KR20240023775A - Polarity metabolite markers changed according to the treatment of pulmonary tuberculosis patients - Google Patents
Polarity metabolite markers changed according to the treatment of pulmonary tuberculosis patients Download PDFInfo
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- KR20240023775A KR20240023775A KR1020220101881A KR20220101881A KR20240023775A KR 20240023775 A KR20240023775 A KR 20240023775A KR 1020220101881 A KR1020220101881 A KR 1020220101881A KR 20220101881 A KR20220101881 A KR 20220101881A KR 20240023775 A KR20240023775 A KR 20240023775A
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- fluid
- tuberculosis
- treatment
- concentration
- antibiotic
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Abstract
본 발명은 극성 대사체의 농도를 측정하는 제제를 유효성분으로 포함하는 결핵균에 의한 감염질환의 중증도 예측용 조성물에 관한 것이다. 본 발명은 폐결핵 환자의 항생제 치료 반응성 예측을 위한 연구로서, 마이코박테리움 튜버큘로시스(Mycobacterium tuberculosis) 감염 폐질환 환자의 치료 시작 후 2 내지 4 개월 시점에 치료에 의해 변화하는 극성대사체를 발굴함으로써, 성공적으로 폐질환 치료 반응을 예측할 수 있는 생물학적 지표를 이용하여, 보다 효과적인 결핵치료에 유용하게 이용될 수 있다.The present invention relates to a composition for predicting the severity of infectious disease caused by Mycobacterium tuberculosis, which contains as an active ingredient an agent that measures the concentration of polar metabolites. The present invention is a study to predict antibiotic treatment responsiveness in patients with pulmonary tuberculosis, and discovers polar metabolites that change due to treatment 2 to 4 months after the start of treatment in patients with Mycobacterium tuberculosis-infected lung disease. By doing so, biological indicators that can successfully predict lung disease treatment response can be used for more effective tuberculosis treatment.
Description
본 발명은 폐결핵 환자의 치료에 따라 변화된 극성대사체 마커에 관한 것이다.The present invention relates to polar metabolite markers that change according to treatment of pulmonary tuberculosis patients.
결핵은 마이코박테리움 튜버큘로시스(Mycobacterium tuberculosis) 박테리아에 의해 야기되는 전염력이 높은 감염성 질환이며, WHO에서 정한 3대 감염질환 중 하나로 높은 발병률과 사망률을 나타내고 있다. 전 세계적으로 약 6천만명의 활동성 결핵 환자가 있으며 매년 5천만 내지는 1억여명이 결핵에 감염되는 것으로 추정되고, 적어도 매년 900만명의 결핵 신환자가 발생하며, 150만 명 이상이 결핵으로 사망한다고 알려졌다. 결핵 발병률(incidence rate)은 인구 10만명 당 146명, 결핵 사망률은 인구 10만명 당 49명으로 단일 감염병 중에서 가장 많은 사망 원인을 차지하고 있어, 세계적으로 심각한 보건 문제로 남아 있다. 최근에는 약제내성을 나타내는 난치성 결핵환자의 증가와 HIV 감염증가로 인해 발병 양상은 더욱 심각해지는 추세이다. 현재 HIV 감염자의 약 50%인 1,500만여명이 결핵균에 동시에 감염되어 있으며, 결핵균이 HIV 증식을 촉진하여 다른 기회 감염균보다 기대수명(life expectancy)을 2분의 1로 단축시켜, HIV 감염자에게는 더욱 위협이 되고 있다. 또한 HIV 양성 결핵환자의 경우 결핵에 의한 사망률이 3배 이상 높고 치료 효과는 2배 정도 낮다고 보고되었다.Tuberculosis is a highly contagious infectious disease caused by the bacterium Mycobacterium tuberculosis, and is one of the three major infectious diseases defined by the WHO with a high incidence and mortality rate. Worldwide, there are approximately 60 million active tuberculosis patients, and it is estimated that 50 to 100 million people are infected with tuberculosis every year. At least 9 million new tuberculosis cases occur every year, and more than 1.5 million people are known to die from tuberculosis. The incidence rate of tuberculosis is 146 per 100,000 population, and the mortality rate of tuberculosis is 49 per 100,000 population, making it the most common cause of death among infectious diseases and remaining a serious global health problem. Recently, the incidence is becoming more serious due to the increase in the number of patients with drug-resistant incurable tuberculosis and the increase in HIV infections. Currently, about 15 million people, or about 50% of HIV-infected people, are simultaneously infected with tuberculosis bacteria. Mycobacterium tuberculosis promotes the proliferation of HIV, shortening life expectancy by one-half compared to other opportunistic infections, posing an even greater threat to HIV-infected people. It is becoming. In addition, it has been reported that for HIV-positive tuberculosis patients, the mortality rate due to tuberculosis is more than three times higher and the treatment effectiveness is about two times lower.
우리나라의 결핵균 감염률은 약 40%로 약 2천만명이 결핵균에 감염되었을 것으로 추정되고 있다. 이 가운데 약 10%인 200만 명은 일생에 한번은 결핵 환자가 될 것으로 예상된다. 우리나라에서 전염병으로 사망하는 사람의 60%가량이 결핵으로 그 심각성을 유추할 수 있으며, 이는 21세기 국가보건 및 복지에 심각한 문제로 대두되고 있다. 최근 결핵 감염 수는 매년 감소 추세에 이르지만 다제내성(MDR; Multi-drug resistant) 및 광범위 내성 (XDR; Extensively-drug resistant)을 지닌 결핵균의 증가로 인하여 결핵 치료가 어려워지고 있다. 이로 인해 결핵의 치료 비용도 증가하였고, 치료 효율마저 낮아져 난치성 결핵으로 발전하는 모습을 보여주고 있다. 상기 결핵을 치료할 수 있는 항생제의 경우, 최초로 사용된지 최소 50년 이상된 것으로서, 현재 결핵과 항생제 내성을 갖는 결핵균에 대한 치료제에 대한 신규 약에 대한 연구는 미비한 실정이다. The tuberculosis infection rate in Korea is approximately 40%, and it is estimated that approximately 20 million people are infected with tuberculosis bacteria. Of these, approximately 10%, or 2 million people, are expected to become tuberculosis patients at least once in their lifetime. The seriousness of tuberculosis can be inferred that approximately 60% of people who die from infectious diseases in Korea are emerging as a serious problem for national health and welfare in the 21st century. Recently, the number of tuberculosis infections has been decreasing every year, but tuberculosis treatment is becoming difficult due to the increase in tuberculosis bacteria with multi-drug resistance (MDR) and extensively-drug resistance (XDR). As a result, the cost of treating tuberculosis has increased, and treatment efficiency has also decreased, leading to the development of incurable tuberculosis. In the case of the antibiotic that can treat tuberculosis, it has been at least 50 years since it was first used, and currently, research on new drugs for treating tuberculosis and antibiotic-resistant tuberculosis bacteria is insufficient.
