WO2021107550A1 - Biomarqueur permettant de prédire la conservation ou non d'une positivité de bactéries après une infection par mycobacterium non tuberculeuse - Google Patents

Biomarqueur permettant de prédire la conservation ou non d'une positivité de bactéries après une infection par mycobacterium non tuberculeuse Download PDF

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WO2021107550A1
WO2021107550A1 PCT/KR2020/016661 KR2020016661W WO2021107550A1 WO 2021107550 A1 WO2021107550 A1 WO 2021107550A1 KR 2020016661 W KR2020016661 W KR 2020016661W WO 2021107550 A1 WO2021107550 A1 WO 2021107550A1
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mycobacterium
infection
prognosis
predicting
tuberculous mycobacteria
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Korean (ko)
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신성재
박지해
김크은산
고원중
전병우
김수영
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주식회사 큐라티스
연세대학교 산학협력단
사회복지법인 삼성생명공익재단
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Publication of WO2021107550A1 publication Critical patent/WO2021107550A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
    • G01N2030/8818—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials involving amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the present invention relates to a prognosis after infection by non-tuberculous mycobacteria, in particular, a biomarker for predicting whether or not spontaneous bacterial negative transformation does not occur and persistent bacterial positivity occurs without appropriate treatment, and a kit or prediction method for the prediction is about
  • Mycobacterium includes not only species that cause serious diseases in humans and animals, such as tuberculosis, tuberculosis bovine tuberculosis, and leprosy, but also fungal species called opportunistic bacteria, and parasitic objects found in the natural environment. About 72 species such as saprophytic species are known so far, of which 25 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 refers to mycobacteria other than Mycobacterium tuberculosis complex and Mycobacterium leprae.
  • MAC Mycobacterium avium complex
  • MAB Mycobacterium abscessus
  • M. abscessus subspecies Absesu. s M. abscessus subspecies abscessus
  • M. abscessus subspecies massiliense M. abscessus subspecies massiliense
  • An object of the present invention is to provide a biomarker composition for predicting whether or not spontaneous bacterial negative transformation does not occur without treatment, in particular, as a prognosis after infection with non-tuberculous mycobacteria, and whether bacteria positivity continues.
  • Another object of the present invention is to provide a kit for predicting the prognosis after infection with non-tuberculous mycobacteria, in particular, whether spontaneous bacterial negative transformation does not occur without treatment and bacterial positivity continues.
  • Another object of the present invention is to provide a method for predicting the prognosis after infection with non-tuberculous mycobacteria, in particular, whether or not spontaneous bacterial negative transformation does not occur without treatment and whether bacterial positivity continues.
  • biomarker composition for predicting prognosis after infection with non-tuberculous mycobacteria, including metabolites.
  • the term "prognosis” means determining whether or not treatment success, recurrence, metastasis, drug reactivity, resistance, etc., in the subject after infection with non-tuberculous mycobacteria, etc., but for the purpose of the present invention, the prognosis is With appropriate treatment after infection with Mycobacterium tuberculosis, for example, without antibiotic administration, it means whether or not spontaneous bacterial transformation does not occur and bacterial positivity persists.
  • the biomarker for predicting prognosis according to the present invention is a person with a relatively poor prognosis after infection with non-tuberculous mycobacterium, that is, a person who does not or is less likely to develop spontaneous bacterial negative transformation without appropriate treatment, a person with a relatively good prognosis, that is, an appropriate It is a substance that can distinguish and diagnose those who spontaneously develop or have a high probability of occurrence without treatment. After being infected with non-tuberculous mycobacteria, it is an appropriate treatment, for example, without antibiotic administration, spontaneous bacterial negative transformation does not occur and the bacteria continue to grow. metabolites showing an increase or decrease in a biological sample derived from a positive subject, preferably a blood metabolite.
  • 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 desired clinical result is, but not limited to, alleviation of symptoms, reduction of the scope of disease. , stabilizing (i.e. not exacerbating) 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
  • the treatment may be performed using an antibiotic, but is not limited thereto.
