-Hydroxyglutaric acid 57.75 L-Aspartate 46.7 Hypoxanthine 78.85 L-isoLeucine 85.2 L-Methionine 88.45 L-Glutamate 65.95 S-Lactate 75.1 L-Tryptophan 90.45

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 112 L-Valine 109 N,N-Dimethylglycine (N,N-Dimethylglycine) 119.5 L-Leucine 108 Choline 129 D-2-Hydroxyglutaric acid 129.5 L-Aspartate 115 L-isoLeucine 134.5 L-Methionine 104.5 S-Lactate 117.5

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Phenylalanine 0.004 1.39 L-Valine 0.009 1.30 N,N-Dimethylglycine (N,N-Dimethylglycine) 0.009 1.47 L-Leucine 0.022 1.32 Choline 0.025 1.37 D-2-Hydroxyglutaric acid 0.026 2.24 L-Aspartate 0.027 2.46 Hypoxanthine 0.029 1.59 L-isoLeucine 0.035 1.58 L-Methionine 0.043 1.81 L-Glutamate 0.064 1.49 S-Lactate 0.074 1.56 L-Tryptophan 0.083 1.26

As shown in Table 12 above, when antibiotic treatment succeeded in negative charge with antibiotic treatment among patients with non-tuberculous mycobacterium-infected bronchiectatic form lung disease, 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment Among the blood metabolites in the obtained serum sample, L-phenylalanine, L-valine, N,N-dimethylglycine, L-leucine, Choline, D-2-Hydroxyglutaric acid, L-Aspartate, L-isoLeucine, L-Methionine ) and it was confirmed that the expression level of S-lactate was significantly decreased.

As shown in Table 13 above, when antibiotic treatment fails to negatively transfer bacteria among patients with non-tuberculous mycobacterium-infected bronchiectatic form lung disease, when 3 months have elapsed from the start of antibiotic treatment compared to the serum sample before antibiotic treatment Among the blood metabolites in the obtained serum sample, L-phenylalanine, L-valine, N,N-dimethylglycine, L-leucine, Choline, D-2-Hydroxyglutaric acid, L-Aspartate, L-isoLeucine, L-Methionine ) and it was confirmed that the expression level of S-lactate was significantly increased.

In addition, as shown in Table 14 and FIGS. 6a to 6j and 7a to 7c, among the blood metabolites, L-phenylalanine (L-Phenylalanine), L-valine (L-Valine), N,N-dimethylglycine ( N,N-Dimethylglycine), L-leucine (L-Leucine), Choline, D-2-hydroxyglutaric acid (D-2-Hydroxyglutaric acid), L-aspartate (L-Aspartate), Hypoxanthine, L-isoLeucine, L-Methionine, L-Glutamate, S-Lactate and L-Tryptophan In ), the ratio of the expression level in the serum sample obtained 3 months after the start of antibiotic treatment to the expression level in the serum sample obtained before the antibiotic treatment is, bronchiectatic form) It was confirmed that the cases of successful antibiotic treatment with lung disease significantly decreased compared to the cases of failure.

[Experimental Example 9] Metabolite analysis results in serum samples according to treatment reactivity in samples before and after antibiotic treatment of a patient infected with Mycobacterium avium (M. avium)

In order to predict the success of antibiotic treatment in Mycobacterium avium (M. avium) infected patients, the same analysis as in Experimental Example 7 was performed, and using the result, A total of two disease-related metabolites were selected based on their respective p-values and fold change values, and are shown in Tables 15 to 17 and FIGS. 8A and 8B below. However, Table 15 shows that, in the patient group who succeeded in negative charge with antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained at the time point 3 months after the start of antibiotic treatment. shows the median of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 17 shows the ratio of the median value of Table 16 to the median value of Table 15 for each metabolite. In addition, in Figures 8a and 8b, Success is the metabolism in the sample obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who succeeded in antibiotic treatment with antibiotic treatment It represents the percentage ratio (%) of the body concentration, and Fail is obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment with antibiotic treatment. It shows the percentage ratio (%) of the metabolite concentration in the sample. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 71 L-isoLeucine 75.2