따라서 본 발명은 결핵환자의 항생제 치료 반응성 예측용 조성물에 관한 연구이다. 결핵환자의 치료반응성을 예측할 수 있는 극성대사체를 발굴함으로써, 보다 높은 효율과 정확도로 폐결핵 환자의 치료반응성을 구현해 내었다. 본 발명은 페질환 환자의 효과적인 항생제 치료에 크게 이용될 것으로 기대된다. Therefore, the present invention is a study on a composition for predicting antibiotic treatment responsiveness in tuberculosis patients. By discovering polar metabolites that can predict the treatment responsiveness of tuberculosis patients, the treatment responsiveness of pulmonary tuberculosis patients was realized with higher efficiency and accuracy. The present invention is expected to be greatly used in effective antibiotic treatment of patients with pulmonary diseases.
본 발명자들은 폐결핵 환자의 항생제 치료 반응성 예측을 위하여 예의 연구 노력하였다. 그 결과, 결핵환자의 치료반응성을 예측할 수 있는 극성대사체를 발굴함으로써, 본 발명을 완성하게 되었다.The present inventors made extensive research efforts to predict antibiotic treatment responsiveness in patients with pulmonary tuberculosis. As a result, the present invention was completed by discovering polar metabolites that can predict the treatment responsiveness of tuberculosis patients.
따라서 본 발명의 목적은 극성 대사체의 농도를 측정하는 제제를 유효성분으로 포함하는 결핵환자의 항생제 치료반응성 예측용 조성물을 제공하는 데 있다.Therefore, the purpose of the present invention is to provide a composition for predicting antibiotic treatment responsiveness in tuberculosis patients, which contains as an active ingredient an agent that measures the concentration of polar metabolites.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.DETAILED DESCRIPTION OF THE INVENTION Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details, such as specific forms, compositions, and processes, are set forth in order to provide a thorough understanding of the invention. However, certain embodiments may be practiced without one or more of these specific details or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Accordingly, the phrases “in one embodiment” or “an embodiment” expressed in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, shapes, compositions, or properties may be combined in any suitable way in one or more embodiments.
명세서에서 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless there is a special definition in the specification, all scientific and technical terms used in the specification have the same meaning as commonly understood by a person skilled in the art in the technical field to which the present invention pertains.
명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있는 것을 의미한다.Throughout the specification, when a part is said to “include” a certain element, this means that it may further include other elements rather than excluding other elements, unless specifically stated to the contrary.
본 발명의 일 양태에 따르면, 본 발명은 극성 대사체의 농도를 측정하는 제제를 유효성분으로 포함하는 결핵 감염 폐질환 환자의 항생제에 대한 치료 반응성 예측용 조성물을 제공한다.According to one aspect of the present invention, the present invention provides a composition for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, comprising as an active ingredient an agent that measures the concentration of polar metabolites.
본 발명자들은 폐결핵 환자의 항생제 치료 반응성 예측을 위하여 예의 연구 노력하였다. 그 결과, 결핵환자의 치료반응성을 예측할 수 있는 극성대사체 6종을 발굴하였다.The present inventors made extensive research efforts to predict antibiotic treatment responsiveness in patients with pulmonary tuberculosis. As a result, six types of polar metabolites that can predict treatment responsiveness of tuberculosis patients were discovered.
본 명세서에서 용어, “항생제(antibiotics)”는 세균(박테리아) 감염을 막거나 세균질환을 치료하는데 사용되는 항미생물질을 의미한다. 세균을 죽이거나 생장을 방해함으로 세균을 억제하는 것으로, 병원성 박테리아 감염의 치료 및 예방에 사용되는 항균제 약물이다. 항균제는 넓은 의미의 항생제로 통용되고 있으며, 항미생물제제, 항진균제가 포함된다. 항생제를 사용 시 약리학적 기전에 의하여 세균을 사멸하거나 생장을 저해하는 효과를 가진다. 일부 약물은 세균 이외에도 특정 곰팡이나 원생생물 등의 미생물에 효과를 보이기도 하나, 바이러스에 효과를 보이는 경우는 없다. 또한, 항생제는 기전 분류, 항생제가 작용하는 양상에 따라 세포벽 합성방해, 세포막 파괴제, 단백합성 억제제, 핵산합성 억제제, 엽산합성 억제제로 분류된다. As used herein, the term “antibiotics” refers to antimicrobial substances used to prevent bacterial infection or treat bacterial diseases. It is an antibacterial drug that suppresses bacteria by killing them or inhibiting their growth, and is used to treat and prevent pathogenic bacterial infections. Antibacterial agents are commonly used as antibiotics in a broad sense and include antimicrobial agents and antifungal agents. When antibiotics are used, they have the effect of killing bacteria or inhibiting their growth through a pharmacological mechanism. Some drugs are effective against microorganisms other than bacteria, such as certain molds and protozoa, but none are effective against viruses. In addition, antibiotics are classified into cell wall synthesis inhibitors, cell membrane destroyers, protein synthesis inhibitors, nucleic acid synthesis inhibitors, and folic acid synthesis inhibitors depending on the mechanism and mode of action of the antibiotic.
구체적으로는, 상기 항생제는 예를 들어 페니실린 G(penicilln G), 아목시실린(amoxicillin), 암피실린(ampicillin), 피페라실린(piperacillin), 아목시실린/클라불란산(amoxicillin/clavulanicacid), 암피실린/설박탐(ampicillin/sulbactam), 피페라실린/타조박탐(piperacillin/tazobactam), 세파졸린(cefazolin), 세팔렉신(cephalexin), 세파클러(cefaclor), 세프메타졸(cefmetazole), 세포티암(cefotiam), 세푸록심(cefuroxime), 세포탁심(cefotaxime), 세프트리악손(ceftriaxone), 세프타지딤(ceftazidime), 세페핌(cefepime), 이미페넴/실라스타틴(imipenem/cilastatin), 메로페넴(meropenem), 도리페넴(doripenem), 에르타페넴(artapenem), 켄타마이신(gentamicin), 토브라마이신(tobramycin), 아미카신(amikacin), 테트라사이클린(tetracycline), 독시사이클린(doxycycline), 미노사이클린(minocycline), 타이제사이클린(tigecycline), 에리스로마이신(erythromycin), 클라리스로마이신(clarithromycin), 아지스로마이신(azithromycin), 시프로플록사신(ciprofloxacin), 레보블록사신(levofloxacin) 및 목시플록사신(moxifloxacin)로 구성된 군으로부터 선택되는 것을 포함할 수 있으나, 이에 제한되는 것은 아니다.Specifically, the antibiotics include, for example, penicillin G, amoxicillin, ampicillin, piperacillin, amoxicillin/clavulanicacid, ampicillin/sulbactam ( ampicillin/sulbactam, piperacillin/tazobactam, cefazolin, cephalexin, cefaclor, cefmetazole, cefotiam, cefuroxime (cefuroxime), cefotaxime, ceftriaxone, ceftazidime, cefepime, imipenem/cilastatin, meropenem, doripenem ), ertapenem, gentamicin, tobramycin, amikacin, tetracycline, doxycycline, minocycline, tigecycline ), erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, and moxifloxacin. However, it is not limited to this.