  • the "antibiotic” may be rifampin, isoniazid, ethambutol, pyrazinamide (PZA), quinolone, or aminoglycoside, but is not limited thereto.
  • the quinolone antibiotic is nalidixic acid, marbofloxacin, oxolinic acid, moxifloxacin, trovafloxacin, gatifloxacin, Flumequine, prulifloxacin, gemifloxacin, ciprofloxacin, sitafloxacin, or clinafloxacin, etc., but may not be limited thereto.
  • 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.
  • the term "bacterial negative” means a state in which non-tuberculous mycobacteria are not detected in a smear test or culture test of sputum, and as an example, 'negative' in which non-tuberculous mycobacteria are not detected in all three consecutive sputum smear tests. ', or may be a case of 'negative' in which non-tuberculous mycobacteria are not detected in one sputum culture test, but is not limited thereto.
  • the term "positive bacteria” means a state in which non-tuberculous mycobacteria are detected in a smear test or culture test of sputum. It may be determined as 'positive' or may be determined as 'positive' in which non-tuberculous mycobacteria are detected in one sputum culture test, but is not limited thereto.
  • the term "continuous" means a continuous predetermined period after infection with non-tuberculous mycobacterium or from the first diagnosis of infection with non-tuberculous mycobacterium, for example, continuous until treatment. period, or any period, specifically 1 month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, 6 months or more, 7 months or more, 8 months or more, 9 months or more, 10 months or more , over 11 months, over 12 months, over 13 months, over 14 months, over 15 months, over 16 months, over 17 months, over 18 months, over 19 months, over 20 months, over 21 months, over 22 months, 23 It may mean more than one month, or more than 24 months, but is not limited thereto.
  • the "metabolite” is also called a metabolite or metabolite, and is an intermediate product or product of metabolism.
  • metabolites are fuel, structure, signaling, catalytic and inhibitory effects on enzymes, their own catalytic activity (usually as cofactors for enzymes), defense, and interactions with other organisms (eg, pigments, aromatic compounds). , pheromones).
  • Primary metabolites are directly involved in normal growth, development and reproduction. Secondary metabolites are not directly involved in these processes, but usually have important ecological functions.
  • the metabolite refers to a sample of biological origin, that is, a metabolite obtained from a biological sample
  • the biological sample refers to a biological body fluid, tissue or cell, for example, whole blood, leukocyte. (leukocytes), peripheral blood 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, 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. It may be more than, but preferably whole blood (whole blood), plasma (plasma) or serum (serum) may be, and more of bronchial
  • whole blood, plasma or serum may be pretreated to detect the metabolite.
  • it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like.
  • the metabolite may include a substance produced by metabolism and metabolic processes or a substance generated by chemical metabolism by biological enzymes and molecules.
  • 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- Dimethyl glycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), lactate (Lactate), malic acid (Malic acid) and glycerol 3-phosphate (Glycerol 3-phosphate) may include at least one selected from the group consisting of have.
  • the lactate is preferably in the S-form, but is not limited thereto.
  • the malic acid is preferably in the L-form, but is not limited thereto.
  • the amino acid and its derivatives are selected from the group consisting of valine, threonine, isoleucine, leucine, tryptophan, methionine and homoserine. It may include more than one species.
  • the amino acid may be in L-form, preferably valine, threonine, isoleucine, leucine, tryptophan, or methionine. is preferably in the L-form (L-form), but is not limited thereto.
  • 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.
  • Mycobacterium intracellulare M. intracellulare
  • mycobacterium kansasii M. kansasii
  • mycobacterium malmoens M. malmoense
  • mycobacterium marinum M. marinum
  • mycobacterium sulgai M) szulgai
  • Mycobacterium terrae M. terrae
  • Mycobacterium scrofulaceum M. scrofulaceum
  • Mycobacterium Ulcerans M. ulcerans
  • Mycobacterium simiae M. simiae
  • Mycobacterium xenopi M. xenopi
  • M. xenopi is preferably selected from the group consisting of, but is not limited thereto.
