KR102142018B1 - Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics - Google Patents

Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics Download PDF

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KR102142018B1
KR102142018B1 KR1020180164212A KR20180164212A KR102142018B1 KR 102142018 B1 KR102142018 B1 KR 102142018B1 KR 1020180164212 A KR1020180164212 A KR 1020180164212A KR 20180164212 A KR20180164212 A KR 20180164212A KR 102142018 B1 KR102142018 B1 KR 102142018B1
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bacteriophage
ymc17
present
bacteria
klebsiella
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KR20200075980A (en
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용동은
전종수
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연세대학교 산학협력단
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    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/34635—Antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3571—Microorganisms; Enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/50—Treatment of water, waste water, or sewage by addition or application of a germicide or by oligodynamic treatment
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F3/00—Biological treatment of water, waste water, or sewage
    • C02F3/34—Biological treatment of water, waste water, or sewage characterised by the microorganisms used
    • C02F3/341—Consortia of bacteria
    • C12R1/91—

Abstract

본 발명은 클렙시엘라 속 세균, 특히는 항생제에 대한 내성을 보이는 클렙시엘라 속 세균을 용균시키는 신규한 박테리오파지 YMC17/01/P6_KPN_BP에 관한 것이다. 본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균에 의해 유발되는 감염성 질환의 예방 또는 치료, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제, 또는 세척제 분야에서 다양하게 사용될 수 있다.The present invention relates to a novel bacteriophage YMC17/01/P6_KPN_BP that lyses bacteria of the genus Klebsiella, particularly Klebsiella, which is resistant to antibiotics. The bacteriophage YMC17/01/P6_KPN_BP of the present invention can be variously used in the field of prevention or treatment of infectious diseases caused by bacteria of the genus Klebsiella, antibiotic composition, composition for adding feed, feed, disinfectant, or detergent.

Description

항생제 내성을 갖는 클렙시엘라 속의 균을 용균하는 신규한 박테리오파지{Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics}Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics}

본 발명은 클렙시엘라 속 세균, 특히는 항생제에 대한 내성을 보이는 클렙시엘라 속 세균을 용균시키는 신규한 박테리오파지에 관한 것이다.The present invention relates to a novel bacteriophage lysing bacteria of the genus Klebsiella, particularly Klebsiella, which is resistant to antibiotics.

일반적으로 클렙시엘라(Klebsiella) 속 세균은 장내세균과의 한 속명으로, 그람음성간균이다. 편모는 없고, 협막을 지나다니면서 점액을 생산하는 것이 특징이다. 구연산염으로부터 탄소원을 얻고, 여러가지 탄수화물에서 황화수소를 제외한 산과 가스를 발생시킨다. 자연계에 널리 존재하며, 사람의 호흡기, 장관, 비뇨기에서 검출되며 급성 폐렴의 원인균으로 알려져 있다. 최근에는 다양한 클렙시엘라 속 세균이 진단, 검출되고 있는데, 폐렴간균(Klebsiella pneumoniae), 클렙시엘라 오자에나에(Klebsiella ozaenae), 클렙시엘라 리노스클레로마티스(Klebsiella rhinoscleromatis) 등이 존재한다.In general, bacteria of the genus Klebsiella are a genus of intestinal bacteria, and are Gram-negative bacilli. It has no flagella and is characterized by producing mucus as it passes through the stenosis. Carbon sources are obtained from citrate, and various carbohydrates generate acids and gases excluding hydrogen sulfide. It is widely present in nature and is detected in human respiratory, intestinal, and urinary tract and is known as a causative agent of acute pneumonia. Recently, various bacteria of the genus Klebsiella have been diagnosed and detected, such as Klebsiella pneumoniae, Klebsiella ozaenae, and Klebsiella rhinoscleromatis.

임상적 측면에서 클렙시엘라 속 세균 중 대부분을 차지하는 것으로 알려진 폐렴간균(Klebsiella pneumoniae)은 그람음성(Gram negative)의 간균, 통성혐기성 또는 호기성 세균으로 사람의 장관 내, 피부, 구강, 호흡기 등에 상재하고 있으며, 폐렴의 10~20%는 이 균에 의한다고 한다. 또한 요로감염증에서 분리되는 경우도 있으며, 패혈증, 복강 내 감염 등의 주 원인균으로 보고되고 있으며, 중환자실 환자에서 발생하는 균혈증의 원인균으로 높은 감염률을 보이고 있다.Klebsiella pneumoniae, which is known to occupy most of the bacteria of the genus Klebsiella in clinical terms, is a Gram negative bacillus, aerobic or aerobic bacteria, and is present in the human intestinal tract, skin, oral cavity, respiratory system, etc. It is said that 10-20% of pneumonia is caused by the bacteria. In addition, it may be isolated from urinary tract infection, and is reported as the main causative agent such as sepsis and intraperitoneal infection, and has a high infection rate as the causative agent of bacteremia occurring in patients in the intensive care unit.

한편, 현재 미생물을 효과적으로 사멸시킬 수 있는 다양한 항균제가 사용되고 있는데, 베타락탐 계열의 항생제는 현재 사용되고 있는 항균제의 약 50% 이상을 차지하고 있다. 그러나 많은 그람음성 세균에서는 이러한 베타락탐 계열의 항생제에 대해 베타락탐분해효소를 생성함으로써 상기 항생제들에 내성을 나타내는 것으로 보고되고 있다. 현재 발견되는 클렙시엘라 속 세균인 폐렴간균 중에서도 항생제 내성을 나타내는 세균인 특히, K. pneumoniae 카바페네메이즈(KPC)-생산 K. pneumoniae (KPC-Kp)는 전 세계적 확산과 함께 감염환자의 사망률을 높이고 있다. 이에 국내에서도 K. pneumoniae 카바페네메이즈(KPC)-생산 K. pneumoniae (KPC-Kp)확산 및 증가 억제를 위한 새로운 전략이 필요한 실정이다.On the other hand, various antibacterial agents that can effectively kill microorganisms are currently used. Betalactam-based antibiotics account for more than 50% of currently used antibacterial agents. However, many Gram-negative bacteria have been reported to exhibit resistance to these antibiotics by generating beta-lactamase against these beta-lactam-based antibiotics. Among the currently found bacteria of the genus Klebsiella pneumonia, K. pneumoniae carbapene maize (KPC)-producing K. pneumoniae (KPC-Kp), which is an antibiotic-resistant bacterium, increases the mortality rate of infected patients with global spread. Raising. Therefore, in Korea, a new strategy is needed to suppress the spread and increase of K. pneumoniae carbapene maize (KPC)-producing K. pneumoniae (KPC-Kp).

한편, 박테리오파지(bacteriophage)는 특정 세균을 감염시켜 감염된 세균의 성장을 억제하고 저해하는 세균 특이적 바이러스를 의미한다. 박테리오파지는 박테리아에 감염(infection)한 후 박테리아 세포 내부에서 증식을 하고, 증식 후 자손 박테리오파지들이 박테리아 밖으로 나올 때 숙주인 박테리아의 세포벽을 파괴하는 방식으로 박테리아를 사멸시키는 능력을 갖고 있다. 박테리오파지의 박테리아 감염 방식은 매우 특이성이 높아서 특정 박테리아에 감염할 수 있는 박테리오파지의 종류는 일부로 한정된다. 즉, 특정 박테리오파지는 특정 범주의 박테리아에만 감염할 수 있고 이로 인하여 특정 박테리오파지는 특정 박테리아만을 사멸시키며 다른 박테리아에는 영향을 주지 않는다. 따라서 최근 세균성 질환의 대처 방안으로 박테리오파지(bacteriophage)의 활용이 크게 주목을 받고 있다. 특히 2000년 이후에 항생제 내성균의 증가로 인하여 기존 항생제의 한계성이 나타나고, 기존 항생제의 대체 물질로의 개발 가능성이 부각되면서 다시 박테리오파지가 항-박테리아제로 주목을 받고 있다.On the other hand, bacteriophage (bacteriophage) refers to a bacteria-specific virus that inhibits and inhibits the growth of infected bacteria by infecting certain bacteria. The bacteriophage has the ability to kill bacteria by destroying the cell wall of the host bacteria when the progeny bacteriophages come out of the bacteria after proliferation inside the bacterial cells after infection. The method of bacterial infection of bacteriophage is very specific, so the type of bacteriophage capable of infecting certain bacteria is limited to a part. That is, a specific bacteriophage can infect only a specific category of bacteria, thereby killing a specific bacteriophage and not affecting other bacteria. Therefore, the recent use of bacteriophage (bacteriophage) as a countermeasure against bacterial diseases has been receiving much attention. In particular, since 2000, due to the increase in antibiotic-resistant bacteria, the limitations of existing antibiotics appeared, and the possibility of development of alternative antibiotics as an alternative material has emerged, and bacteriophage has attracted attention as an anti-bacterial agent.

현재까지 클렙시엘라 속 세균에 의한 감염증을 예방 또는 치료하기 위한 신규한 박테리오파지에 대한 연구는 여전히 부족한 실정이다. 따라서 클렙시엘라 속 세균에 특이적인 용균 활성을 갖는 박테리오파지 및 이의 응용에 대한 기술 개발이 필요하다.To date, research into novel bacteriophage to prevent or treat infections caused by bacteria of the genus Klebsiella is still insufficient. Therefore, it is necessary to develop a technology for bacteriophage having a lytic activity specific to bacteria of the genus Klebsiella and its application.

본 발명의 일 목적은 클렙시엘라 속 세균, 특히는 항생제에 대한 내성을 갖는 클렙시엘라 속 세균에 대하여 특이적 감염 및 사멸능을 갖는 신규한 박테리오파지를 제공하는 것이다.One object of the present invention is to provide a novel bacteriophage having specific infection and killing ability against bacteria of the genus Klebsiella, in particular resistant to antibiotics.

본 발명의 다른 목적은 클렙시엘라 속 세균, 특히는 항생제에 대한 내성을 갖는 클렙시엘라 속 세균에 대하여 특이적 감염 및 사멸능을 갖는 신규한 박테리오파지에 의해 유발되는 감염성 질환의 예방 및 치료용 조성물과 질환 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is a composition for the prevention and treatment of infectious diseases caused by novel bacteriophage having specific infection and killing ability against bacteria of the genus Klebsiella, in particular resistant to antibiotics. It is to provide a food composition for improving the disease.

본 발명의 일 구현 예에 따르면, 클렙시엘라(Klebsiella) 속 세균에 특이적인 사멸능을 갖는 박테리오파지 YMC17/01/P6_KPN_BP를 제공한다.According to an embodiment of the present invention, it provides a bacteriophage YMC17/01/P6_KPN_BP having a specific killing ability to bacteria of the genus Klebsiella.

본 발명에서, 용어 "박테리오파지(bacteriophage)"는 특정 세균에 감염하여 당해 세균의 성장을 억제하고 저해하는 세균 특이적 바이러스로, 단일 혹은 이중 사슬의 DNA 또는 RNA를 유전 물질로 포함하는 바이러스를 의미한다.In the present invention, the term "bacteriophage (bacteriophage)" is a bacterial specific virus that inhibits and inhibits the growth of the bacteria by infecting a specific bacterium, and refers to a virus comprising a single or double chain DNA or RNA as a genetic material. .