본 명세서에서 용어, “예측”은 특정 병원균, 예를 들어 결핵균에 감염된 객체가 항생제 치료에 대한 반응성이 있는지 혹은 저항성이 있는지 여부를 치료 반응성과 유의한 상관관계를 가지는 표지자를 기반으로 평가하는 것을 의미한다.As used herein, the term “prediction” refers to evaluating whether a subject infected with a specific pathogen, for example, Mycobacterium tuberculosis, is responsive or resistant to antibiotic treatment based on markers that have a significant correlation with treatment responsiveness. do.
본 명세서에서 용어, “예측용 조성물”은 대상체의 결핵균의 감염에 대한 항생제 치료 반응성을 가지는지를 예측하기 위해 지질대사체(lipid metabolites)의 농도 측정 수단을 포함하는 통합적인 혼합물(mixture) 또는 장비(device)를 의미하며, 이에“예측용 키트”로 표현될 수도 있다. 본 발명의 예측용 조성물은 본 발명에서 발굴된 대사체를 측정하기 위한 수단이 포함되므로, 용어“예측용 조성물”은 대사체의“정량 장치”로 표현될 수도 있다. As used herein, the term “predictive composition” refers to an integrated mixture or device ( device), and can also be expressed as a “prediction kit.” Since the composition for prediction of the present invention includes a means for measuring the metabolites discovered in the present invention, the term “composition for prediction” may also be expressed as a “device for quantifying metabolites.”
본 명세서에서 용어, "대사체(metabolite)"는 대사물질 또는 대사산물이라고도 불리우며, 물질 대사의 중간 생성물 또는 생성물이다. 이러한 대사체는 연료, 구조, 신호전달, 효소에 대한 촉진 및 저해 효과, 그 자신의 촉매 활성(일반적으로 효소에 대한 보조 인자로서), 방어, 다른 생물체와의 상호작용(예: 색소, 방향 화합물, 페로몬)을 포함하는 다양한 기능을 가지고 있다. 1차 대사체는 정상적인 생장, 발생 및 생식에 직접적으로 관여한다. 2차 대사체는 이러한 과정들에 직접적으로 관여하지 않지만, 대개 중요한 생태학적 기능을 가지고 있다.As used herein, the term “metabolite” is also called a metabolite or metabolite, and is an intermediate product or product of metabolism. These metabolites provide fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, their own catalytic activity (usually as cofactors for enzymes), defense, and interactions with other organisms (e.g. pigments, aroma compounds). , pheromones). Primary metabolites are directly involved in normal growth, development, and reproduction. Although secondary metabolites are not directly involved in these processes, they often have important ecological functions.
본 발명에 따르면, 상기 대사체는 생체 기원의 시료, 즉 생물학적 시료로부터 수득한 대사 물질을 말하는 것으로, 상기 생물학적 시료는 생물학적 체액, 조직 또는 세포를 의미하는 것이다.According to 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.
본 발명에 따르면, 상기 대사체는 혈액, 구체적으로는 혈청 기원의 액상 시료로부터 수득한 대사물질일 수 있다.According to the present invention, the metabolite may be a metabolite obtained from a liquid sample of blood, specifically serum origin.
본 명세서에서 용어, "결핵((Mycobacterium Tuberculosis, TB)"은 결핵균에 의해 전염되는 감염성질환을 의미한다. 결핵균은 수천 년 동안 인류에게 질병을 일으켜 왔으며, 이 질환은 인체의 어느 곳에나 발생할 수 있는 전염성인 동시에 감염성인 급성 질환이며 만성질환이다. 폐결핵 같은 질환이 대표적이다. 결핵은 폐에 잘 걸리는데 약 85%정도가 폐에 발생하며, 혈류나 임파관을 따라 몸의 어느 기관에나 전파되어 영향을 줄 수 있다. As used herein, the term "Mycobacterium Tuberculosis (TB)" refers to an infectious disease transmitted by Mycobacterium tuberculosis. Mycobacterium tuberculosis has been causing disease in humans for thousands of years, and this disease can occur anywhere in the human body. It is an acute and chronic disease that is both contagious and infectious. A representative example is pulmonary tuberculosis. Tuberculosis is easily affected by the lungs, and approximately 85% of cases occur in the lungs, and can spread to any organ in the body through the bloodstream or lymphatic vessels, affecting any organ. You can.
본 발명의 구체적인 구현예에 따르면, 상기 극성 대사체는 알란토인(Allantoin), 페닐알라닌(phenylalanine), 호모세린(Homoserine), 알라닌(alanine), 메티오닌(methionine), 및 히스티딘(histidine)으로 구성된 군으로부터 선택되는 어느 하나 이상인 것인, 조성물이다.According to a specific embodiment of the present invention, the polar metabolite is selected from the group consisting of allantoin, phenylalanine, homoserine, alanine, methionine, and histidine. It is a composition that is one or more things.
본 명세서에서 용어, "알란토인(Allantoin)"은 화학식 C4H6N4O3의 화합물을 의미하며, 5-우레이도히단토인 또는 글리옥실디우레이드라고도 한다. 알란토인은 동물, 식물 및 박테리아를 포함한 대부분의 유기체에서 주요 대사 중간체이다.As used herein, the term “Allantoin” refers to a compound of the formula C 4 H 6 N 4 O 3 and is also called 5-ureidohydantoin or glyoxyldiureide. Allantoin is a major metabolic intermediate in most organisms, including animals, plants, and bacteria.
본 명세서에서 용어, "페닐알라닌(phenylalanine)"은 필수 아미노산 중 하나를 의미한다. 체내에 이 아미노산을 분해하는 효소가 없을 경우엔 페닐케톤뇨증에 걸리게 되고, 티로신의 전구물질이 될 수 있다.As used herein, the term “phenylalanine” refers to one of the essential amino acids. If your body does not have an enzyme to break down this amino acid, you will suffer from phenylketonuria and it can become a precursor to tyrosine.
본 명세서에서 용어, "호모세린(Homoserine)"은 화학식이 HO2CCHCH₂CH₂OH인 α-아미노산을 의미하며, 아이소트레오닌이라고도 한다. As used herein, the term “homoserine” refers to an α-amino acid with the chemical formula HO 2 CCHCH₂CH₂OH, and is also called isothreonine.