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-isoLeucine 120

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Phenylalanine 0.035 1.56 L-isoLeucine 0.061 1.60

As shown in Table 15 above, when antibiotic treatment among Mycobacterium avium-infected patients succeeded in negative charge, compared to the serum sample before antibiotic treatment, it was obtained at a time point 3 months after the start of antibiotic treatment. In the serum sample, it was confirmed that the expression levels of L-phenylalanine (L-Phenylalanine) and L-isoleucine (L-isoLeucine) among blood metabolites were significantly reduced.

As shown in Table 16 above, when antibiotic treatment fails to negatively affect Mycobacterium avium among patients infected with M. In the serum sample, it was confirmed that the expression level of L-isoLeucine among blood metabolites was significantly increased.

In addition, as shown in Table 17 and FIGS. 8A and 8B, the expression of L-phenylalanine and L-isoLeucine in blood metabolites in serum samples obtained before antibiotic treatment The ratio of the expression level in the serum sample obtained at the time point 3 months after the start of antibiotic treatment to the level is, the case where the success of antibiotic treatment with antibiotic treatment among patients infected with Mycobacterium avium failed. It was confirmed that there was a significant decrease compared to the case.

[Experimental Example 10] Metabolite analysis results in serum samples according to treatment reactivity in samples before and after antibiotic treatment of a patient infected with Mycobacterium intracellulare (M. intracellulare)

In order to predict the success of antibiotic treatment in Mycobacterium intracellulare-infected patients, the same analysis as in Experimental Example 7 was performed, and the result could be used to predict the success of bacterial negative charge. A total of three disease-related metabolites were selected based on their respective p-values and fold change values, and are shown in Tables 18 to 19 and FIGS. 9A to 9C below. However, Table 18 shows that in the patient group who succeeded in negative transfer by antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained 3 months after the start of antibiotic treatment. shows the median of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 20 shows the ratio of the median value of Table 19 to the median value of Table 18 for each metabolite. In addition, in Figures 9a to 9c, Success is the metabolism in the sample obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who succeeded in negative charge with antibiotic treatment It represents the percentage ratio (%) of the body concentration, and Fail is obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment with antibiotic treatment. It shows the percentage ratio (%) of the metabolite concentration in the sample. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) Hypoxanthine 87.9 Allantoin 103.5 L-Aspartate 80.5

Metabolites (Compounds) Fold Change
(T3/T0 X 100) Hypoxanthine 119 Allantoin 96.3 L-Aspartate 239

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) Hypoxanthine 0.041 1.49 Allantoin 0.075 0.89 L-Aspartate 0.089 1.73

As shown in Table 18 above, when antibiotic treatment was successful among Mycobacterium intracellulare-infected patients, it was obtained at a time point 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment. In one serum sample, the expression levels of hypoxanthine and L-aspartate among blood metabolites were significantly decreased, and it was confirmed that the expression level of allantoin was significantly increased. .

As shown in Table 19 above, in the case of failure of antibiotic treatment among Mycobacterium intracellulare-infected patients, it was obtained at a time point 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment. In one serum sample, the expression levels of hypoxanthine and L-aspartate among blood metabolites among blood metabolites were significantly increased, and the expression level of allantoin was significantly decreased. could confirm that

In addition, as shown in Table 20 and FIGS. 9A to 9C , in the blood metabolites, hypoxanthine and L-aspartate, the expression level in the serum sample obtained before the antibiotic treatment The ratio of expression levels in serum samples obtained 3 months after the start of antibiotic treatment for It was significantly decreased compared to the case, and it was confirmed that allantoin was significantly increased.