본 발명에서, 상기 클렙시엘라 속 세균은 클렙시엘라 뉴모니아(Klebsiella pneumoniae), 클렙시엘라 오자에나에(Klebsiella ozaenae), 클렙시엘라 리노스클레로마티스(Klebsiella rhinoscleromatis), 클렙시엘라 옥시토카(Klebsiella oxytoca), 클렙시엘라 플란티콜라(Klebsiella planticola) 및 클렙시엘라 테리게나(Klebsiella terrigena)로 구성된 군으로부터 선택되는 어느 1종 이상일 수 있으며, 임상적 측면에서 폐렴간균으로 클렙시엘라 속 세균 중 대부분을 차지하는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 클렙시엘라 속 세균을 대표하는 세균으로 알려져 있다. In the present invention, the bacteria of the genus Klebsiella, Klebsiella pneumoniae , Klebsiella ozaenae , Klebsiella rhinoscleromatis , Klebsiella oxytoca ( Klebsiella oxytoca ), Klebsiella planticola and Klebsiella terrigena may be any one or more selected from the group consisting of Klebsiella oxytoca. Klebsiella pneumoniae , which accounts for most of the species, is known as a representative bacteria of the genus Klebsiella pneumoniae .

본 발명에서 상기 박테리오파지는 클렙시엘라 속 세균에 특이적 사멸능을 가지지만, 상기 클렙시엘라 속 세균 중에서도 항생제 내성을 가진 클렙시엘라 속 세균에 대하여도 특이적 사멸능을 가진다. In the present invention, the bacteriophage has a specific killing ability against bacteria of the genus Klebsiella, but among the bacteria of the genus Klebsiella, it also has a specific killing ability against bacteria of the genus Klebsiella.

본 발명에서 상기 "항생제 내성"은 특정 항생제에 내성을 보여 약효가 듣지 않는 것을 의미하며, 본 발명의 목적상 상기 항생제는 카바페넴(Carbapenem)의 구조를 갖는 항생제일 수 있다. 구체적으로, 아미카신(Amicacin), 엠피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 이미페넴(Imipenem), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록세신(Levoflocacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa) 및 티게사이클린(Tigecyline)으로 구성된 군으로부터 선택되는 1종 이상일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 목적상 상기 클렙시엘라 뉴모니아는 항생제 내성을 갖는 것일 수 있고, 상기 항생제 내성은 상기 카바페넴을 분해하여 효과의 발휘를 억제하는 카바페넴아제 효소(carbapenemase)를 생산함으로써 발생될 수 있다. In the present invention, the "antibiotic resistance" means resistance to a specific antibiotic and thus does not listen to the medicinal effect. For the purposes of the present invention, the antibiotic may be an antibiotic having a structure of carbapenem. Specifically, Amikacin, Ampicillin, Ampicillin/Sulbactam, Aztreonam, Ceftazidime, Cefazolin, Imipenem ), Ertapenem, Cefepime, Cefoxitin, Cefotaxime, Gentamicine, Levoflocacin, Meropenem, Piperacillin / Tazobactam (Piperacillin/Tazobactam), may be one or more selected from the group consisting of Cotrimoxa (Cortrimoxa) and tigecycline (Tigecyline), but is not limited thereto. For the purposes of the present invention, the Klebsiella pneumoniae may have antibiotic resistance, and the antibiotic resistance may be generated by producing a carbapenemase that decomposes the carbapenem and suppresses the effect of the effect. .

본 발명에서 박테리오파지 YMC17/01/P6_KPN_BP는 서열번호 1로 표시되는 염기 서열을 전체 유전자의 전체 또는 일부로써 포함할 수 있다. 또한, 본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 서열번호 1로 표시되는 염기 서열, 및 상기 염기 서열의 기능적 동등물로 이루어질 수 있다. 상기 기능적 동등물이란 염기 서열의 변형, 치환의 결과, 상기 서열번호 1로 표시되는 염기 서열과 적어도 70% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 서열번호 1로 표시되는 염기 서열과 실질적으로 동질의 생리 활성을 나타내는 서열을 의미한다.In the present invention, the bacteriophage YMC17/01/P6_KPN_BP may include the nucleotide sequence represented by SEQ ID NO: 1 as all or part of the entire gene. In addition, the bacteriophage YMC17/01/P6_KPN_BP of the present invention may consist of the nucleotide sequence represented by SEQ ID NO: 1, and a functional equivalent of the nucleotide sequence. The functional equivalent is at least 70% or more, preferably 80% or more, more preferably 90% or more, even more preferably 95% of the base sequence represented by SEQ ID NO: 1 as a result of modification or substitution of the base sequence. As having the above sequence homology, it means a sequence exhibiting substantially the same physiological activity as the base sequence represented by SEQ ID NO: 1.

또한, 본 발명에서 제공하는 상기 박테리오파지는 서열번호 2 및 3 중 어느 하나의 단백질을 포함하는 것일 수 있다. 본 발명에서 상기 서열번호 2 및 3 각각은 상기 박테리오파지의 ORF(Open reading frame)로, 상기 클렙시엘라속 균에 흡착 및 용균의 기능을 수행하는 단백질 중에서도 특히 홀린(holin) 또는 안티-홀린(antiholin)으로 추정되는 단백질의 아미노산 서열일 수 있으며, 보다 상세하게는 상기 서열번호 2 및 3은 각각 ORF57 및 ORF59의 아미노산 서열일 수 있다. In addition, the bacteriophage provided by the present invention may include any one of SEQ ID NO: 2 and 3. In the present invention, each of SEQ ID NOs: 2 and 3 is an open reading frame (ORF) of the bacteriophage, among proteins that adsorb and bind to the genus Klebsiella, especially holin or anti-holin ) May be the amino acid sequence of the protein, and more specifically, SEQ ID NOs: 2 and 3 may be the amino acid sequences of ORF57 and ORF59, respectively.

또한, 본 발명에서 제공하는 상기 박테리오파지는 서열번호 4 및 5 중 어느 하나로 표시되는 유전체를 포함하는 것일 수 있다. 여기서 상기 서열번호 4는 ORF57을 코딩하는 유전체의 염기 서열이고, 서열번호 5는 ORF59를 코딩하는 유전체의 염기 서열이다.Further, the bacteriophage provided by the present invention may include a genome represented by any one of SEQ ID NOs: 4 and 5. Here, SEQ ID NO: 4 is the base sequence of the genome encoding ORF57, and SEQ ID NO: 5 is the base sequence of the genome encoding ORF59.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균, 특히 카바페넴계 항생제 내성 페렴간균에 대해 용균활성이 탁월하다. 상기 박테리오파지 YMC17/01/P6_KPN_BP는 각이 진 머리와 꼬리를 갖는 형태인 시포비리대(Siphoviridae) 과에 속함을 확인하였으며, 전체 염기 서열 분석 결과 54,880 bp의 크기를 갖고 전체 ORF의 수는 87개임을 확인하였다. The bacteriophage YMC17/01/P6_KPN_BP of the present invention has excellent lytic activity against bacteria of the genus Klebsiella, particularly carbapenem antibiotic-resistant pneumococcus. It was confirmed that the bacteriophage YMC17/01/P6_KPN_BP belongs to the Siphoviridae family, which has an angled head and tail, and the total sequencing analysis has a size of 54,880 bp and the total number of ORFs is 87. Confirmed.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 병원 내 하수처리장으로부터 시료를 채취하여 분리한 박테리오파지로서, 박테리오파지 YMC17/01/P6_KPN_BP로 명명하고 2018년 11월 15일에 한국미생물보존센터에 기탁번호 KFCC11804P로 기탁하였다.The bacteriophage of the present invention YMC17/01/P6_KPN_BP is a bacteriophage obtained by collecting and separating samples from a sewage treatment plant in a hospital. Did.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 4 ℃ 내지 60 ℃의 범위 내에서 용균 활성이 유지되나, 이에 제한되는 것은 아니다.The bacteriophage YMC17/01/P6_KPN_BP of the present invention maintains lytic activity within a range of 4°C to 60°C, but is not limited thereto.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 pH 3.0 내지 pH 11.0의 범위, 바람직하게는 pH 5.0 내지 pH 10.0의 범위 내에서 용균 활성이 유지되나, 이에 제한되는 것은 아니다.The bacteriophage YMC17/01/P6_KPN_BP of the present invention maintains lytic activity within a range of pH 3.0 to pH 11.0, preferably pH 5.0 to pH 10.0, but is not limited thereto.

본 발명에서 상기 박테리오파지 YMC17/01/P6_KPN_BP의 클렙시엘라 속 세균 특이적 용균 활성, 내산성 및 내염기성은, 본 발명의 박테리오파지를 클렙시엘라 속 세균에 의해 유발되는 감염성 질환의 예방 및 치료용 조성물이나, 상기 박테리오파지를 유효 성분으로 포함하는 다양한 제품에 적용함에 있어, 다양한 pH 범위의 적용이 가능하게 한다.In the present invention, the bacteriophage YMC17/01/P6_KPN_BP specific bactericidal activity, acid resistance and basicity of the genus Klebsiella, is a composition for the prevention and treatment of infectious diseases caused by the bacteria of the Klebsiella genus of the present invention, or , When applied to a variety of products containing the bacteriophage as an active ingredient, it is possible to apply a variety of pH range.

본 발명의 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 유효 성분으로 포함하는 클렙시엘라 속 세균에 의해 유발되는 질환의 예방, 개선 또는 치료용 조성물을 제공한다.According to another embodiment of the present invention, it provides a composition for preventing, improving or treating diseases caused by bacteria of the genus Klebsiella, which includes the bacteriophage YMC17/01/P6_KPN_BP as an active ingredient.

본 발명의 조성물에서 상기 박테리오파지 YMC17/01/P6_KPN_BP 및 상기 클렙시엘라 속 세균에 관한 내용은 상기 박테리오파지에서 기재된 바와 중복되어 이하 자세한 기재를 생략한다. In the composition of the present invention, the contents of the bacteriophage YMC17/01/P6_KPN_BP and the bacteria of the genus Klebsiella overlap with those described in the bacteriophage, and detailed description thereof will be omitted below.

본 발명에서 상기 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균, 특히 카바페넴 항생제 내성을 갖는 폐렴간균을 특이적으로 사멸시키므로, 상기 클렙시엘라 속 세균에 의해 유발되는 다양한 질환의 치료에 효과를 나타낸다. In the present invention, since the bacteriophage YMC17/01/P6_KPN_BP specifically kills bacteria of the genus Klebsiella, particularly pneumonia bacterium having carbapenem antibiotic resistance, it is effective in the treatment of various diseases caused by the bacteria of the genus Klebsiella. Shows.