본 명세서에서 용어, "알라닌(alanine)"은 HO2CCHCH₃의 화학식을 갖는 α-아미노산을 의미하며, 단백질 합성에 쓰이는 단백질성 아미노산이다. 화학적으로는 아민기와 카복실기를 포함하며 두 작용기는 메틸 작용기를 가지는 중심 탄소 원자에 붙어있다. 알라닌은 무극성인 지방족 아미노산이다.As used herein, the term “alanine” refers to an α-amino acid with the chemical formula HO 2 CCHCH₃, and is a proteinaceous amino acid used in protein synthesis. Chemically, it contains an amine group and a carboxyl group, and both functional groups are attached to the central carbon atom, which has a methyl functional group. Alanine is a nonpolar aliphatic amino acid.
본 명세서에서 용어, "메티오닌(methionine)"은 단백질의 생합성에 필요한 알파-아미노산 중의 하나를 의미한다.As used herein, the term “methionine” refers to one of the alpha-amino acids required for protein biosynthesis.
본 명세서에서 용어, "히스티딘(histidine)"은 단백질에 존재하는 스무 개의 표준 아미노산들 가운데 하나를 의미한다. 히스티딘은 아미노산으로써 α-아미노기를 가지고 있고 카복실기도 가진다. 그리고 부분적으로 양성자 첨가된 이미다졸 작용기를 가지는데, 이 성질 덕에 히스티딘은 생리학적 PH에서 양전하를 띠는 아미노산으로 분류된다.As used herein, the term “histidine” refers to one of the twenty standard amino acids present in proteins. Histidine is an amino acid that has an α-amino group and a carboxyl group. It also has a partially protonated imidazole functional group, and thanks to this property, histidine is classified as an amino acid with a positive charge at physiological pH.
본 발명의 구체적인 구현예에 따르면, 상기 극성 대사체는 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 내 존재하는 것인, 조성물이다.According to a specific embodiment of the present invention, the polar metabolite is produced in whole blood, leukocytes, peripheral blood mononuclear cells, leukocyte buffy coat, plasma, serum ( serum, sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva 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, cell , a composition that exists in cell extract and cerebrospinal fluid.
구체적으로는, 상기 대사체를 검출하기 위해 전혈, 혈장 또는 혈청을 전처리할 수 있다. 예를 들어, 여과, 증류, 추출, 분리, 농축, 방해 성분의 불활성화, 시약의 첨가 등을 포함할 수 있다. 또한, 상기 대사체는 대사 및 대사 과정에 의해 생산된 물질 또는 생물학적 효소 및 분자에 의한 화학적 대사작용으로 발생한 물질 등을 포함할 수 있다.Specifically, whole blood, plasma, or serum can be pretreated to detect the metabolites. For example, it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, etc. Additionally, the metabolites may include substances produced through metabolism and metabolic processes or substances generated through chemical metabolism by biological enzymes and molecules.
본 발명의 다른 양태에 따르면, 본 발명은 목적하는 개체로부터 분리된 시료를 대상으로 극성 대사체의 농도를 측정하는 단계;를 포함하는, 결핵 감염 폐질환 환자의 항생제에 대한 치료 반응성 예측 방법을 제공한다.According to another aspect of the present invention, the present invention provides a method for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, comprising the step of measuring the concentration of polar metabolites in a sample isolated from the subject of interest. do.
본 발명의 구체적인 구현예에 따르면, 상기 극성 대사체는 알란토인(Allantoin), 페닐알라닌(phenylalanine), 호모세린(Homoserine), 알라닌(alanine), 메티오닌(methionine), 및 히스티딘(histidine)으로 구성된 군으로부터 선택되는 어느 하나 이상인 것인, 방법이다.According to a specific embodiment of the present invention, the polar metabolite is selected from the group consisting of allantoin, phenylalanine, homoserine, alanine, methionine, and histidine. It is a method that is more than one thing.
본 발명의 구체적인 구현예에 따르면, 상기 알란토인 또는 페닐알라닌의 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 낮은 경우, 상기 목적하는 개체는 항생제에 대한 치료 반응성이 있는 것으로 예측하는 것인, 방법이다.According to a specific embodiment of the present invention, when the concentration of allantoin or phenylalanine before antibiotic administration is lower than the concentration measured after antibiotic administration, the subject of interest is predicted to have treatment responsiveness to the antibiotic.
본 발명의 구성 중 “알란토인 또는 페닐알라닌”을 언급하면서 사용되는 용어 “농도의 감소 또는 낮음” 은 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 유의하게 낮은 경우를 의미하며, 구체적으로는 상기 대사체의 항생제 투여 전과 항생제 투여 후 농도를 비교하여 약 5% 이상 감소, 보다 구체적으로는 약 10% 이상 감소를 의미하고, 가장 구체적으로는 약 15% 이상 감소하는 경우를 의미하나, 이를 벗어나는 범위를 제외하는 것은 아니다.The term “reduced or low concentration” used while referring to “allantoin or phenylalanine” in the present invention refers to the case where the concentration before antibiotic administration is significantly lower than the concentration measured after antibiotic administration, and specifically, the metabolite By comparing the concentration before and after antibiotic administration, it means a decrease of more than about 5%, more specifically, a decrease of about 10% or more, and most specifically, a decrease of more than about 15%, excluding the range beyond this. It's not like that.
본 명세서에서 용어 “치료 반응성이 있다”는 항생제가 투여된 개체에서 투여되지 않은 개체에 비하여 결핵균의 생존률, 증식률, 활성 또는 병원성이 임상적으로 측정 가능할 정도로 감소하는 것을 의미한다. As used herein, the term “responsive to treatment” means a clinically measurable decrease in the survival rate, proliferation rate, activity, or pathogenicity of Mycobacterium tuberculosis in subjects administered antibiotics compared to subjects not administered antibiotics.
본 발명의 구체적인 구현예에 따르면, 상기 호모세린, 알라닌, 메티오닌, 또는 히스티딘의 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 높은 경우, 상기 목적하는 개체는 항생제에 대한 치료 반응성이 있는 것으로 예측하는 것인, 방법이다.According to a specific embodiment of the present invention, when the concentration of homoserine, alanine, methionine, or histidine before antibiotic administration is higher than the concentration measured after antibiotic administration, the subject of interest is predicted to have treatment responsiveness to the antibiotic. It is a thing, a method.