[Experimental Example 11] Metabolite analysis results in serum samples according to treatment reactivity in samples before and after antibiotic treatment of a male patient infected with non-tuberculous mycobacteria

In a male patient infected with Mycobacterium avium complex (MAC), in order to predict the success of antibiotic treatment, the same analysis as in Experimental Example 7 was performed, and the result could be used to predict the success of bacterial negative charge A total of five disease-related metabolites were selected based on their respective p-values and fold change values, and are shown in Tables 21 to 22 and FIGS. 10A to 10E. However, Table 21 shows that, in the patient group who succeeded in negative charge with antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained at the time point 3 months after the start of antibiotic treatment. shows the median of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 23 shows the ratio of the median value of Table 22 to the median value of Table 21 for each metabolite. In addition, in Figures 10a to 10e, Success is the metabolism in the sample obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who succeeded in antibiotic treatment with antibiotic treatment It represents the percentage ratio (%) of the body concentration, and Fail is obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment with antibiotic treatment It shows the percentage ratio (%) of the metabolite concentration in the sample. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Phenylalanine 84.8 Hypoxanthine 87.6 L-Glutamate 85.6

Metabolites (Compounds) Fold Change
(T3/T0 X 100) L-Methionine 163.5 L-Phenylalanine 124.5 Hypoxanthine 130 L-Threonine 159 L-Glutamate 183

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) L-Methionine 0.021 1.70 L-Phenylalanine 0.021 1.47 Hypoxanthine 0.043 1.48 L-Threonine 0.071 1.41 L-Glutamate 0.081 2.14

As shown in Table 21 above, when antibiotic treatment among male patients infected with Mycobacterium avium complex (MAC) succeeded in negative charge, compared to the serum sample before antibiotic treatment, it was obtained at a time point 3 months after the start of antibiotic treatment. In the serum sample, it was confirmed that the expression levels of L-phenylalanine, hypoxanthine, and L-glutamate among blood metabolites were significantly reduced.

As shown in Table 22 above, when antibiotic treatment fails to negatively affect male patients infected with Mycobacterium avium, it is obtained at a time point 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment. Among blood metabolites in one serum sample, L-methionine, L-Phenylalanine, Hypoxanthine, L-Threonine, and L-Glutamate It was confirmed that the expression level was significantly increased.

In addition, as shown in Table 23 and FIGS. 10a to 10e, among the blood metabolites, L-methionine (L-Methionine), L-phenylalanine (L-Phenylalanine), hypoxanthine (Hypoxanthine), L-threonine (L- Threonine) and L-glutamate (L-Glutamate), the ratio of the expression level in the serum sample obtained 3 months after the start of antibiotic treatment to the expression level in the serum sample obtained before the antibiotic treatment is, Among male patients infected with Mycobacterium avium, it was confirmed that the case of successful antibiotic treatment with antibiotic treatment was significantly reduced compared to the case of failure.

[Experimental Example 12] Metabolite analysis results in serum samples according to treatment reactivity in samples before and after antibiotic treatment of a female patient infected with non-tuberculous mycobacteria

In a female patient infected with Mycobacterium avium complex (MAC), in order to predict the success of antibiotic treatment, the same analysis as in Experimental Example 7 was performed, and the result could be used to predict the success of bacterial negative charge. A total of two disease-related metabolites were selected based on their respective p-values and fold change values, and are shown in Tables 24 to 25 and FIGS. 11A and 11B below. However, Table 24 shows that, in the patient group who succeeded in negative transfer by antibiotic treatment, the metabolite concentration (T0) in the serum sample before antibiotic treatment for each metabolite was obtained at the time point 3 months after the start of antibiotic treatment. shows the median value of the percent ratio (%) (ie, T3/T0 x 100) of the metabolite concentration (T3) of It shows the median value of the percentage ratio (%) of the metabolite concentration in the sample obtained at the time point 3 months after the start of antibiotic treatment with respect to the metabolite concentration in the sample. Table 26 shows the ratio of the median value of Table 25 to the median value of Table 24 for each metabolite. In addition, in Figures 11a and 11b, Success is the metabolism in the sample obtained 3 months after the start of the antibiotic treatment for the expression level of each metabolite in the serum sample before the antibiotic treatment of the patient who succeeded in the antibiotic treatment with the antibiotic treatment It represents the percentage ratio (%) of the body concentration, and Fail is obtained at the time point 3 months after the start of antibiotic treatment for the expression level of each metabolite in the serum sample before antibiotic treatment of a patient who failed antibiotic treatment with antibiotic treatment. It shows the percentage ratio (%) of the metabolite concentration in the sample. In addition, *P<0.05 in the significance unpaired t-test; **P<0.01; *** means P<0.001.