본 발명에서 상기 클렙시엘라 속 세균에 의해 유발되는 감염성 질환은 폐렴, 요로감염, 창상감염, 뇌수막염, 골수염, 상처감염, 내안구염, 안내염, 간농양, 인후염, 설사, 패혈증, 축농증, 비염, 중이염, 균혈증, 심내막염, 담낭염 또는 이하선염을 포함하며, 이는 특히 폐렴간균에 의하여 발생하는 질병이나, 이에 제한되는 것은 아니다.In the present invention, the infectious disease caused by bacteria of the genus Klebsiella is pneumonia, urinary tract infection, wound infection, meningitis, osteomyelitis, wound infection, endophthalmitis, intraocular infection, hepatitis, sore throat, diarrhea, sepsis, sinusitis, rhinitis, otitis media , Bacteremia, endocarditis, cholecystitis or parotitis, which is a disease caused by pneumococcal bacteria, but is not limited thereto.

본 발명의 조성물은 1 X 103 내지 1 X 1010 PFU/mL의 박테리오파지를 포함할 수 있고, 바람직하게는 1 X 106 내지 1 X 109 PFU/mL의 박테리오파지를 포함할 수 있다. 본 발명에 사용된 용어, PFU(plaque forming unit)는 박테리오파지가 플라크를 형성하는 것을 수치화한 단위이다.The composition of the present invention may include a bacteriophage of 1 X 10 3 to 1 X 10 10 PFU/mL, preferably a bacteriophage of 1 X 10 6 to 1 X 10 9 PFU/mL. As used in the present invention, the term PFU (plaque forming unit) is a unit in which bacteriophage forms plaques.

본 발명에서 용어 "예방"이란 조성물의 투여로 질병을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to all actions that suppress the disease or delay the onset of the administration of the composition.

본 발명에서 용어 "치료"란 조성물의 투여로 상기 질병의 증세가 호전되거나 상기 질병의 억제 또는 경감 및 이롭게 변경되는 모든 행위를 의미한다.In the present invention, the term "treatment" means any action in which the symptoms of the disease are improved or the disease is suppressed or alleviated and beneficially changed by administration of the composition.

본 발명의 상기 조성물은 약학적 조성물, 식품 조성물 또는 화장료 조성물로 사용될 수 있다. The composition of the present invention can be used as a pharmaceutical composition, food composition or cosmetic composition.

본 발명의 또 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 유효 성분으로 포함하는 포함하는, 항생용 조성물을 제공한다. According to another embodiment of the present invention, the bacteriophage YMC17/01/P6_KPN_BP comprising as an active ingredient, provides an antibiotic composition.

본 발명에서, 용어 "항생용 조성물"은 약제 형태로 동물에게 제공되어 균을 사멸시킬 수 있는 제제를 의미하며, 방부제, 살균제, 항생제 및 항균제를 총칭하는 것이다. In the present invention, the term "antibiotic composition" refers to an agent that can be provided to animals in the form of a drug to kill bacteria, and collectively refers to preservatives, fungicides, antibiotics and antibacterial agents.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 기존 항생제에 비하여 클렙시엘라 속 세균에 대한 특이성이 매우 높고, 특히는 카바페넴계 항생제 내성을 갖는 클렙시엘라 속 세균에서도 작용하며, 유익균은 죽이지 않으면서 특정 병원균만 사멸시킬 수 있다. 아울러, 약물 내성 내지 저항성을 유도하지 않아, 기존의 항생물질에 비하여 제품수명(life cycling)이 긴 신규 항생제로서 이용될 수 있다는 이점이 있다.The bacteriophage YMC17/01/P6_KPN_BP of the present invention has a very high specificity to the bacteria of the genus Klebsiella compared to the existing antibiotics, and particularly acts on the bacterium of the genus Klebsiella, which is resistant to the carbapenem-based antibiotics. Only pathogens can be killed. In addition, since it does not induce drug resistance or resistance, there is an advantage that it can be used as a new antibiotic with a long product life (life cycling) compared to an existing antibiotic.

본 발명의 또 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 유효 성분으로 포함하는, 사료 첨가용 조성물을 제공한다.According to another embodiment of the present invention, the bacteriophage YMC17/01/P6_KPN_BP as an active ingredient, provides a composition for feed addition.

일반적으로, 축산, 수산업에서 사용되는 사료 첨가용 항생제는 질병의 예방 목적으로 사용되고 있는데, 예방 목적의 항생제 투여는 내성균 발생 가능성을 높이고 가축에 잔류하는 항생제가 사람에게 전달될 수 있어서 문제이다. 항생제가 육류를 통해 인체에 흡수되면 항생제 내성을 유발해 질병의 확산을 부를 수도 있다. 또한, 사료에 섞여 먹이는 항생제의 종류가 많고 이는 다제 내성균 발생 확률이 높아지는 문제점이 있기 때문에 좀 더 자연 친화적이면서도 기존의 항생제의 사용에서 발생한 문제를 해결할 새로운 사료 첨가용 항생 물질로서 본 발명의 상기 박테리오파지 YMC17/01/P6_KPN_BP를 이용할 수 있다.In general, antibiotics for feed addition used in livestock and fishery are used for the purpose of preventing diseases, and administration of antibiotics for prevention purposes is a problem because antibiotics that increase resistance to germs can be delivered to humans. When antibiotics are absorbed into the human body through meat, they can cause antibiotic resistance and cause disease spread. In addition, since there are many types of antibiotics mixed with feed and this has a problem of increasing the probability of multi-drug resistant bacteria, the bacteriophage YMC17 of the present invention is used as a new feed additive antibiotic to solve the problems arising from the use of existing antibiotics. /01/P6_KPN_BP can be used.

또한, 본 발명은 상기 사료 첨가용 조성물을 포함하는 사료를 제공할 수 있으며, 본 발명의 사료는 박테리오파지 YMC17/01/P6_KPN_BP를 사료 첨가제 형태로 따로 제조하여 사료에 혼합시키거나, 사료 제조 시 직접 첨가시켜 제조할 수 있다. 본 발명의 사료 내 박테리오파지 YMC17/01/P6_KPN_BP는 액상 또는 건조 상태일 수 있으며, 바람직하게는 건조된 분말 형태일 수 있다. 건조 방법은 통풍 건조, 자연 건조, 분무 건조 및 동결 건조가 가능하지만, 이에 제한되는 것은 아니다. 본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 분말 형태로 사료 중량의 0.05 내지 10 중량%, 바람직하게는 0.1 내지 2 중량%의 성분비로 혼합될 수 있다. 또한, 상기 사료는 본 발명의 박테리오파지 외에 사료의 보존성을 높일 수 있는 통상의 첨가제들을 추가로 포함할 수 있다.In addition, the present invention can provide a feed containing the composition for adding the feed, the feed of the present invention is a bacteriophage YMC17/01/P6_KPN_BP separately prepared in the form of feed additives to be mixed into the feed, or directly added during feed preparation Can be prepared. The bacteriophage YMC17/01/P6_KPN_BP in the feed of the present invention may be in a liquid or dry state, preferably in the form of a dried powder. The drying method may include, but is not limited to, air drying, natural drying, spray drying, and freeze drying. The bacteriophage YMC17/01/P6_KPN_BP of the present invention may be mixed in a powder form at a component ratio of 0.05 to 10% by weight, preferably 0.1 to 2% by weight of the feed weight. In addition, the feed may further include conventional additives that can increase the preservability of the feed in addition to the bacteriophage of the present invention.

본 발명의 사료 첨가용 조성물에는 비병원성의 다른 미생물이 추가로 첨가될 수 있다. 첨가될 수 있는 미생물로는 단백질 분해 효소, 지질 분해효소 및 당 전환 효소를 생산할 수 있는 바실러스 서브틸리스(Bacillus subtilis)와 같은 고초균, 소의 위와 같은 혐기적 조건에서 생리적 활성 및 유기물 분해능이 있는 락토바실러스 균주(Lactobacillus sp.), 가축의 체중을 증가시키며 우유의 산유량을 늘리고 사료의 소화 흡수율을 높이는 효과를 보여주는 아스퍼질러스 오리자에(Aspergillus oryzae)와 같은 사상균 및 사카로미세스 세레비지에 (Saccharomyces cerevisiae)와 같은 효모로 구성된 군으로부터 선택될 수 있다.In the composition for adding feed of the present invention, other non-pathogenic microorganisms may be further added. Microorganisms that can be added include proteases such as Bacillus subtilis , which can produce proteolytic enzymes, lipid-degrading enzymes, and sugar-converting enzymes, and Lactobacillus with physiological activity and organic matter-decomposing ability in anaerobic conditions such as stomach. Strains ( Lactobacillus sp. ), filamentous fungi such as Aspergillus oryzae and Saccharomyces cerevisiae, which show the effect of increasing the weight of livestock, increasing the milk yield and increasing the digestion and absorption rate of the feed. ) May be selected from the group consisting of yeast.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP를 포함하는 사료에는 식물성으로는 곡물류, 근과류, 식품가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류, 곡물부산물류 등이 있으며, 동물성으로는 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질, 동물성 플랑크톤류, 남은 음식물 등이 있으며 이에 제한되는 것은 아니다.In the feed containing the bacteriophage YMC17/01/P6_KPN_BP of the present invention, there are grains, muscles, food processing by-products, algae, fiber, pharmaceutical by-products, fats and oils, starch, peels, grain by-products, etc. , Animals include proteins, inorganics, fats and oils, minerals, fats and oils, single cell proteins, animal plankton, and leftover foods.

본 발명의 사료 첨가용 조성물에는 품질 저하를 방지하기 위하여 첨가하는 결착제, 유화제, 보존제 등이 포함될 수 있고, 효용 증대를 위하여 사료에 첨가하는 아미노산제, 비타민제, 효소제, 생균제, 향미제, 비단백태질소화합물, 규산염제, 완충제, 착색제, 추출제, 올리고당 등이 있으며, 그 외에도 사료 혼합제 등을 추가로 포함할 수 있다.The composition for feed addition of the present invention may include a binder, an emulsifier, a preservative, etc., added to prevent quality degradation, and an amino acid agent, vitamin agent, enzyme agent, probiotic agent, flavoring agent, non-proteinaceous agent added to the feed for increased utility Nitrogen compounds, silicates, buffers, colorants, extractants, oligosaccharides, etc. In addition, it may further include a feed mixture.

본 발명의 또 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 포함하는, 음용수 첨가제를 제공한다.According to another embodiment of the present invention, to provide a drinking water additive, including the bacteriophage YMC17/01/P6_KPN_BP.

본 발명의 음용수 첨가제는 상기 박테리오파지 YMC17/01/P6_KPN_BP 또는 이를 포함하는 조성물을 음용수 첨가제 형태로 따로 제조하여 사료 또는 음용수에 혼합하는 방식으로 사용되거나, 음용수 제조 시 직접 첨가하는 방식으로 사용할 수 있다. 상기와 같이 음용수에 혼합하여 공급함으로써 지속적으로 클렙시엘라 속 세균의 숫자를 감소시킬 수 있는 효과가 있다.The drinking water additive of the present invention can be used as a method of separately preparing the bacteriophage YMC17/01/P6_KPN_BP or a composition containing it in the form of a drinking water additive or mixing it with feed or drinking water, or directly adding it when preparing drinking water. As described above, there is an effect of continuously reducing the number of bacteria in the genus Klebsiella by mixing and supplying it with drinking water.