본 발명의 구성 중 호모세린, 알라닌, 메티오닌, 또는 히스티딘을 언급하면서 사용되는 용어 “농도의 증가 또는 높음” 은 환자에서의 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 유의하게 높은 경우를 의미하며, 구체적으로는 상기 대사체의 항생제 투여 전 농도가 항생제 투여 후 농도와 비교하여 약 5% 이상 증가, 구체적으로는 약 10% 이상 증가, 보다 구체적으로는 약 15% 이상 증가, 보다 더 구체적으로는 약 20% 이상 증가, 보다 더 구체적으로는 약 25% 이상 증가, 보다 더 구체적으로는 약 30% 이상 증가를 의미하고, 가장 구체적으로는 약 35% 이상 증가하는 경우를 의미하나, 이를 벗어나는 범위를 제외하는 것은 아니다.The term “increased or high concentration” used while referring to homoserine, alanine, methionine, or histidine in the present invention means that the concentration before antibiotic administration in a patient is significantly higher than the concentration measured after antibiotic administration. , Specifically, the concentration of the metabolite before antibiotic administration increases by about 5% or more, specifically, about 10% or more, more specifically, about 15% or more compared to the concentration after antibiotic administration, more specifically. It means an increase of about 20% or more, more specifically, it means an increase of about 25% or more, and even more specifically, it means an increase of about 30% or more, and most specifically, it means an increase of about 35% or more, but the range beyond this is It is not excluded.
본 발명의 구체적인 구현예에 따르면, 상기 항생제 투여 후의 측정은 상기 항생제 투여 후 2 내지 4개월 경과 후 수행되는 것인, 방법이다.According to a specific embodiment of the present invention, the measurement after administration of the antibiotic is a method in which the measurement is performed 2 to 4 months after administration of the antibiotic.
본 발명의 구체적인 구현예에 따르면, 상기 대사체의 농도를 측정하는 단계는 크로마토그래피 또는 질량분석기인 정량 장치를 이용하여 수행되는 것인, 방법이다.According to a specific embodiment of the present invention, the step of measuring the concentration of the metabolite is a method in which the step is performed using a quantitative device such as a chromatography or mass spectrometer.
본 발명에서 이용되는 크로마토그래피는 고성능 액체 크로마토그래피(High erformance Liquid Chromatography, HPLC), 액체-고체 크로마토그래피(Liquid-Solid Chromatography, LSC), 종이크로마토그래피(Paper Chromatography, PC), 박층 크로마토그래피(Thin-Layer Chromatography, TLC), 기체-고체 크로마토그래피(Gas-Solid Chromatography, GSC), 액체-액체 크로마토그래피(Liquid-Liquid Chromatography, LLC), 포말 크로마토그래피(Foam Chromatography, FC), 유화 크로마토그래피(Emulsion Chromatography, EC), 기체-액체 크로마토그래피(Gas-Liquid Chromatography, GLC), 이온 크로마토그래피(Ion Chromatography, IC), 겔 여과 크로마토그래피(Gel Filtration Chromatograhy, GFC) 또는 겔 투과 크로마토그래피(Gel Permeation Chromatography, GPC)를 포함될수 있으나, 이에 제한되지 않고 당업계에서 통상적으로 사용되는 모든 정량용 크로마토그래피를 사용할 수 있다.Chromatography used in the present invention includes high performance liquid chromatography (HPLC), liquid-solid chromatography (LSC), paper chromatography (PC), and thin layer chromatography (Thin layer chromatography). -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 (GFC) GPC) may be included, but is not limited thereto, and any quantitative chromatography commonly used in the art may be used.
본 발명에서 상기 질량분석기는 특별한 제한없이 종래 공지된 질량 분석기를 이용할 수 있지만, 구체적으로 예를 들면, 푸리에 변환 질량분석기(FTMS, Fourier transform mass spectrometer), 말디토프 질량분석기(MALDI-TOF MS), Q-TOF MS 또는 LTQ-Orbitrap MS일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the mass spectrometer may be a conventionally known mass spectrometer without particular restrictions, but specifically, for example, a Fourier transform mass spectrometer (FTMS), a MALDI-TOF MS, It may be Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.
본 발명의 구체적인 구현예에 따르면, 상기 극성 대사체는 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 내 존재하는 것인, 방법이다.According to a specific embodiment of the present invention, the polar metabolite is produced in whole blood, leukocytes, peripheral blood mononuclear cells, leukocyte buffy coat, plasma, serum ( serum, sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva 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, cell , a method that exists in cell extract and cerebrospinal fluid.
본 발명의 다른 양태에 따르면, 본 발명은 극성 대사체의 농도를 측정하는 제제를 유효성분으로 포함하는 결핵 감염 폐질환 환자의 항생제에 대한 치료 반응성 예측용 키트를 제공한다.According to another aspect of the present invention, the present invention provides a kit for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, comprising as an active ingredient an agent that measures the concentration of polar metabolites.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 극성 대사체의 농도를 측정하는 제제를 유효성분으로 포함하는 결핵에 의한 감염 환자의 항생제에 대한 치료 반응성 예측용 조성물을 제공한다.(a) The present invention provides a composition for predicting treatment responsiveness to antibiotics in patients infected with tuberculosis, comprising as an active ingredient an agent that measures the concentration of polar metabolites.
(b) 본 발명은 폐결핵 환자의 항생제 치료 반응성 예측을 위한 연구로서, 마이코박테리움 튜버큘로시스(Mycobacterium tuberculosis) 감염 폐질환 환자의 치료 시작 후 2 내지 4개월 시점에 치료에 의해 변화하는 극성대사체를 발굴함으로써, 성공적으로 폐질환 치료 반응을 예측할 수 있는 생물학적 지표를 이용하여, 보다 효과적인 결핵치료에 유용하게 이용될 수 있다.(b) The present invention is a study to predict antibiotic treatment responsiveness in patients with pulmonary tuberculosis, and determines the polarity of metabolism changed by treatment 2 to 4 months after the start of treatment in patients with Mycobacterium tuberculosis-infected lung disease. By discovering the body, biological indicators that can successfully predict lung disease treatment response can be used to effectively treat tuberculosis.
도 1a은 본 발명의 일 실시예에 따른, 치료 후 2 내지 4개월 시점에 폐결핵 환자의 성공적인 치료반응 예측을 위한 극성대사체 마커인 알란토인(Allantoin), 페닐알라닌(phenylalanine) 및 호모세린(Homoserine)을 나타낸다.
도 1b는 본 발명의 일 실험예에 따른, 치료 후 2 내지 4개월 시점에 폐결핵 환자의 성공적인 치료반응 예측을 위한 극성대사체 마커인 알라닌(alanine), 메티오닌(methionine) 및 히스티딘(histidine)를 나타낸다.Figure 1a shows allantoin, phenylalanine, and homoserine, which are polar metabolite markers for predicting successful treatment response of pulmonary tuberculosis patients at 2 to 4 months after treatment, according to an embodiment of the present invention. indicates.
Figure 1b shows alanine, methionine, and histidine, which are polar metabolite markers for predicting successful treatment response in pulmonary tuberculosis patients at 2 to 4 months after treatment, according to an experimental example of the present invention. .