  • kits for predicting prognosis after infection with non-tuberculous mycobacteria including a quantitative device for measuring the concentration of a metabolite.
  • the metabolite refers to a sample of biological origin, that is, a metabolite obtained from a biological sample
  • the biological sample refers to a biological body fluid, tissue or cell, for example, whole blood, leukocyte. (leukocytes), peripheral blood 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, 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. It may be more than, but preferably whole blood (whole blood), plasma (plasma) or serum (serum) may be, and more of bronchial
  • whole blood, plasma or serum may be pretreated to detect the metabolite.
  • it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like.
  • 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- Dimethyl glycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), lactate (Lactate), malic acid (Malic acid) and glycerol 3-phosphate (Glycerol 3-phosphate) may include at least one selected from the group consisting of have.
  • the lactate is preferably in the S-form, but is not limited thereto.
  • the malic acid is preferably in the L-form, but is not limited thereto.
  • the amino acid and its derivatives are selected from the group consisting of valine, threonine, isoleucine, leucine, tryptophan, methionine and homoserine. It may include more than one species.
  • the amino acid may be in L-form, preferably valine, threonine, isoleucine, leucine, tryptophan, or methionine. is preferably in the L-form (L-form), but is not limited thereto.
  • the quantitative device may be a nuclear magnetic resonance spectrometer (NMR), chromatography, or mass spectrometer, but is not limited thereto.
  • NMR nuclear magnetic resonance spectrometer
  • chromatography chromatography
  • 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.
  • HPLC high performance liquid chromatography
  • LSC liquid-solid chromatography
  • PC Paper chromatography
  • TLC thin layer chromatography
  • GSC Gas-Solid Chromatography
  • LLC Liquid
  • 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.
  • FTMS Fourier transform mass spectrometer
  • MALDI-TOF MS Malditope mass spectrometer
  • Q-TOF MS Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.
  • it relates to a method for providing information for predicting the prognosis after infection with non-tuberculous mycobacterium, comprising measuring the expression level of a metabolite in a biological sample isolated from a target subject.
  • the "target subject” refers to an individual whose infection is uncertain by non-tuberculous mycobacterium, means an individual with a high probability of infection, or is infected or diagnosed as infected by non-tuberculous mycobacterium, but continues to be positive without antibiotic administration An individual whose occurrence is uncertain, which means an individual with a high probability of developing a bacterium.
  • 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.
  • a step of pre-treating the biological sample preferably whole blood, plasma or serum may be performed prior to measuring the expression level of the metabolite.
  • the pretreatment may include, for example, filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, and the like, but is not limited thereto.
  • 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- Dimethyl glycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), lactate (Lactate), malic acid (Malic acid) and glycerol 3-phosphate (Glycerol 3-phosphate) may include at least one selected from the group consisting of have.
  • the lactate is preferably in the S-form, but is not limited thereto.
  • the malic acid is preferably in the L-form, but is not limited thereto.
  • the amino acid and its derivatives are selected from the group consisting of valine, threonine, isoleucine, leucine, tryptophan, methionine and homoserine. It may include more than one species.
  • the amino acid may be in L-form, preferably valine, threonine, isoleucine, leucine, tryptophan, or methionine. is preferably in the L-form (L-form), but is not limited thereto.
  • the expression level of the metabolite may be performed using a quantitative device.
  • 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.
  • HPLC high performance liquid chromatography
  • LSC liquid-solid chromatography
  • PC Paper chromatography
  • TLC thin layer chromatography
  • GSC Gas-Solid Chromatography
  • LLC Liquid
  • 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.
  • FTMS Fourier transform mass spectrometer
  • MALDI-TOF MS Malditope mass spectrometer
  • Q-TOF MS Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.
  • the prognosis after infection by non-tuberculous mycobacteria is preferably poor, preferably without antibiotic administration.