Metabolites (Compounds) Fold Change
(T3/T0 X 100) N,N-Dimethylglycine (N,N-Dimethylglycine) 87.7 L-Phenylalanine 86

Metabolites (Compounds) Fold Change
(T3/T0 X 100) N,N-Dimethylglycine (N,N-Dimethylglycine) 113.5 L-Phenylalanine 108

Metabolites (Compounds) Significance (p-value) Fold Change
(Fail/Success) N,N-Dimethylglycine (N,N-Dimethylglycine) 0.04 1.29 L-Phenylalanine 0.06 1.26

As shown in Table 24 above, when antibiotic treatment among female patients infected with Mycobacterium avium complex (MAC) succeeded in negative charge, it was obtained at a time point 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment. In the serum sample, it was confirmed that the expression levels of N,N-dimethylglycine and L-phenylalanine among blood metabolites were significantly reduced.

As shown in Table 25 above, when antibiotic treatment among female patients infected with Mycobacterium avium fails to produce negative bacterium, it is obtained at a time point 3 months after the start of antibiotic treatment compared to the serum sample before antibiotic treatment. In one serum sample, it was confirmed that the expression levels of N,N-dimethylglycine and L-Phenylalanine among blood metabolites were significantly increased.

In addition, as shown in Table 26 and FIGS. 11a and 11b, in the blood metabolites N,N-dimethylglycine (N,N-Dimethylglycine) and L-phenylalanine (L-Phenylalanine), obtained before antibiotic treatment The ratio of the expression level in the serum sample obtained 3 months after the start of the antibiotic treatment to the expression level in the serum sample was It was confirmed that the case of success in negative charge significantly decreased compared to the case of failure.

Claims (30)