본 발명에서 음용수는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 음용수를 사용할 수 있다.In the present invention, drinking water is not particularly limited, and drinking water commonly used in the art may be used.

본 발명의 또 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 포함하는, 소독제를 제공한다.According to another embodiment of the present invention, to provide a disinfectant, including the bacteriophage YMC17/01/P6_KPN_BP.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균에 특이적 사멸능을 가지므로, 본 발명에서는 상기 박테리오파지 YMC17/01/P6_KPN_BP를 포함하는 소독제는 병원 감염을 막기 위한 병원 및 보건용의 소독제로 유용하게 사용될 수 있고 일반 생활 소독제, 식품 및 조리 장소 및 설비의 소독제, 양계장, 축사 등의 건물, 축체, 음수, 깔짚, 난좌, 운반차량, 식기 등의 각종 생육 용품의 소독 등에 사용될 수 있다.Since the bacteriophage YMC17/01/P6_KPN_BP of the present invention has a specific killing ability against bacteria of the genus Klebsiella, in the present invention, the disinfectant containing the bacteriophage YMC17/01/P6_KPN_BP is a disinfectant for hospitals and health for preventing hospital infection It can be usefully used as a general disinfectant, disinfectant for food and cooking places and facilities, poultry farms, houses, and other buildings, livestock, drinking water, litter, egg seats, transport vehicles, and disinfection of various growth products such as tableware.

본 발명의 또 다른 구현 예에 따르면, 상기 박테리오파지 YMC17/01/P6_KPN_BP를 포함하는, 세척제를 제공한다.According to another embodiment of the present invention, it provides a cleaning agent comprising the bacteriophage YMC17/01/P6_KPN_BP.

본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균에 특이적 사멸능을 가지므로, 클렙시엘라 속 세균에 노출되었거나 노출될 가능성이 있는 개체의 피부 표면 또는 신체 각 부위 등을 세척하는 용도로도 사용될 수 있다.The bacteriophage YMC17/01/P6_KPN_BP of the present invention has a specific killing ability against bacteria of the genus Klebsiella, so it is used to wash the skin surface or each part of the body of the individual exposed or possibly exposed to the bacteria of the genus Klebsiella Can also be used.

본 발명에 있어서, 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be characterized in that it is in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized as targeting humans.

본 발명의 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용 가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여 시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.The pharmaceutical composition of the present invention is not limited to these, but may be used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, according to a conventional method. Can. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., when administered orally, and in the case of injections, buffers, preservatives, painless Agents, solubilizers, isotonic agents, stabilizers, etc. can be used in combination. For topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, when administered orally, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., may be prepared, and in the case of injections, unit dosage ampoules or multiple dosages may be prepared. have. Others can be formulated as solutions, suspensions, tablets, capsules, and sustained release preparations.

한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.On the other hand, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.

본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition according to the present invention is not limited to these, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , Sublingual or rectal. Oral or parenteral administration is preferred.

본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.In the present invention, “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, epidural, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of suppositories for rectal administration.

본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention depends on a number of factors, including the activity, age, weight, general health, sex, diet, administration time, route of administration, release rate, drug combination and severity of the particular disease to be prevented or treated, of the specific compound used. It may vary, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, degree of disease, dosage form, administration route and duration, but can be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day It can be administered in kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be divided into several times. The above dosage does not limit the scope of the invention in any aspect. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions.

본 발명에서 화장료 조성물은 화장수, 영양로션, 영양에센스, 마사지 크림, 미용 목욕물 첨가제, 바디로션, 바디밀크, 배스오일, 베이비오일, 베이비파우더, 샤워겔, 샤워크림, 선스크린로션, 선스크린크림, 선탠크림, 스킨로션, 스킨크림, 자외선차단용 화장품, 크렌징밀크, 탈모제{화장용}, 페이스 및 바디로션, 페이스 및 바디크림, 피부미백크림, 핸드로션, 헤어로션, 화장용크림, 쟈스민오일, 목욕비누, 물비누, 미용비누, 샴푸, 손세정제(핸드클리너), 약용비누{비의료용}, 크림비누, 페이셜 워시, 전신 세정제, 두피 세정제, 헤어린스, 화장비누, 치아미백용 겔, 치약 등의 형태로 제조될 수 있다. 이를 위해 본 발명의 조성물은 화장료 조성물의 제조에 통상적으로 사용하는 용매나, 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.Cosmetic composition in the present invention is a lotion, nutrient lotion, nutrient essence, massage cream, beauty bath additives, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream, Suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, hair loss agent {for cosmetics}, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, Bath soap, water soap, beauty soap, shampoo, hand cleaner (hand cleaner), medicinal soap {non-medical use}, cream soap, facial wash, whole body cleaner, scalp cleaner, hair rinse, cosmetic soap, tooth whitening gel, toothpaste, etc. It can be produced in the form. To this end, the composition of the present invention may further include a solvent or a suitable carrier, excipient or diluent, which is commonly used in the preparation of cosmetic compositions.

본 발명의 화장료 조성물 내에 더 추가될 수 있는 용매의 종류는 특별히 한정하지 않으나, 예를 들어, 물, 식염수, DMSO 또는 이들의 조합을 사용할 수 있고, 담체, 부형제 또는 희석제로는 정제수, 오일, 왁스, 지방산, 지방산 알콜, 지방산 에스테르, 계면활성제, 흡습제(humectant), 증점제, 항산화제, 점도 안정화제, 킬레이팅제, 완충제, 저급 알콜 등이 포함되지만, 이에 제한되는 것은 아니다. 또한, 필요에 따라 미백제, 보습제, 비타민, 자외선 차단제, 향수, 염료, 항생제, 항박테리아제, 항진균제를 포함할 수 있다. The type of the solvent that can be further added in the cosmetic composition of the present invention is not particularly limited, for example, water, saline, DMSO, or a combination thereof can be used, and as a carrier, excipient or diluent, purified water, oil, wax , Fatty acids, fatty acid alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, and the like. In addition, whitening agents, moisturizers, vitamins, sunscreens, perfumes, dyes, antibiotics, antibacterial agents, and antifungal agents may be included as necessary.

상기 오일로서는 수소화 식물성유, 피마자유, 면실유, 올리브유, 야자인유, 호호바유, 아보카도유가 이용될 수 있으며, 왁스로는 밀랍, 경랍, 카르나우바, 칸델릴라, 몬탄, 세레신, 액체 파라핀, 라놀린이 이용될 수 있다.Hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, avocado oil may be used as the oil, and waxes include beeswax, mellow, carnauba, candelilla, montan, ceresin, liquid paraffin, and lanolin. Can be used.

지방산으로는 스테아르산, 리놀레산, 리놀렌산, 올레산이 이용될 수 있고, 지방산 알콜로는 세틸 알콜, 옥틸 도데칸올, 올레일 알콜, 판텐올, 라놀린 알콜, 스테아릴 알콜, 헥사데칸올이 이용될 수 있으며 지방산 에스테르로는 이소프로필 미리스테이트, 이소프로필 팔미테이트, 부틸 스테아레이트가 이용될 수 있다. 계면 활성제로는 당업계에 알려진 양이온 계면활성제, 음이온 계면활성제 및 비이온성 계면활성제가 사용가능하며 가능한 한 천연물 유래의 계면활성제가 바람직하다.As the fatty acid, stearic acid, linoleic acid, linolenic acid, and oleic acid may be used, and as the fatty acid alcohol, cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, and hexadecanol may be used. As the fatty acid ester, isopropyl myristate, isopropyl palmitate, and butyl stearate can be used. As the surfactant, cationic surfactants, anionic surfactants, and nonionic surfactants known in the art can be used, and surfactants derived from natural products are preferred if possible.

그 외에도 화장품 분야에서 널리 알려진 흡습제, 증점제, 항산화제 등을 포함할 수 있으며, 이들의 종류와 양은 당업계에 공지된 바에 따른다. In addition, it may include a hygroscopic agent, a thickener, an antioxidant, etc., which are widely known in the cosmetic field, and their types and amounts are as known in the art.

본 발명의 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 본 발명의 식품 조성물은 독성 및 부작용이 거의 없는 식물추출물로 구성된 것이므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다.The food composition of the present invention may be prepared in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, cookies, rice cakes, breads, and the like. Since the food composition of the present invention is composed of plant extracts having little toxicity and side effects, it can be safely used even for a long period of time for prevention purposes.

본 발명의 박테리오파지가 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있다.When the bacteriophage of the present invention is included in the food composition, the amount may be added at a rate of 0.1 to 50% of the total weight.

여기서, 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등을 들 수 있다.Here, when the food composition is prepared in the form of a beverage, there are no particular limitations other than containing the food composition in an indicated ratio, and it may contain various flavoring agents or natural carbohydrates, etc., as additional components, like a conventional beverage. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose, and common sugars such as polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol. can do. Examples of the flavoring agent include natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).

그 외 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.Other food compositions of the present invention include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, and protective colloidal thickeners , pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonic acid used in carbonated beverages, and the like.

이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택되는 것이 일반적이다.These ingredients can be used independently or in combination. The proportion of these additives is not so critical, but is generally selected from 0.1 to about 50 parts by weight per 100 parts by weight of the composition of the present invention.

본 발명에서 제공하는 신규한 박테리오파지 YMC17/01/P6_KPN_BP는 기존의 항생제 등의 화학 물질에 비해 클렙시엘라 속 세균, 특히는 항생제에 대하여 내성을 갖는 클렙시엘라 속 세균에 대하여 특이적 사멸능을 가진다. The novel bacteriophage YMC17/01/P6_KPN_BP provided by the present invention has a specific killing ability against bacteria of the genus Klebsiella, in particular resistant to antibiotics, compared to chemicals such as conventional antibiotics .

또한, 본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 사람, 동물 및 식물 등 세균외의 다른 숙주는 감염시키지 않으므로, 항생제의 오남용으로 인한 항생제 내성균의 문제점, 식품 내의 항생제의 잔류 문제, 광범위한 숙주 범위의 문제점을 해결할 수 있는 장점이 있다. In addition, the bacteriophage YMC17/01/P6_KPN_BP of the present invention does not infect other hosts other than bacteria, such as humans, animals, and plants, so that problems of antibiotic-resistant bacteria due to misuse of antibiotics, residual problems of antibiotics in foods, and problems with a wide range of hosts are addressed. There is an advantage that can be solved.

따라서, 본 발명의 박테리오파지 YMC17/01/P6_KPN_BP는 클렙시엘라 속 세균에 의해 유발되는 감염성 질환의 예방 또는 치료, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제, 또는 세척제 분야에서 다양하게 사용될 수 있다.Therefore, the bacteriophage YMC17/01/P6_KPN_BP of the present invention can be variously used in the field of prevention or treatment of infectious diseases caused by bacteria of the genus Klebsiella, antibiotic composition, composition for adding feed, feed, disinfectant, or detergent. .