  • the method may further include predicting that the positivity persists or is highly likely to persist.
  • the expression level of one or more selected from the group consisting of the group is increased compared to the control group, the prognosis after infection by non-tuberculous mycobacteria is poor, preferably, without appropriate treatment, for example, antibiotic administration, bacterial negative charge does not occur, It may further include the step of predicting that the bacterium positivity continues or is highly likely to continue.
  • the method may further include predicting that the bacterial positivity continues or is highly likely to continue without appropriate treatment, for example, antibiotic administration.
  • control group is a normal control not infected with non-tuberculous mycobacteria, the median value of the patient population (or the average value of the patient) infected with non-tuberculous mycobacteria, or the prognosis after infection with non-tuberculous mycobacteria.
  • the prognosis after infection by non-tuberculous mycobacteria is poor as described above, and preferably, if it is predicted that the positivity continues or is highly likely to continue without administration of an appropriate treatment, for example, antibiotics, the It may further include the step of performing an appropriate treatment such as administration of a drug for the disease to the target subject, for example, antibiotics.
  • the "antibiotic” may be rifampin, isoniazid, ethambutol, pyrazinamide (PZA), quinolone, or aminoglycoside, but is not limited thereto.
  • the quinolone antibiotic is nalidixic acid, marbofloxacin, oxolinic acid, moxifloxacin, trovafloxacin, gatifloxacin, Flumequine, prulifloxacin, gemifloxacin, ciprofloxacin, sitafloxacin, or clinafloxacin, etc., but may not be limited thereto.
  • 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.
  • non-tuberculous mycobacterium infectious disease overlaps with that described in the biomarker composition of the present invention, and thus description thereof will be omitted below to avoid excessive congestion of the specification.
  • the present invention by measuring the expression level of a blood metabolite in a biological sample of a target individual, it is possible to simply, easily and accurately predict the prognosis after infection by non-tuberculous mycobacteria, in particular, the occurrence of fungal negativity. Accordingly, it is expected that appropriate treatment, such as an early decision on whether to treat antibiotics or not, will be possible.
  • the prognosis after infection by non-tuberculous mycobacteria is simple, easy and accurate, in particular, whether continuously showing positivity without appropriate treatment. predictable.
  • L-valine L-Valine
  • MAC Mycobacterium avium complex
  • Figure 2 is a comparison of the expression level of L-threonine (L-Threonine) in the serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in an embodiment of the present invention and a patient who continuously develops bacteria. A graph is shown.
  • L-Threonine L-threonine
  • MAC Mycobacterium avium complex
  • FIG. 3 is a comparison of the expression level of L-isoleucine in serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in one embodiment of the present invention and patients who continuously develop bacterium positivity. A graph is shown.
  • MAC Mycobacterium avium complex
  • L-Leucine L-leucine
  • MAC Mycobacterium avium complex
  • L-Methionine L-methionine
  • MAC Mycobacterium avium complex
  • L-tryptophan L-tryptophan
  • MAC Mycobacterium avium complex
  • N,N-dimethylglycine N,N-Dimethylglycine
  • MAC Mycobacterium avium complex
  • FIG. 8 is a graph comparing the expression level of homoserine in the serum sample of a patient with Mycobacterium avium complex (MAC) infection before antibiotic treatment in an embodiment of the present invention and a patient who continuously develops bacteria. it has been shown
  • FIG. 9 is a view showing the expression level of S-lactate in serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in an embodiment of the present invention and patients who continuously developed bacteria. A comparison graph is shown.
  • MAC Mycobacterium avium complex
  • Figure 10 shows the expression level of glycerol 3-phosphate in the serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in an embodiment of the present invention and patients who continuously developed bacteria. A graph comparing them is shown.
  • MAC Mycobacterium avium complex
  • FIG. 11 shows the expression level of glycerol L-malic acid (L-Malic acid) in serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in one embodiment of the present invention and patients who continuously developed bacteria. A graph comparing them is shown.