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실험목적 Purpose of experiment
본 발명은 마이코박테리움 튜버큘로시스(Mycobacterium tuberculosis) 감염 폐질환 환자가 치료를 시작한 후 2 내지 4개월 시점에 치료에 의해 변화하는 극성대사체를 탐색함으로써 성공적인 치료 반응을 예측할 수 있는 생물학적 지표의 후보물질을 개발하고자 한다.The present invention provides a biological indicator that can predict a successful treatment response by exploring polar metabolites that change due to treatment 2 to 4 months after a patient with Mycobacterium tuberculosis-infected lung disease begins treatment. We want to develop candidate substances.
실시예 1. 결핵 감염 폐질환 환자의 진단 시점과 치료 중 2 내지 4개월 시점의 혈청 수집Example 1. Collection of serum from patients with tuberculosis-infected lung disease at the time of diagnosis and at 2 to 4 months during treatment
본 발명은 2011년 09월부터 2013년 02월까지 서울대학교 병원(서울시 종로구 연건동 28번지 서울대학교병원 호흡기내과)에서 수집한 마이코박테리움 튜버큘로시스(Mycobacterium tuberculosis) 감염 환자 42명의 치료 전 시점과 치료 시작 후 2 내지 4개월 시점에 대한 혈청 샘플을 이용하였다. 42명의 환자는 항생제 감수성 결핵균에 감염되어, 치료 완료 후 2년 내 재발하지 않는 환자이며 동공이 없는 환자(non-cavity, NC) 26명과 동공이 있는 환자(cavity, C)의 환자 16명을 대상으로 하였다. The present invention relates to the pre-treatment time point of 42 patients infected with Mycobacterium tuberculosis collected at Seoul National University Hospital (Department of Respiratory Medicine, Seoul National University Hospital, 28 Yeongeon-dong, Jongno-gu, Seoul) from September 2011 to February 2013. Serum samples were used 2 to 4 months after starting treatment. 42 patients were infected with antibiotic-susceptible tuberculosis bacteria and did not relapse within 2 years after completing treatment; 26 patients without pupils (non-cavity, NC) and 16 patients with pupils (cavity, C) were included. It was done as follows.
치료 시작 시점과 치료 시작 후 2 내지 4개월 시점에 채혈 된 결핵 폐질환 환자의 혈청 샘플로부터 추출한 극성대사체는 고성능 액체 크로마토그래피-삼중 사중극자 질량 분석기(high performance liquid chromatography-triple quadrupole mass spectrometry; HPLC-QQQ-MS)를 이용하여 분석하였다. 치료 완료 후 2년 내 재발하지 않는 결핵 감염 폐질환 환자를 대상으로 연구함으로써, 치료반응에 의하여 변화되는 혈청 내 극성대사체는 성공적인 치료반응을 예측할 수 있는 바이오마커 후보로 이용될 수 있다. Polar metabolites extracted from serum samples of patients with tuberculosis lung disease collected at the beginning of treatment and 2 to 4 months after the start of treatment were analyzed using high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC). -QQQ-MS) was used to analyze. By studying patients with tuberculosis-infected lung disease who do not relapse within 2 years after completing treatment, polar metabolites in serum that change in response to treatment can be used as biomarker candidates that can predict successful treatment response.
실시예 2. 혈청(serum)내 극성대사체 분석을 위한 시료 처리 방법 Example 2. Sample processing method for analysis of polar metabolites in serum
혈청 시료 (50μl)에 300μl 클로로포름, 150μl 메탄올(chloroform-methanol, 2:1, v/v, 4℃)를 첨가하고 30초 동안 섞어 주었다. 여기에 150 ㎕ 물을 첨가하고 30초 동안 섞은 뒤 ICE에 넣어 10분간 방치하여 추출을 진행하였다. 이후, 원심분리기기를 이용하여 10분간 13,000 rpm, 4℃에서 원심분리한 뒤 상층액(200 ㎕)과 하층액(200 ㎕) 분리해내어 Speed vacuum (full vacuum, no temp, 1-2hours)을 이용하여 건조하였으며, 대사체 분석 전까지 -20℃에서 보관하였다. 극성대사체 질량 분석을 위하여 상층액의 건조된 시료에 Acetonitrile-H2O(75:25, v/v) 용매 200 ㎕를 넣어 재용해하였다. 이 때, 재용해 용액 내 13C-labeled yeast extract인 ISO1을 1:20으로 희석하여 추가하고, 13C-taurine 100ppb, 13C-allantoin 100ppb, 13C-hypoxanthine 100ppb, 13C-2-chloro adenosine 100ppb, 13C-Lactate 100ppb, 13C-Glucose 100ppb, 13C-Uric acid 100ppb을 추가하여 내부표준물질로 이용하였다. 각 대사체의 내부표준물질은 표 2와 4에 나열하였다. 재용해 후, 존재할 가능성이 있는 불순물 제거하기 위하여 상층과 하층 모두 필터 튜브(Filter tube, Costar 8169)를 이용하여 여과한 후 분석을 진행하였다. 기계 품질 관리(Machinery Quality Control, MQC)로 MS/MS 기기 상태를 체크하기 위하여 구입한 Human의 혈청 샘플을 환자 혈청 샘플과 같은 전 처리방법으로 기계 품질 관리(MQC)의 샘플로 사용하였으며, 배치 당 5회 반복 분석하였다. 시료 품질 관리(Sample Quality Control; SQC)를 위하여 각 배치 안에서 시료 간의 차이를 비교하기 위해 샘플 당 10 ㎕씩 모아 시료 품질 관리(SQC)를 제작하여 배치 당 5회 반복 분석하였다.To the serum sample (50 μl), 300 μl chloroform and 150 μl methanol (chloroform-methanol, 2:1, v/v, 4°C) were added and mixed for 30 seconds. 150 ㎕ of water was added here, mixed for 30 seconds, placed in ICE, left for 10 minutes, and extraction was performed. Afterwards, centrifugation was performed at 13,000 rpm and 4°C for 10 minutes using a centrifugal separator, and the supernatant (200 ㎕) and lower layer (200 ㎕) were separated and subjected to speed vacuum (full vacuum, no temp, 1-2 hours). It was dried and stored at -20°C until metabolite analysis. For polar metabolite mass analysis, the dried sample of the supernatant was re-dissolved in 200 ㎕ of Acetonitrile-H 2 O (75:25, v/v) solvent. At this time, 13C-labeled yeast extract ISO1 in the re-dissolved solution was diluted 1:20 and added, 13C-taurine 100ppb, 13C-allantoin 100ppb, 13C-hypoxanthine 100ppb, 13C-2-chloro adenosine 100ppb, 13C-Lactate. 100ppb, 13C-Glucose 100ppb, and 13C-Uric acid 100ppb were added and used as internal standards. Internal standards for each metabolite are listed in Tables 2 and 4. After re-dissolution, both the upper and lower layers were filtered using a filter tube (Costar 8169) to remove impurities that may be present, and then analysis was performed. To check the status of the MS/MS device through Machinery Quality Control (MQC), purchased human serum samples were used as samples for Machinery Quality Control (MQC) using the same preprocessing method as patient serum samples, per batch. The analysis was repeated 5 times. For sample quality control (SQC), 10 ㎕ of each sample was collected to compare the differences between samples within each batch, and the analysis was repeated 5 times per batch.