도 1은 본 발명의 일 실시예에 따른 박테리오파지의 전자 현미경 촬영 사진을 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 박테리오파지의 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 흡착능을 그래프로 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 용균성 박테리오파지의 1단 증식 곡선을 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 생체 외에서 박테리오파지의 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 용균능을 그래프로 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 용균성 박테리오파지의 pH 안정성을 그래프로 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 용균성 박테리오파지의 온도 안정성을 그래프로 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라 속 세균에 대한 용균성 박테리오파지의 전체 유전체 서열 분석 결과를 나타낸 것이다.1 shows an electron microscope photograph of a bacteriophage according to an embodiment of the present invention.
Figure 2 is a graph showing the adsorption capacity of bacteria of the genus Klebsiella having antibiotic resistance of bacteriophage according to an embodiment of the present invention.
Figure 3 shows a single-stage proliferation curve of the lytic bacteriophage against bacteria of the genus Klebsiella having antibiotic resistance according to an embodiment of the present invention.
4 is a graph showing the solubility of bacteria in the genus Klebsiella having antibiotic resistance of bacteriophage in vitro according to an embodiment of the present invention.
5 is a graph showing pH stability of lytic bacteriophage against Klebsiella genus bacteria having antibiotic resistance according to an embodiment of the present invention.
6 is a graph showing temperature stability of lytic bacteriophage against Klebsiella genus bacteria having antibiotic resistance according to an embodiment of the present invention.
Figure 7 shows the results of the entire genome sequence analysis of lytic bacteriophage against Klebsiella genus bacteria with antibiotic resistance according to an embodiment of the present invention.

이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

실시예Example

[실시예 1] 임상검체 분리 및 항생제 내성 균주 선별[Example 1] Separation of clinical samples and selection of antibiotic resistant strains

하기 표 1과 같이 세브란스 병원 환자들 또는 그 분변 등으로부터 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 세균을 배양하여 분리하였다. 균주 동정은 키트/ ATB 32 GN 시스템 (bioM

Figure 112018127300657-pat00001
erieux, Marcy l'Etoile, France)을 이용하여 수행하였다. 그 뒤, 항생제 감수성 시험은 뮬러-힌튼(Mueller-Hinton) 아가를 사용하여 외기 37 ℃에서 하룻밤 동안 배양하는 CLSI 디스크 확산 시험 방법을 사용하였다. 클렙시엘라 뉴모니아 세균에 대한 시험 항생제는 아미카신(Amicacin), 엠피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 이미페넴(Imipenem), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록사신(Levofloxacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa), 및 티게ㅅ사이클린(Tigecyline)을 사용하였다. 감수성 결과는 Clinical and Laboratory Standards Institute (CLSI, 2016)를 기준으로 판독하였다. 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 47 개 균주의 항생제 내성 프로파일은 하기 표 2에 나타내었다. 단, 하기 표 2에서 S, I 및 R은 항균제에 대한 감수성을 평가한 결과로, 'S'는 민감(Susceptible), 'I'는 중간(Intermediate), 'R'은 내성(Resistant)를 의미한다.As shown in Table 1 below, Klebsiella pneumoniae bacteria were cultured and separated from patients at Severance Hospital or their feces. Strain identification kit / ATB 32 GN system (bioM
Figure 112018127300657-pat00001
erieux, Marcy l'Etoile, France). Subsequently, the antibiotic susceptibility test was performed using a CLSI disc diffusion test method incubated overnight at 37°C using a Mueller-Hinton agar. Test antibiotics against Klebsiella pneumoniae bacteria include Amicacin, Ampicillin, Ampicillin/Sulbactam, Aztreonam, Ceztazidime, Cefazolin, Imipenem, Ertapenem, Cefepime, Cefoxitin, Cefotaxime, Gentamicine, Levofloxacin, Meropenem (Meropenem), Piperacillin/Tazobactam, Cortrimoxa, and Tigecyline were used. Susceptibility results were read based on Clinical and Laboratory Standards Institute (CLSI, 2016). The antibiotic resistance profile of 47 strains of Klebsiella pneumoniae collected is shown in Table 2 below. However, in Table 2 below, S, I and R are the results of evaluating susceptibility to antibacterial agents,'S' is susceptible,'I' is intermediate, and'R' is resistance. do.

숙주 균주Host strain 시료 유래Sample origin 숙주 균주Host strain 시료 유래Sample origin YMC16/12/N708YMC16/12/N708 분변Feces YMC17/05/N331YMC17/05/N331 분변Feces YMC16/12/N681YMC16/12/N681 분변Feces YMC17/05/N355YMC17/05/N355 분변Feces YMC17/01/N115YMC17/01/N115 분변Feces YMC17/05/R3201YMC17/05/R3201 가래 (pneumonia)Phlegm (pneumonia) YMC17/01/P6YMC17/01/P6 스왑 또는 배액관
골반Swap or drain pipe
pelvis YMC17/05/N405YMC17/05/N405 분변Feces YMC17/01/N167YMC17/01/N167 분변Feces YMC17/05/N500YMC17/05/N500 분변Feces YMC17/01/N132YMC17/01/N132 분변Feces YMC17/05/N424YMC17/05/N424 분변Feces YMC17/01/N270YMC17/01/N270 분변Feces YMC17/05/N421YMC17/05/N421 분변Feces YMC17/01/N189YMC17/01/N189 분변Feces YMC17/06/U687YMC17/06/U687 임의의 소변Random urine YMC17/02/N103YMC17/02/N103 분변Feces YMC17/06/N182YMC17/06/N182 분변Feces YMC17/02/N97YMC17/02/N97 분변Feces YMC17/06/N196YMC17/06/N196 분변Feces YMC17/02/N84YMC17/02/N84 분변Feces YMC17/06/N263YMC17/06/N263 분변Feces YMC17/02/N151YMC17/02/N151 분변Feces YMC17/06/N297YMC17/06/N297 분변Feces YMC17/02/N183YMC17/02/N183 분변Feces YMC17/06/R4267YMC17/06/R4267 가래 (pneumonia)Phlegm (pneumonia) YMC17/02/N180YMC17/02/N180 분변Feces YMC17/06/N445YMC17/06/N445 분변Feces YMC17/02/N189YMC17/02/N189 분변Feces YMC17/07/N293YMC17/07/N293 분변Feces YMC17/02/N232YMC17/02/N232 분변Feces YMC17/07/N393YMC17/07/N393 분변Feces YMC17/02/N227YMC17/02/N227 분변Feces YMC17/07/R3882YMC17/07/R3882 가래 (pneumonia)Phlegm (pneumonia) YMC17/02/N245YMC17/02/N245 분변Feces YMC17/08/N34YMC17/08/N34 분변Feces YMC17/02/N254YMC17/02/N254 분변Feces YMC17/07/U6299YMC17/07/U6299 임의의 소변Random urine YMC17/02/R2881YMC17/02/R2881 기관 흡입 (pneumonia)Trachea inhalation (pneumonia) YMC17/08/N153YMC17/08/N153 분변Feces YMC17/02/N312YMC17/02/N312 분변Feces YMC17/08/N243YMC17/08/N243 분변Feces YMC17/05/N213YMC17/05/N213 분변Feces YMC17/08/N456YMC17/08/N456 분변Feces YMC17/05/R1069YMC17/05/R1069 가래 (pneumonia)Phlegm (pneumonia) YMC17/10/N291YMC17/10/N291 분변Feces YMC17/05/N300YMC17/05/N300 분변Feces

Figure 112018127300657-pat00002
Figure 112018127300657-pat00002

Figure 112018127300657-pat00003
Figure 112018127300657-pat00003

Figure 112018127300657-pat00004
Figure 112018127300657-pat00004

Figure 112018127300657-pat00005
Figure 112018127300657-pat00005

상기 표 2에서 보는 바와 같이, 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 47개 세균은 다양한 카바페넴계 항생제에 대하여 내성을 가지는 다재내성 균주임을 알 수 있었다.As shown in Table 2, the collected Klebsiella pneumoniae 47 bacteria were found to be multi-resistant strains resistant to various carbapenem-based antibiotics.

[실시예 2] 박테리오파지 검체 수집[Example 2] Collecting bacteriophage samples

2-1. 파지 은행 구축을 위한 검체 수집2-1. Sample collection for phage banking

세브란스 병원의 하수 처리시설에서 최초 침전지 거친 후 부유물질 및 침사물이 제거된 원수를 확보하였다. 이는 화학 처리 시설 전 단계의 하수로 제한하였다. 수집한 시료에 1 L 당 염화나트륨 58 g을 첨가한 후 10,000 g에서 10 분간 원심 분리하여 220 nm 밀리포어 필터로 여과하였다. 얻어진 여과액에 폴리에틸렌글리콜(PEG, 분자량 8000)을 10% W/V으로 첨가하고 4 ℃에서 12 시간 동안 냉장 보관하였다. 12 시간 냉장 보관된 여과액을 12,000 g에서 20 분간 원심 분리하여 침전물을 파지 희석 완충액 (SM 완충액)에 재부유한 뒤, 동일한 양의 클로로포름을 첨가하여 냉동 보관하였다. 이를 3 회 반복하여 300 mL의 박테리오파지 부유액을 채취하였다.The raw water from which suspended solids and sediments were removed was secured after the first sedimentation at a sewage treatment facility at Severance Hospital. This was limited to sewage at all stages of the chemical treatment facility. 58 g of sodium chloride per 1 L was added to the collected sample, and then centrifuged at 10,000 g for 10 minutes and filtered through a 220 nm millipore filter. To the obtained filtrate, polyethylene glycol (PEG, molecular weight 8000) was added at 10% W/V and stored refrigerated at 4° C. for 12 hours. The filtrate stored for 12 hours was centrifuged at 12,000 g for 20 minutes to resuspend the precipitate in phage dilution buffer (SM buffer), and then stored frozen by adding the same amount of chloroform. This was repeated 3 times to collect 300 mL of bacteriophage suspension.

2-2 용균성 파지 선별 및 용균역가 측정2-2 Soluble phage screening and lysis titer measurement

용균성 파지의 분리 정제는 스팟 테스트(Spot Test)법 (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009)으로 실행하였다. 확보된 균주를 맥콘키 한천배지에서 접종 후 외기 35 ℃에서 하룻밤 동안 배양하였다. 배양 후, 투명한 플라크 형성을 보고 파지에 감수성인 균주를 선별하였다. 감수성인 균주를 맥콘키 한천 배지에 접종하여 35 ℃에서 12 시간 동안 배양하였다. 살린 1ml 튜브에 McFarland 0.5 탁도로 각 균주의 현탁액 제조하고 H 탑 아가 (3 ml), 감수성 박테리아 100 ㎕ 및 파지 용액 (각각 1 ㎕, 10 ㎕ 및 50 ㎕)을 섞어 LB 아가에 도포한 후, 35 ℃에서 12 시간 동안 배양하였다. 플라크 관찰한 후에 파스퇴르 파이펫으로 플라크를 채취하여 SM 완충 용액에 희석하고, 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지 YMC17/01/P6_KPN_BP는 SM 완충 용액에 희석하고 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지 YMC17/01/P6_KPN_BP는 SM 완충 용액에 희석하여 보관하였다.Separation and purification of lytic phage was performed by the Spot Test method (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009). The inoculated strains were inoculated on a McConkie agar medium and cultured overnight at 35° C. outside. After cultivation, strains susceptible to phage were selected by seeing transparent plaque formation. The susceptible strains were inoculated in McConkie agar medium and cultured at 35°C for 12 hours. Prepare a suspension of each strain with McFarland 0.5 turbidity in a 1 ml tube, and mix with H top agar (3 ml), 100 µl of susceptible bacteria and phage solution (1 µl, 10 µl and 50 µl, respectively) and apply to LB agar, 35 Incubation was carried out for 12 hours at ℃. After observing the plaque, the plaque was collected with a Pasteur pipette, diluted in SM buffer solution, and purified again 3 times using a susceptible strain suspension. The thus obtained pure bacteriophage YMC17/01/P6_KPN_BP was diluted in SM buffer solution and purified again 3 times using a susceptible strain suspension. The thus obtained pure bacteriophage YMC17/01/P6_KPN_BP was stored diluted in SM buffer solution.