Amino acids, amino acid derivatives, allantoin, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, 3- Contains at least one metabolite selected from the group consisting of hydroxybutyric acid, glycerol 3-phosphate, choline, lactate, and malic acid which, as a biomarker composition for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients,
The non-tuberculous mycobacterium is Mycobacterium avium (M. avium),
The amino acid and its derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, lysine, tryptophan ( Tryptophan), methionine, serine, homoserine, and threonine, which contains at least one selected from the group consisting of, non-tuberculous mycobacterium-infected patients bio for predicting treatment responsiveness marker composition. delete According to claim 1,
The amino acid is L-form (L-form), a biomarker composition for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients. According to claim 1,
Wherein the metabolite is derived from whole blood, plasma or serum of a target individual, a biomarker composition for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients. delete According to claim 1,
The biomarker composition is for predicting therapeutic responsiveness to antibiotics, a biomarker composition for predicting therapeutic responsiveness of non-tuberculous mycobacteria-infected patients. Amino acids, amino acid derivatives, allantoin, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, 3- Concentration of one or more metabolites selected from the group consisting of hydroxybutyric acid, glycerol 3-phosphate, choline, lactate, and malic acid As a kit for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients, comprising a quantitative device for measuring
The non-tuberculous mycobacterium is Mycobacterium avium (M. avium),
The amino acid and its derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, lysine, tryptophan ( Tryptophan), methionine (Methionine), serine (Serine), homoserine (Homoserine), and threonine (Threonine) will contain at least one selected from the group consisting of, a kit for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients . delete 8. The method of claim 7,
The amino acid is L-form (L-form), a kit for predicting treatment responsiveness of non-tuberculous mycobacteria-infected patients. 8. The method of claim 7,
Wherein the metabolite is derived from whole blood, plasma, or serum of a target individual, a kit for predicting therapeutic responsiveness of non-tuberculous mycobacteria-infected patients. 8. The method of claim 7,
The quantitative device is a nuclear magnetic resonance spectrometer (NMR), chromatography, or mass spectrometer, a kit for predicting treatment responsiveness of a non-tuberculous mycobacterium-infected patient. delete 8. The method of claim 7,
The kit is for predicting therapeutic responsiveness to antibiotics, a kit for predicting therapeutic responsiveness of non-tuberculous mycobacteria-infected patients. For biological samples isolated from individuals, amino acids, amino acid derivatives, allantoin, N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid ( From the group consisting of 2-hydroxyglutaric acid, 3-hydroxybutyric acid, glycerol 3-phosphate, choline, lactate and malic acid As an information providing method for predicting the treatment responsiveness of a patient infected with non-tuberculous mycobacterium comprising the step of measuring the expression level of one or more selected metabolites,
The non-tuberculous mycobacterium is Mycobacterium avium (M. avium),
The amino acid and its derivatives are arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, lysine, tryptophan ( Tryptophan), methionine (Methionine), serine (Serine), homoserine (Homoserine) and threonine (Threonine) to include at least one selected from the group consisting of, predicting the treatment responsiveness of non-tuberculous mycobacteria-infected patients How to provide information for 15. The method of claim 14,
The biological sample includes whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, tears ( tears), mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, Ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, cell extract and cerebrospinal fluid ( cerebrospinal fluid), etc., and at least one selected from the group consisting of, an information providing method for predicting the treatment responsiveness of a non-tuberculous mycobacterium-infected patient. 15. The method of claim 14,
Prior to measuring the expression level of the metabolite, the biological sample is pretreated by filtration, distillation, extraction, separation, concentration, inactivation of interfering components, or addition of a reagent. An informational method for predicting a patient's therapeutic responsiveness. delete 15. The method of claim 14,
The amino acid is an L-form (L-form), information providing method for predicting the treatment responsiveness of a patient infected with Mycobacterium tuberculosis. 15. The method of claim 14,
The step of measuring the expression level of the metabolite is performed using a quantitative device that is nuclear magnetic resonance spectroscopy (NMR), chromatography, or mass spectrometry, providing information for predicting the treatment responsiveness of non-tuberculous mycobacteria-infected patients Way. 15. The method of claim 14,
Phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, tryptophan, methionine, threonine measured for the biological sample (Threonine), N,N-dimethylglycine, hypoxanthine, 2-hydroxyglutaric acid, choline, lactate, malic acid (Malic acid), when the expression level of one or more selected from the group consisting of serine and arginine is reduced compared to the control group, predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is high. , an information providing method for predicting the treatment responsiveness of non-tuberculous mycobacterium-infected patients. 15. The method of claim 14,