실시예 3. HPLC-Triple Quad-MS를 통한 극성대사체 분석 방법Example 3. Polar metabolite analysis method through HPLC-Triple Quad-MS
혈청에서 처리한 분석시료내의 극성대사체를 분석하기 위해 액체크로마토그래피-텐덤 질량분석기(HPLC-MS/MS)를 이용하여 분석을 진행하였다. 사용된 장비는 Agilent 1200 HPLC와 Sciex API4000 triple quadrupole MS를 이용하였다. HPLC를 이용한 극성대사체의 positive mode 분석 조건으로는 XBridge BEH Amide (4.6 x 250 mm, 3.5 μm, Waters) 컬럼을 이용하여 40 ℃에서 용매에 따른 기울기 용리를 이용하였다. 이동상으로는 (A) 85% water+15% acetonitrile (30mM ammonium acetate + 0.2% acetic acid) 및 (B) 85% Acetonitrile (0.2% acetic acid)를 이용하였다. 극성대사체의 negative mode 분석 조건으로는 Luna PFPP (2.0 x 150 mm, 3μm, Phenomenex) 컬럼을 이용하여 40°C에서 용매에 따른 기울기 용리를 이용하였다. 이동상으로는 (A) Water (0.1% formic acid) 및 (B) 100% Acetonitrile를 이용하였다. 각 조건의 기울기 용리는 동일하며 총 분석 시간을 15분으로 하여 아래 표 1과 같이 수행하였다. MS/MS를 이용한 질량분석 조건으로는 분무기 가스(Ion-Source Gas 1/2)단위는 50/50 arbitrary unit이었으며, 커튼 가스(Curtain Gas)의 단위는 25 arbitrary unit이었다. 소스 온도(Source temperature)는 500°C였으며, 이온스프레이 부유 전압(Ion-spray Floating Voltage)는 5.5kV(negative -4.5kV)이었으며, 매스 범위(Mass range)는 50-1000 m/z였다. 시료 주입은 HTC_PAL system/CTC analytics auto-sampler를 이용하여 3 ㎕씩 주입하였으며, 텐덤 질량 분석기 조건(예약 다중 반응 검지법; Scheduled Multiple Reaction Monitoring, sMRM)은 아래 표 2 내지 5와 같이 수행하였다. sMRM 분석을 통해 얻어진 결과는 Sciex의 Quantitative Analysis Software를 통하여 raw data를 계산하였고, SQC data 평균값을 이용하여 상대표준편차(RSD<20)이하의 극성대사체를 산출하였다. 극성대사체 분석을 위한 HPLC 기울기 용리 조건은 표 1에 나타내었으며, 극성대사체 51종 positive mode의 sMRM분석 조건은 표 2에 나타내었고, 극성대사체 내부표준물질 positive mode의 sMRM분석 조건은 표 3에 나타내었다. 또한, 극성대사체 23종 negative mode의 sMRM분석 조건은 표 4에 나타내었으며, 극성대사체 내부표준물질 negative mode의 sMRM분석 조건은 표 5에 나타내었다.To analyze polar metabolites in the analysis samples processed from serum, analysis was performed using liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The equipment used was Agilent 1200 HPLC and Sciex API4000 triple quadrupole MS. As conditions for positive mode analysis of polar metabolites using HPLC, gradient elution according to solvent was used at 40°C using an XBridge BEH Amide (4.6 x 250 mm, 3.5 μm, Waters) column. As mobile phases, (A) 85% water + 15% acetonitrile (30mM ammonium acetate + 0.2% acetic acid) and (B) 85% Acetonitrile (0.2% acetic acid) were used. As conditions for negative mode analysis of polar metabolites, gradient elution according to solvent was used at 40°C using a Luna PFPP (2.0 x 150 mm, 3μm, Phenomenex) column. As mobile phases, (A) Water (0.1% formic acid) and (B) 100% Acetonitrile were used. The gradient elution for each condition was the same and was performed as shown in Table 1 below with a total analysis time of 15 minutes. Under the mass analysis conditions using MS/MS, the unit of nebulizer gas (Ion-Source Gas 1/2) was 50/50 arbitrary unit, and the unit of curtain gas was 25 arbitrary unit. Source temperature was 500°C, ion-spray floating voltage was 5.5kV (negative -4.5kV), and mass range was 50-1000 m/z. Sample injection was performed at 3 μl each 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. The results obtained through sMRM analysis were raw data calculated through Sciex's Quantitative Analysis Software, and the average value of SQC data was used to calculate polar metabolites below the relative standard deviation (RSD<20). The HPLC gradient elution conditions for polar metabolite analysis are shown in Table 1, the sMRM analysis conditions for the positive mode of 51 polar metabolites are shown in Table 2, and the sMRM analysis conditions for the positive mode of the polar metabolite internal standard are shown in Table 3. shown in In addition, the sMRM analysis conditions for the negative mode of 23 types of polar metabolites are shown in Table 4, and the sMRM analysis conditions for the negative mode of the polar metabolite internal standard are shown in Table 5.
Q1은 분자이온에 대한 질량 대 전하 비율(mass to charge ratio; m/z) 값을 갖는 전구체 이온(precursor ion)을 의미하고, Q3는 분자이온에 대한 조각이온의 m/z 값을 갖는 프로덕트 이온(product ion)을 의미한다. 또한, RT는 보유 시간(Retention time)을 의미하며, CE는 충돌 에너지(Collision energy)를 의미한다.Q1 refers to the precursor ion with the mass to charge ratio (m/z) value for the molecular ion, and Q3 refers to the product ion with the m/z value of the fragment ion for the molecular ion. It means (product ion). Additionally, RT stands for retention time, and CE stands for collision energy.