실시예 1에서 확인한 항생제 내성 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 47개 균주 각각을 맥콘키 한천배지에서 접종하여 배양한 후, 상기 과정에 의해 정제된 박테리오파지 YMC17/01/P6_KPN_BP를 도말된 각각의 내성 균주에 5 ㎕로 접종하여 플라그 형성을 확인하고, 역가 범위를 확인하여, 용균성을 하기 표 3에 나타내었다. 단, 하기 표 3에서 + 및 -는 수집된 균주에 대한 플라크 활성을 평가한 것으로, '+'는 투명한 플라크(clear plaque)를 의미하고, '-'는 용균이 일어나지 않은 것을 의미한다.After inoculating and incubating each of the 47 strains of antibiotic-resistant Klebsiella pneumoniae identified in Example 1 in a McConkie agar medium, each of the bacteriophage purified by the above procedure was smeared YMC17/01/P6_KPN_BP Tolerant strains were inoculated with 5 μl to confirm plaque formation, and to confirm the titer range, solubility was shown in Table 3 below. However, in Table 3 below, + and-are evaluations of plaque activity for the collected strains,'+' means transparent plaque, and'-' means that no lysis occurred.

숙주 균주Host strain 용균 여부Lysis 숙주 균주Host strain 용균 여부Lysis YMC16/12/N708YMC16/12/N708 ++++ YMC17/05/N331YMC17/05/N331 ++ YMC16/12/N681YMC16/12/N681 ++++ YMC17/05/N355YMC17/05/N355 ++ YMC17/01/N115YMC17/01/N115 ++ YMC17/05/R3201YMC17/05/R3201 ++ YMC17/01/P6YMC17/01/P6 ++ YMC17/05/N405YMC17/05/N405 ++ YMC17/01/N167YMC17/01/N167 ++ YMC17/05/N500YMC17/05/N500 ++ YMC17/01/N132YMC17/01/N132 ++ YMC17/05/N424YMC17/05/N424 -- YMC17/01/N270YMC17/01/N270 ++ YMC17/05/N421YMC17/05/N421 -- YMC17/01/N189YMC17/01/N189 ++ YMC17/06/U687YMC17/06/U687 -- YMC17/02/N103YMC17/02/N103 ++++ YMC17/06/N182YMC17/06/N182 -- YMC17/02/N97YMC17/02/N97 ++++ YMC17/06/N196YMC17/06/N196 -- YMC17/02/N84YMC17/02/N84 ++++ YMC17/06/N263YMC17/06/N263 -- YMC17/02/N151YMC17/02/N151 ++++ YMC17/06/N297YMC17/06/N297 -- YMC17/02/N183YMC17/02/N183 ++++ YMC17/06/R4267YMC17/06/R4267 -- YMC17/02/N180YMC17/02/N180 ++++ YMC17/06/N445YMC17/06/N445 -- YMC17/02/N189YMC17/02/N189 ++++ YMC17/07/N293YMC17/07/N293 ++ YMC17/02/N232YMC17/02/N232 ++++ YMC17/07/N393YMC17/07/N393 ++ YMC17/02/N227YMC17/02/N227 ++++ YMC17/07/R3882YMC17/07/R3882 ++ YMC17/02/N245YMC17/02/N245 ++++ YMC17/08/N34YMC17/08/N34 -- YMC17/02/N254YMC17/02/N254 ++++ YMC17/07/U6299YMC17/07/U6299 ++ YMC17/02/R2881YMC17/02/R2881 ++++ YMC17/08/N153YMC17/08/N153 -- YMC17/02/N312YMC17/02/N312 ++++ YMC17/08/N243YMC17/08/N243 -- YMC17/05/N213YMC17/05/N213 ++ YMC17/08/N456YMC17/08/N456 ++ YMC17/05/R1069YMC17/05/R1069 ++ YMC17/10/N291YMC17/10/N291 ++ YMC17/05/N300YMC17/05/N300 ++

상기 표 3에서 보는 바와 같이, 본 발명에 따른 박테리오파지 YMC17/01/P6_KPN_BP는 항생제 내성 클렙시엘라 뉴모니아 47개 균주 중 35개 균주(74%)를 용균 시키는 것을 확인할 수 있었다.As shown in Table 3, it was confirmed that the bacteriophage YMC17/01/P6_KPN_BP according to the present invention lysed 35 strains (74%) of 47 strains of antibiotic resistant Klebsiella pneumoniae.

[실시예 3] 항생제 내성 클렙시엘라 뉴모니아균에 대한 용균성 박테리오파지의 전자 현미경 분석[Example 3] Electron microscopic analysis of lytic bacteriophage against antibiotic-resistant Klebsiella pneumoniae

상기 실시예 2의 방법에 의해 정제된 박테리오파지를 감수성 균주 배양 배지(20 ml LB 배지)에 접종 및 배양한 뒤 220 nm 밀리포어 필터로 여과하고, 상청액에 폴리에틸렌글리콜(MW 8,000)을 10 %(w/v)의 양으로 첨가한 후 밤새 냉장 보관하였다. 이후 12,000 g의 조건으로 20 분 동안 원심 분리한 뒤, 에너지 여과 투과 전자현미경(Energy-Filtering Transmission Electron Microscope)을 이용하여 박테리오파지의 형태를 분석하여, 그 결과를 도 1에 나타내었다.After inoculating and incubating the bacteriophage purified by the method of Example 2 in a susceptible strain culture medium (20 ml LB medium), filtering with a 220 nm millipore filter, and 10% (w 8,000) of polyethylene glycol (MW 8,000) in the supernatant. /v) and kept refrigerated overnight. After centrifugation for 20 minutes under the condition of 12,000 g, the shape of the bacteriophage was analyzed using an Energy-Filtering Transmission Electron Microscope, and the results are shown in FIG. 1.

도 1에서 보는 바와 같이, 본 발명에 따른 상기 YMC17/01/P6_KPN_BP 박테리오파지를 모양으로 분류하는 기준으로 보았을 때, 각이 진 머리와 꼬리를 갖는 시포비리대(Siphoviridae) 과에 속하는 것으로 분류하였다.As shown in FIG. 1, when viewed as a criterion for classifying YMC17/01/P6_KPN_BP bacteriophage according to the present invention, it was classified as belonging to the Siphoviridae family having an angled head and tail.

[실시예 4] 박페리오파지의 흡착능 및 1단 증식 곡선(One-step growth curve) 분석[Example 4] Analysis of bacteriophage adsorption capacity and one-step growth curve

항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.5가 되도록 배양한 뒤, 클렙시엘라 뉴모니아균에 상기 실시예 2에서 정제된 박테리오파지 YMC17/01/P6_KPN_BP를 MOI 0.001로 넣고 상온에서 배양한 뒤, 100 ㎕ 시료를 1, 2, 3, 4, 5 분에 1 ml씩 채취하여 LB 배지에 희석한 뒤 플라그 분석을 통해 상기 박테리오파지의 흡착능을 평가하여, 그 결과를 도 2에 나타내었다.After culturing the antibiotic-resistant Klebsiella pneumoniae to have an OD value of 0.5, the Klebsiella pneumoniae bacteriophage YMC17/01/P6_KPN_BP purified in Example 2 was put into MOI 0.001 and cultured at room temperature. Subsequently, 100 µl samples were collected at 1, 2, 3, 4, and 5 minutes for 1 ml, diluted in LB medium, and then the plaque analysis was performed to evaluate the adsorption capacity of the bacteriophage, and the results are shown in FIG. 2.

또한, 항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.3이 되도록 배양한 뒤, 4 ℃에서 5 분 동안 7,000 g로 원심 분리하여 세포를 침전시킨 후, 0.5 ml의 LB 배지에 희석시키고, 상기 실시예 2에서 정제된 박테리오파지를 MOI 0.001(titer 108 pfu/cells)를 넣고 37 ℃에서 5 분 동안 배양하였다. 배양된 혼합 시료를 13,000 g에서 1 분 동안 원심 분리하여 얻어진 펠렛을 10ml의 LB 배지에 희석시키고 37 ℃에서 배양하였다. 배양 도중 10 분 마다 시료를 채취하여 플라그 분석을 통해 상기 박테리오파지의 1단 증식 곡선을 평가하여, 그 결과를 도 3에 나타내었다.In addition, after culturing the antibiotic-resistant Klebsiella pneumoniae to have an OD value of 0.3, the cells were precipitated by centrifugation at 7,000 g for 5 minutes at 4° C., and then diluted in 0.5 ml of LB medium, The bacteriophage purified in Example 2 was added with MOI 0.001 (titer 10 8 pfu/cells) and incubated at 37° C. for 5 minutes. The pellet obtained by centrifuging the cultured mixed sample at 13,000 g for 1 minute was diluted in 10 ml of LB medium and incubated at 37°C. During the culture, samples were taken every 10 minutes to evaluate the 1-stage proliferation curve of the bacteriophage through plaque analysis, and the results are shown in FIG. 3.

도 2에서 보는 바와 같이, 상기 박테리오파지 YMC17/01/P6_KPN_BP의 접종 후 5분 이내에 박테리오파지의 99 % 정도가 클렙시엘라 뉴모니아균에 흡착하였다(10 분: 1.05 %).As shown in Figure 2, within about 5 minutes after inoculation of the bacteriophage YMC17/01/P6_KPN_BP, about 99% of the bacteriophage adsorbed to Klebsiella pneumoniae (10 min: 1.05%).

또한, 도 3에서 보는 바와 같이, 1단 증식 곡선 결과 43 PFU/감염 세포의 높은 버스트 사이즈를 나타내었다(0 분: 20 PFU/ml, 95 분: 872 PFU/ml).In addition, as shown in Figure 3, the results of the single-stage proliferation curve showed a high burst size of 43 PFU/infected cells (0 min: 20 PFU/ml, 95 min: 872 PFU/ml).