When the expression level of allantoin measured with respect to the biological sample is increased compared to the control group, the method further comprising predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is high. A method of providing information for predicting treatment responsiveness. 15. The method of claim 14,
The biological sample is isolated before or at the time of initiation of treatment for non-tuberculous mycobacterium infection,
Arginine, Phenylalanine, Valine, Isoleucine, Lysine, Methionine, Homoserine, Threonine, N, When the expression level of one or more selected from the group consisting of N-dimethylglycine (N,N-Dimethylglycine) and 3-hydroxybutyric acid is increased compared to the control group, treatment of patients with non-tuberculous mycobacteria A method for providing information for predicting the treatment responsiveness of a patient infected with non-tuberculous mycobacterium, further comprising the step of predicting that the reactivity is high. 15. The method of claim 14,
The biological sample is isolated after 10 days to 24 months after initiation of treatment for non-tuberculous mycobacterium infection,
Arginine, phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, methionine, N measured for the biological sample ,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid, glycerol 3-phosphate, choline, lac When the expression level of at least one selected from the group consisting of tate (Lactate) and malic acid (Malic acid) is reduced compared to the control group, the non-tuberculosis further comprising the step of predicting that the treatment responsiveness of the non-tuberculous mycobacterium-infected patient is high A method for providing information for predicting treatment responsiveness in patients with mycobacterial infection. 15. The method of claim 14,
The non-tuberculous mycobacterium-infected patient is a patient with nodular bronchiectatic form lung disease infected with non-tuberculous mycobacterium,
Phenylalanine, glutamate, aspartate, valine, leucine, isoleucine, tryptophan, methionine, N measured with respect to the biological sample ,N-dimethylglycine (N,N-Dimethylglycine), hypoxanthine, 2-hydroxyglutaric acid (2-hydroxyglutaric acid), choline (Choline) and one selected from the group consisting of lactate (Lactate) When the above expression level is reduced compared to the control, the method for providing information for predicting the therapeutic responsiveness of a non-tuberculous mycobacterium-infected patient further comprising the step of predicting that the therapeutic responsiveness is high. 15. The method of claim 14,
When the expression level of at least one of phenylalanine and isoleucine measured with respect to the biological sample is reduced compared to the control group, further comprising the step of predicting that the treatment responsiveness is high, non-tuberculous mycobacterium-infected patient An informational method for predicting therapeutic responsiveness of delete 15. The method of claim 14,
The gender of the non-tuberculous mycobacterium-infected patient is male,
When the expression level of one or more selected from the group consisting of Phenylalanine, Glutamate, Methionine, Threonine and Hypoxanthine measured for the biological sample is reduced compared to the control group, A method for providing information for predicting treatment responsiveness of a patient infected with non-tuberculous mycobacterium, further comprising the step of predicting that the treatment responsiveness is high. 15. The method of claim 14,
The gender of the non-tuberculous mycobacterium-infected patient is female,
When the expression level of at least one of phenylalanine and N,N-dimethylglycine measured for the biological sample is reduced compared to the control, predicting that the treatment responsiveness is high. Further comprising , an information providing method for predicting the treatment responsiveness of non-tuberculous mycobacterium-infected patients. 15. The method of claim 14,
Phenylalanine, glutamate, aspartate, and valine measured in a biological sample isolated from a target subject after 10 days to 24 months after the start of treatment for the non-tuberculous mycobacterium infection , Leucine, Isoleucine, Tryptophan, Methionine, Threonine, N,N-dimethylglycine (N,N-Dimethylglycine), Hypoxanthine, 2-hydroxy The expression level of one or more metabolites selected from the group consisting of glutaric acid (2-hydroxyglutaric acid), choline (Choline), lactate (Lactate), malic acid (Malic acid), serine (Serine) and arginine (Arginine) is , When the expression level of the metabolite measured in a biological sample isolated from the subject before the start of treatment or at the time of initiation of treatment for the non-tuberculous mycobacterium infection is reduced compared to the expression level of the non-tuberculous mycobacterium-infected patient The method of providing information for predicting the treatment responsiveness of a patient infected with non-tuberculous mycobacterium, further comprising the step of predicting that the treatment reactivity is high. 15. The method of claim 14,
The expression level of Allantoin measured in a biological sample isolated from a target subject after 10 days to 24 months after initiation of treatment for the non-tuberculous mycobacterium infection, before the initiation of treatment for the non-tuberculous mycobacterium infection, or When the expression level of allantoin measured in the biological sample isolated from the subject at the time of initiation of treatment is increased, the method further comprising the step of predicting that the patient infected with non-tuberculous mycobacterium has high therapeutic responsiveness An informational method for predicting treatment responsiveness in patients infected with Mycobacterium tuberculosis.

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