실시예 4. 극성대사체 분석 데이터 통계 Example 4. Polar metabolite analysis data statistics
결핵 감염 폐질환 환자 42명의 치료시작 시점과 치료시작 후 2 내지 4개월 시점에 대한 혈청 샘플내 극성대사체 농도를 비교하기 위해 통계분석 프로그램인 Metaboanalyst, Compound Discoverer, SPSS 및 Prism을 이용하여 그룹간 유의성 있는 (p-value<0.05) 극성대사체를 산출하였다. 이 때, 42명의 모든 환자(NC+C)에 대하여 치료시작 전(Tx0)과 치료 후 2 내지 4개월 시점(Tx2 내지 4)에 대하여 unpaired t-test와 paired t-test를 각각 수행하였고, 추가적으로 non-cavity(NC) 그룹과 cavity(C) 그룹을 분류한 후 각 그룹 내 치료 전 후 반응에 대해서는 paired t-test를 실시하였다. 그 결과를 통해 결핵 감염 폐질환 환자에서 항생제 치료에 의해 변화하는 대사체를 탐색하였고, 이는 성공적인 치료반응을 예측할 수 있는 지표가 될 수 있으며 극성대사체 6종을 p-value와 배수 변화(Fold change)값을 토대로 선정하였다(표 6, 또는 도 1). 결핵 감염 폐질환 환자의 성공적인 치료반응 예측을 위한 극성대사체 마커 후보물질은 표 6에 나타내었다.Statistical analysis programs Metaboanalyst, Compound Discoverer, SPSS, and Prism were used to compare polar metabolite concentrations in serum samples of 42 patients with tuberculosis-infected lung disease at the time of starting treatment and 2 to 4 months after starting treatment to determine significance between groups. Polar metabolites with (p-value<0.05) were calculated. At this time, unpaired t-test and paired t-test were performed on all 42 patients (NC+C) before starting treatment (Tx0) and 2 to 4 months after treatment (Tx2 to 4), respectively. Additionally, After classifying the non-cavity (NC) group and cavity (C) group, a paired t-test was performed on the responses before and after treatment within each group. Through the results, we explored the metabolites that change due to antibiotic treatment in patients with tuberculosis-infected lung disease, which can be an indicator for predicting successful treatment response, and p-value and fold change (Fold change) for 6 types of polar metabolites. ) was selected based on the value (Table 6, or Figure 1). Candidate polar metabolite marker substances for predicting successful treatment response in patients with tuberculosis-infected lung disease are shown in Table 6.
(NC+C)Unpaired t-test
(NC+C)
도 1은 치료 완료 후 2개월 내 재발이 없는 결핵 폐질환 환자에서 치료시작 전과 치료한 지 2 내지 4개월이 경과함에 따라서 혈청 내 농도가 변화하는 6종의 극성대사체를 나타낸다. 알란토인(Allantoin), 및 페닐알라닌(phenylalanine)은 치료된 지 2 내지 4개월 시점에 혈청 내 농도가 감소하며, 호모세린(Homoserine), 알라닌(alanine), 메티오닌(methionine) 및 히스티딘(histidine)은 치료된 지 2 내지 4개월 시점에 혈청 내 농도가 증가한다. Figure 1 shows six types of polar metabolites whose serum concentrations change before starting treatment and 2 to 4 months after treatment in patients with tuberculosis lung disease without recurrence within 2 months after completion of treatment. Allantoin and phenylalanine decrease in serum concentration 2 to 4 months after treatment, and homoserine, alanine, methionine, and histidine decrease after treatment. The concentration in serum increases at 2 to 4 months.
이들은 치료 후 2년내 재발하지 않는 결핵 감염 폐질환 환자를 대상으로 연구함으로써, 항생제 치료반응에 의하여 변화된 대사체는 환자의 성공적인 치료 반응을 예측할 수 있는 극성 대사체 바이오마커가 될 수 있다.By studying patients with tuberculosis-infected lung disease that does not recur within two years after treatment, metabolites changed in response to antibiotic treatment can become polar metabolite biomarkers that can predict a patient's successful treatment response.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (11)
A composition for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, comprising as an active ingredient an agent that measures the concentration of polar metabolites.
상기 극성 대사체는 알란토인(Allantoin), 페닐알라닌(phenylalanine), 호모세린(Homoserine), 알라닌(alanine), 메티오닌(methionine), 및 히스티딘(histidine)으로 구성된 군으로부터 선택되는 어느 하나 이상인 것인, 조성물.
According to clause 1,
The composition, wherein the polar metabolite is at least one selected from the group consisting of allantoin, phenylalanine, homoserine, alanine, methionine, and histidine.
상기 극성 대사체는 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 내 존재하는 것인, 조성물.
According to claim 1,
The polar metabolites are found in whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, and 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. A composition that exists in (cerebrospinal fluid).
A method for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, comprising: measuring the concentration of polar metabolites in a sample isolated from a subject of interest.
상기 극성 대사체는 알란토인(Allantoin), 페닐알라닌(phenylalanine), 호모세린(Homoserine), 알라닌(alanine), 메티오닌(methionine), 및 히스티딘(histidine)으로 구성된 군으로부터 선택되는 어느 하나 이상인 것인, 방법.
According to clause 4,
The method wherein the polar metabolite is at least one selected from the group consisting of allantoin, phenylalanine, homoserine, alanine, methionine, and histidine.
상기 알란토인 또는 페닐알라닌의 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 낮은 경우, 상기 목적하는 개체는 항생제에 대한 치료 반응성이 있는 것으로 예측하는 것인, 방법.
According to clause 5,
When the concentration of allantoin or phenylalanine before antibiotic administration is lower than the concentration measured after antibiotic administration, the method predicts that the subject of interest is therapeutically responsive to the antibiotic.
상기 호모세린, 알라닌, 메티오닌, 또는 히스티딘의 항생제 투여 전 농도가 항생제 투여 후 측정한 농도보다 높은 경우, 상기 목적하는 개체는 항생제에 대한 치료 반응성이 있는 것으로 예측하는 것인, 방법.
According to clause 5,
If the concentration of homoserine, alanine, methionine, or histidine before antibiotic administration is higher than the concentration measured after antibiotic administration, the subject of interest is predicted to have treatment responsiveness to the antibiotic.
상기 항생제 투여 후의 측정은 상기 항생제 투여 후 2 내지 4개월 경과 후 수행되는 것인, 방법.
According to any one of claims 6 to 7,
Method wherein the measurement after administration of the antibiotic is performed 2 to 4 months after administration of the antibiotic.
상기 대사체의 농도를 측정하는 단계는 크로마토그래피 또는 질량분석기인 정량 장치를 이용하여 수행되는 것인, 방법.
According to clause 4,
The method of measuring the concentration of the metabolite is performed using a quantitative device such as a chromatography or mass spectrometer.
상기 극성 대사체는 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 내 존재하는 것인, 방법.
According to clause 5,
The polar metabolites are found in whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, and 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) What exists within me, how.
A kit for predicting treatment responsiveness to antibiotics in patients with tuberculosis-infected lung disease, containing as an active ingredient an agent that measures the concentration of polar metabolites.
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KR1020220101881A KR20240023775A (en) | 2022-08-16 | 2022-08-16 | Polarity metabolite markers changed according to the treatment of pulmonary tuberculosis patients |
PCT/KR2023/011926 WO2024039143A1 (en) | 2022-08-16 | 2023-08-11 | Polar metabolite markers changed according to treatment of pulmonary tuberculosis patients |
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