상기 결과를 통해 본 발명에 따른 상기 박테리오파지 YMC17/01/P6_KPN_BP는 항생제 내성을 갖는 클렙시엘라 뉴모니아균에 비교적 빠른 시간 내에 흡착할 수 있고, 43 PFU/감염 세포의 높은 버스트 사이즈를 나타내 항생제 내성 클렙시엘라 뉴모니아균에 용균 효과를 발휘하는 것을 알 수 있다.Through the above results, the bacteriophage YMC17/01/P6_KPN_BP according to the present invention can be adsorbed to Klebsiella pneumoniae bacteria having antibiotic resistance within a relatively short time, and exhibits a high burst size of 43 PFU/infected cells. It can be seen that it exerts a lytic effect on the Ciella pneumoniae.

[실시예 5] 생체 외 항생제 내성 클렙시엘라 속 세균에 대한 박테리오파지의 용균능 검증[Example 5] In vitro antibiotic-resistant Klebsiella genus bacteriophage validation of bacteria

항생제 내성 클렙시엘라 뉴모니아균 1 X 109 CFU/ml에 준비된 박테리오파지 YMC17/01/P6_KPN_BP를 1 X 108 CFU/ml(MOI: 0.1), 1 X 109 PFU/ml(MOI: 1), 1 X 1010 PFU/ml(MOI: 10)의 양으로 각각 처리하고 시간 별로 OD 값(파장 600 nm)을 측정하였다. 단, 음성 대조군으로는 PBS+SM 버퍼를 처리하여, 그 값을 도 4에 나타내었다.Bacteriophage YMC17/01/P6_KPN_BP prepared in antibiotic resistant Klebsiella pneumoniae 1 X 10 9 CFU/ml is 1 X 10 8 CFU/ml (MOI: 0.1), 1 X 10 9 PFU/ml (MOI: 1), Each was treated with an amount of 1 X 10 10 PFU/ml (MOI: 10) and OD values (wavelength 600 nm) were measured by time. However, PBS+SM buffer was treated as a negative control, and the values are shown in FIG. 4.

도 4에서 보는 바와 같이, 음성 대조군과 비교할 때, 클렙시엘라 뉴모니아균에 대하여 박테리오파지를 처리한 경우 OD 값이 감소하였고, MOI 값이 증가할수록 OD 값은 더욱 감소하였으며, 특히 MOI 10일 때 가장 용균능이 높았다.As shown in FIG. 4, when compared to the negative control group, when the bacteriophage was treated with Klebsiella pneumoniae, the OD value decreased, and as the MOI value increased, the OD value decreased further, especially when it was MOI 10 The solubility was high.

상기 결과를 통해, 본 발명에 따른 박테리오파지는 항생제 내성 클렙시엘라 뉴모니아균에 대하여 용균성을 갖는 것을 알 수 있다.Through the above results, it can be seen that the bacteriophage according to the present invention has solubility against antibiotic resistant Klebsiella pneumoniae.

[실시예 6] 항생제 내성 클렙시엘라 속 균에 대한 박테리오파지의 안정성 평가[Example 6] Evaluation of stability of bacteriophage against antibiotic-resistant Klebsiella genus

본 발명에 따른 박테리오파지 YMC17/01/P6_KPN_BP가 온도 및 알칼리에서 파괴되지 않고 안정성을 유지하는지 확인하였다.It was confirmed that the bacteriophage YMC17/01/P6_KPN_BP according to the present invention does not break at temperature and alkali and maintains stability.

상기 실시예 2의 방법에 의해 정제된 박테리오 파지 1 ㎕를 4, 5, 6, 7, 8, 9 및 10의 pH로 맞춘 SM 버퍼 40 ㎕에 넣은 뒤, 37 ℃에서 1 시간 동안 배양한 뒤 항생제 내성 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 5에 나타내었다.1 μl of the bacteriophage purified by the method of Example 2 was added to 40 μl of SM buffer adjusted to a pH of 4, 5, 6, 7, 8, 9 and 10, and then incubated for 1 hour at 37° C., followed by antibiotics A plaque analysis was performed by the method of Example 4 above with the resistant Klebsiella pneumoniae, and the results are shown in FIG. 5.

또한, 상기 박테리오파지 용액을 각각 4 ℃, 37 ℃, 60 ℃ 및 70 ℃에서 배양하는 1 시간 동안 10 분 단위로 각각의 샘플을 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 6에 나타내었다.In addition, plaque analysis by the method of Example 4 with each sample of Klebsiella pneumoniae in 10 minutes for 1 hour to incubate the bacteriophage solution at 4 ℃, 37 ℃, 60 ℃ and 70 ℃, respectively It was carried out and the results are shown in FIG. 6.

도 5에서 보는 바와 같이, 본 발명에 따른 상기 박테리오파지 YMC17/01/P6_KPN_BP는 pH 7에 해당하는 산성, 중성 및 알카리성 모두에서 안정성을 나타내었고, 30일 동안 상기 박테리오파지는 특히 중성/알카리성에서 비교적 안정성을 나타내었다.As shown in FIG. 5, the bacteriophage YMC17/01/P6_KPN_BP according to the present invention exhibited stability at both acidic, neutral and alkaline properties corresponding to pH 7, and for 30 days, the bacteriophage was relatively stable at particularly neutral/alkaline properties. Shown.

또한, 도 6에서 보는 바와 같이, 상기 박테리오파지 YMC17/01/P6_KPN_BP는 60℃의 고온에서 까지 매우 높은 안정성을 보였다. In addition, as shown in Figure 6, the bacteriophage YMC17/01/P6_KPN_BP showed very high stability up to a high temperature of 60 ℃.

[실시예 7] 항생제 내성 클렙시엘라 속 균에 대한 박테리오파지의 전체 게놈 서열 분석[Example 7] Total genome sequence analysis of bacteriophage against antibiotic-resistant Klebsiella genus

본 발명에 따른 상기 박테리오파지 YMC17/01/P6_KPN_BP의 특성을 규명하기 위하여 전체 유전자 서열 분석을 Illumina sequencer(Roche)를 통하여 통상의 기술자에게 자명한 전체 게놈 서열 분석 방법을 기초로 분석하여, 그 결과를 도 7 및 표 4에 나타내었다.In order to characterize the bacteriophage YMC17/01/P6_KPN_BP according to the present invention, the entire gene sequence analysis is analyzed based on the whole genome sequencing method apparent to a person skilled in the art through an Illumina sequencer (Roche), and the results are shown. 7 and Table 4.

Figure 112018127300657-pat00006
Figure 112018127300657-pat00006

Figure 112018127300657-pat00007
Figure 112018127300657-pat00007

Figure 112018127300657-pat00008
Figure 112018127300657-pat00008

Figure 112018127300657-pat00009
Figure 112018127300657-pat00009

Figure 112018127300657-pat00010
Figure 112018127300657-pat00010

도 7 및 상기 표 4에서 보는 바와 같이, 상기 박테리오파지 YMC17/01/P6_KPN_BP는 선형의 dsDNA(linear dsDNA)를 포함하며, 87개의 ORF로 구성되어 있었다. As shown in FIG. 7 and Table 4, the bacteriophage YMC17/01/P6_KPN_BP includes linear dsDNA (dsDNA), and consists of 87 ORFs.

본 발명에 따른 박테리오파지 YMC17/01/P6_KPN_BP의 서열을 기존의 박테리오파지의 서열과 대조한 결과, 본 발명에 따른 박테리오파지와 유사성을 갖는 박테리오파지는 검출되지 않았다. 상기 결과를 통해 본 발명에 따른 박테리오파지 YMC17/01/P6_KPN_BP는 기존에 발견되지 않은 신규한 박테리오파지에 해당함을 알 수 있다.As a result of comparing the sequence of the bacteriophage YMC17/01/P6_KPN_BP according to the present invention with the sequence of the existing bacteriophage, no bacteriophage having similarity to the bacteriophage according to the present invention was detected. Through the above results, it can be seen that the bacteriophage YMC17/01/P6_KPN_BP according to the present invention corresponds to a new bacteriophage not previously found.

이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.The present invention has been described in detail above, but the scope of the present invention is not limited thereto, and it is common in the art that various modifications and variations are possible without departing from the technical spirit of the present invention as set forth in the claims. It will be obvious to those who have the knowledge of

한국미생물보존센터(국내)Korea Microbial Conservation Center (domestic) KFCC11804PKFCC11804P 2018111520181115