  • L-Malic acid glycerol L-malic acid
  • MAC Mycobacterium avium complex
  • FIG. 12 is a graph comparing the expression level of hypoxanthine in serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in one embodiment of the present invention and a patient who continuously develops bacteria. it has been shown
  • FIG. 13 is a graph comparing the expression level of Allantoin in the serum samples of patients with Mycobacterium avium complex (MAC) infection before antibiotic treatment in one embodiment of the present invention and patients who continuously developed bacteria. will be.
  • MAC Mycobacterium avium complex
  • the present invention relates to a method for providing information for predicting the prognosis after infection with non-tuberculous mycobacteria, comprising the step of measuring the expression level of a metabolite in a biological sample isolated from a target subject.
  • the metabolite is preferably a metabolite obtained from a liquid sample derived from blood, preferably serum
  • specific examples include amino acids, amino acid derivatives, allantoin, N,N- Dimethyl glycine (N,N-Dimethylglycine), hypoxanthine (Hypoxanthine), lactate (Lactate), malic acid (Malic acid) and glycerol 3-phosphate (Glycerol 3-phosphate) may include at least one selected from the group consisting of have.
  • the amino acid and its derivatives are one selected from the group consisting of valine, threonine, isoleucine, leucine, tryptophan, methionine and homoserine. may include more than one.
  • the lactate may be in the S-form, and the malic acid and the amino acid may be in the L-form.
  • Mycobacterium avium complex ( avium : 46, intracellulare : 50, total 96) collected from Samsung Hospital in Seoul for approximately 6 years from January 2012 to August 2016. 96 serum samples before antibiotic treatment and 30 serum samples from patients who were continuously positive but not worsened without antibiotic treatment were prepared.
  • sample quality control SQC
  • SQC sample quality control
  • Dx0 (Success & Fail) represents the expression level of each metabolite in the serum samples of 96 patients infected with Mycobacterium avium complex (MAC) before the start of antibiotic treatment, and Persistence is without antibiotic treatment.
  • the expression level of each metabolite is shown in the serum samples of 30 patients with persistent bacterial positivity.
  • L-valine, L-threonine, L-isoleucine, L-leucine, L-tryptophan, L-methionine (L-Methionine), homoserine (Homoserine), N,N-dimethylglycine (N,N-Dimethylglycine), S-lactate (S-Lactate), glycerol 3-phosphate (Glycerol 3-phosphate), L-Malic acid, hypoxanthine, and allantoin are biomarkers for determining whether to treat with antibiotics by predicting that bacteria will continue to be positive without antibiotic administration after infection with non-tuberculous mycobacteria. found that it can be used as
  • the present invention relates to a prognosis after infection by non-tuberculous mycobacteria, in particular, a biomarker for predicting whether or not spontaneous bacterial negative transformation does not occur and persistent bacterial positivity occurs without appropriate treatment, and a kit or prediction method for the prediction is about

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Abstract

La présente invention concerne un biomarqueur, un nécessaire de prédiction, ou un procédé de prédiction, le biomarqueur permettant de prédire si une positivité de bactéries est conservée ou non sans négativité spontanée des bactéries sans traitement approprié, en tant que pronostic après une infection par mycobacterium non tuberculeuse au moyen de métabolites.
PCT/KR2020/016661 2019-11-25 2020-11-24 Biomarqueur permettant de prédire la conservation ou non d'une positivité de bactéries après une infection par mycobacterium non tuberculeuse WO2021107550A1 (fr)

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* Cited by examiner, † Cited by third party
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CN114019055A (zh) * 2021-11-09 2022-02-08 中国科学院城市环境研究所 评价细菌氨基糖苷类抗生素耐药效应的试剂盒及其应用
CN114019055B (zh) * 2021-11-09 2024-03-01 中国科学院城市环境研究所 评价细菌氨基糖苷类抗生素耐药效应的试剂盒及其应用

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