<110> Industry-Academic Cooperation Foundation, Yonsei University <120> Novel bacteriophage specific for Klebsiella genus bacteria <130> PDPB187324 <160> 5 <170> KoPatentIn 3.0 <210> 1 <211> 54880 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP <400> 1 gtaaaccata caagcacatt tggtaagctg taactaaaat ccttatttat taataactta 60 ctactttata acatagataa catagataac atagataata taaaaaagta taaaccctat 120 aaagataggc tagttaaact ggtaagctgt aacaaggtaa actaggaggg atttaaaagt 180 tatagggaaa tagtatgtaa actatgattt tctatgtttt caacaactta aagtatgttg 240 tagacaccgg gtggtaattt gtgcaaaata acccaaaagt gtaagaggaa actagcttat 300 gaaaatttca gaccgtgcta aacgtgcaag tctggagtta actaccaacc aacttagatt 360 tgctaatctg tggctagatc gtgcgaataa cggcctcagt aatgctcagt gcgttttaga 420 ggcttaccca ggacataaag acttaaacgc cgcacaggtc actgcacacc gtctgttgtc 480 gaatacgaag gtgttaaact acctcgacgc gatgggtagt catgcgctgg aatctgttgg 540 tgaatcgttg tcatctcgtg tcgaatggtg gaagcgtgcg gcaagcaccg ctgaagaatt 600 actggagcca ttttgcaaac gcgttgtgat cccaggcgag gacgatgacg aatgcaaaca 660 cctgtgggtg aacagcactg acgatatccc gaaccacctg caacaatacg tggtgcgtta 720 caaacgttat ctattgggcg ggtacacgct ggagacgcgt gaactgttcg atcctaagac 780 gcgggcgaaa gcatcagaga acttggataa aatcaccggg aacagtgttg agcgtgtgga 840 attgtcagga acggtgggta atgtggttca gagtgttccc gaaggtgcca gcattgaaga 900 tatcgcgcag ttatatcaga aggcgctgaa gtagcaggtt agaccgcctc aaattcagcc 960 ggaaaccgtt tgcgttttga cgatcggcgg ttaggtagtg taaaggtaca ggttgatata 1020 agaaagcccc ttacggggcg tttacgataa aatttaaagc acctgtttta ccagtgcgtt 1080 caacnttaca ttttcaacga tgactggggc gattttctta aattcgttaa tcattttctt 1140 gtctccggta gttcgttttc tatgaactaa caatacactt ccctgtgtaa tccgtcaaga 1200 attattttaa atattcatcg tcaccaggaa cacagaacat ttcccagggc atcttttcag 1260 ttacttccag ttccagatcg ccgcgtgtgt tttcagcgat aatcttcacg ggtacaccgt 1320 cataggtttt catttgtttc tggcctccat catcgcatca gcataggcgt aagcaccttt 1380 tgcgtaatag gaaaacgctt catccggggt attaaatatc ggctgatttt cggatgaatg 1440 agcgatcaac ccctgtaaag cagcaattgc aaactggtca cgaacggtca gtgttttctg 1500 gttaatttct tccagagttt ccgctgactg aaagtgggaa agacagtttt gaccttcaat 1560 agatttataa ccctgagagt gtttatgttc ggcatcacta cgtttcatcg ttgagcctcc 1620 ccgcccagac cagttacaag ctgtttgatc agcgactgca gttcacctgt catcagtgta 1680 aaatcagcgt cgaaccgcgc taacacatct tcatgatcga tatcgtcgtt ctgttcaatc 1740 agttcgtcgc agaacttcag gcgcgttaaa atcgcatcat tagttagtgt gaacgtgatc 1800 cgctgttgcc agtccagcgc cagtttagta acaacttttc cggcttcgat gtgcgttgcg 1860 atttcatcgc ttaccagatc ctgtttctta actttcgcaa taccaccatc agccaggatc 1920 gctttcagtt ccgccgcatc accgatcgcg aagtaatcgc cagggacttt accgagcttg 1980 atccattcag tcatcgtcag ttcaacaggg ttttcaatcg tgagcgggat aaccgggagg 2040 ctacccagac ttttacgcag cagtgcaagc gcgtcctctg ctttacgagc gctggacgca 2100 tcgacaacaa tcaacccgtt cataacatcg atccacaact gcgtacggct gtctttggta 2160 aatgcccgtg gtaataacga atgcaacact tcgtctttca ggctgtcttt ctctgttttc 2220 ttcagcttac gaccctgttc actttccagt ttagcaatac gcgcattcag ttcctgttta 2280 ataaccggac cgggcaggat tttttcctga cgttgcacgg ttaacagata ctgagtgtgt 2340 gaccgatgcg ccagggtctg gctgaaagca gtcgccggaa cccatccagt gcgtgccata 2400 tcgttagaac cgcacggcgt aaactggaac ggcaacaact gttgttcgat ggttaccagt 2460 tgtgccatca gcgacatagg gttaccgatg cgatagataa ttgcattttt gaagaagttc 2520 ataattattc ctgttcgtta aaagtagcga caatacgcgg taaatggttt tgaatttcca 2580 gtgaccaaac accacgtact ttggttaatt tccacgttac accgtctttt tcgtcatccg 2640 ggatagatac accatcatct ttataaacgg cattgtacgt tttacccacc gtaaaccacg 2700 gacaagattt atccacggtt aaacaggtga atccggttgg aaagcgtttc atggtgtcga 2760 taatcctctt agtttgtaat tcaaccgcac acagaacatt tcccaagaac ggtcgttaaa 2820 tttaaaacat gggtcaaatg aaccataagc ccagaaattg acatactgac cgcatgtttc 2880 acagtgcgta tcaatttcag cagcattatt cgcgactgtg tcggtaatgg tgtctttaaa 2940 ccgtgcacca ccacaatcag gacagcgaac acattcacca tctttgctgt aattgctgcg 3000 gatcgaccac aactttttca ccttcaatat cctctttaat aaccggtaca attctgcagc 3060 ggcagttgat cattcgttca cgaccgttat catcaaccgc tgccgggatg taagttacgc 3120 ctggttcaag ttcaatcgtg ggcgaccagt cgaaacggtt catttattat cccatttcac 3180 atgagcaatg attaaaccca atgcaaacat tccgcaatgt cccacaatca atgaccatac 3240 gggaacatca atttttgcac aggtcattga aatcggaagc gctaatataa aaaccgacaa 3300 tacgatcgtt aaacttttca ttttcggttc cttcttttcc gtgcatcgcg ccgggactgt 3360 gcaacaccag ttttacggcg cggctgtttg gtcggtaact gttgggttat ttgtggttgt 3420 gctgcccagt tttcatgatt actagcaact gaaccaacaa tactgagaaa gtggtataac 3480 cacggtgtat gtctcatacg ttcagcaccg caaaatcagg cgacaggctg cggtgatcgt 3540 gctgcccgga ccaggtgaaa gaaaaggtgt aatcgcactg ttcaccattg aacaggaagg 3600 ggatttgaaa ccccgtatcg tcggtaatgc gaacttttac ggggtattca gcttgtgggt 3660 cgatggcgac aatctggccg aaaggttttg ttttccgacg tgcgagaacg tcgattagtt 3720 gtggattggt gatttccaca tgttgaccaa catgatagat agacattttg ttgactccgg 3780 gttgtgtgta caaccagaag tctatcgggt aattcgtaat ccgtcaagaa ttattttaaa 3840 ccgtcctgta ctgtctatcg cgtaacagat accgttactg taaacggtgg tggtctgagt 3900 aatcctttga taatcggtgc attggctgcg aacacgtaaa tcatacgcag actgtatgac 3960 gaaccaggca accattattg ctaaaagttt taacacaaat ctgaacattt ccgcaccctc 4020 cagtgtttcc cccagagtag tgcggatttc tggggtggct atggggttaa tctgatttaa 4080 cagtgatacc agcagttttg aggactctgg tgcaatcctg aacaccctga cggtaacagt 4140 cagcacggct tgcatctttc ggtattacga tgaatgaagt atccggcaac tcaaccatta 4200 actgttcccg actggctttc cagccttccc acattacagc catcgtcaag aaccagaggt 4260 ttccgcattc actctttttg ttgtcgaaaa accaatcaat aaattctttc gacatgccgt 4320 ttcgttcagc caattcgtaa cgatcatctt tcatagtttg tgcaccttaa aattacagcc 4380 ggaatagcga tgtttaccgc acagtttaca gcggtgttct tcagtcgcgt agttgcgttc 4440 gtccccgtga atggttctga acagatacca ctgatgtttg caaaaaagac gcttaatgaa 4500 gttcatattt aatcatccac atgataaatt acatactttg catcattcga agtatcaacg 4560 gtcttaccgc agcgcgtatt tgaagtattg aatattcagg aaacaagcgt tccatttcag 4620 accatacttc atttgcatta tttttaacgc gacaaagacg gaccatcgcc atctgcattt 4680 cagcttcatc gtcttgtatt ttactcacta tcagtaaccc ctctttgact ggtattcaat 4740 tttgttcagc gtgttttgca cgatctgcca tgagcgcatc atgaacaacg acgcatactg 4800 tgataacaag acacaacgcg gctgaacact gtacgcggtg atcgtgtcca tatcatcagg 4860 tgtcaggagg aaacgccagg gtgagttatt catgttcaag ccgctccagc agttcgcgga 4920 tgttctgtag aacgtgttgc tttgtctgcg tcgttacaca aacaccatca gtacgcccga 4980 acgtattcag caccgtttga agtacctggt acatctgttc gttgtgtgta atagacgttt 5040 caacaaacca tgcagatcta accaaaacac catgaatcca gtgtaaatca gcatcacggt 5100 ctgctttctt cattttctca ctgctgatgg ctttactgat gtgacattta actaactcgt 5160 cgtgcagttc taatgcttct tttacggtaa aaccaccgtg cataattctt tcagtattca 5220 tcacaaaccc catattaatt taatgagcag ccagagagcg agtatcatta atgaaataaa 5280 agctggtccg tacatgattg cgaatgagtg tttcagtcgc cagacagacg gtatgtaaaa 5340 acaaataacg ccttgaaata aacaaacggc gaaaagtgtt cctaataatt tatccaatag 5400 ttcaaccatg ttactcaccc cgctgtactt tcaacctggt tagggaaatt taaaacttca 5460 tcgaagactg caccaatacg atctgcgctg ggaatgaaat caccacttcc attatcaaca 5520 gcatcacata tttcatgata acgggtcgca tcgaatagtg ttacctcaca atcaccaata 5580 gtggcaaatg caatacgatg tgatgggcat tgagctaata atttatttaa ttttttaacc 5640 catgcgcgtt cttctttagt aagtgttccc aataatttat ccaagagttc aaccatttta 5700 gtcgcctcgt tattagatgg tgacaaaata tctcttcaac ccgtcgcaac tagtctcaca 5760 atccccgcag gaaccactat caatcagata gtgcatcgtg tgtgatttcg tggagtgagt 5820 tacgctttat actcaccgta gcgcctgaca atcagcggta tcttcagccg gacattaccg 5880 ggttactaca tacttggtca ggtattttgt ctatgtgtaa gactatagcc gcacatctgc 5940 aatccgtcaa gaattatttt aaccaatacc agctacgata acccgtggta aactgtacag 6000 aactgttgga aacggaacct tacaatgatt aaattcactg gtaacattca caagtacccg 6060 cgctggcggg acgcttacgc agaggacgaa cggatctggc gcaagggtga acaacgacct 6120 gattaccgtc agtgttacct tgaccgtatc aacctgttaa accgtatgcg cacggatcgg 6180 gcgattgtcc cgatactgaa aaaatattat gaaactaacc cggtggcgtt catcctcgac 6240 tgggcgttta cttatgaccc gcgtaacgtt ggtacggaat acccgccgaa tatgccgttc 6300 tgcctatttg agcgccagat cgatatgatt cagttcgttt atgaagcgct cgaagataag 6360 gagaaagggt tatgggaaaa atcccgcgac tatggcgcaa cgtgggtagc ctgtggttta 6420 tccgtgtggg cctggcttta tcgtcctggt tcgtcggtag gttggggatc gcgtaaagaa 6480 acactggtcg ataaactggg ggatcctgac agcatatttg aaaaaatcag gcagattatc 6540 cgcgctttac cacctgaatt acgcccggtt ggataccgtg aaaaagatca cctgacgttc 6600 atgaaatgta ttaacccgga aaacggatcg acgataactg gtgaggcagg ggataatatt 6660 gggcgcggtg gtcgtaagtc gatttatttt ctggatgagg ctgcacacgt tgatcgccct 6720 gaactgatcg aagcatcgtt atcagctaac accaacgttc gtatcgatat cagttctgtt 6780 aatggtgtcg gtaacgtttt ttaccgtaat cgtaaagcag gtctggaatg ggaaccaggt 6840 aaaaagatcc cccgtggtaa attgcgtgtc atggttctgg actggcgcga tcacccggcg 6900 aaaaatgatg aatggtacga acgggaaaag aaatcatttg ctgaaaaagg tctgcaacat 6960 attttcgcac aggaagttga ccgcgattac gccgcagcag ttcagggcgt gctgattaaa 7020 gctgactggg tgcgtgctgc gtttgatgcg ttccgcgatg tggaatggcg taaagcaaat 7080 ggtctgctca ctccacacgg taaacgtgtt gccggacagg atgccgcaga tggcggtgaa 7140 gatgcgagcg ccctggcgat aatgcacggc gtatttataa cctacctgca gcttgaccac 7200 cgtagcgcgg aactggcagc acctggaatg ctgcttaacg cgaacgtgca acagtgcgat 7260 gaatactggt atgaatcgat cggtgtcggt acaggcgtaa aagtagcggc gcacaatatg 7320 aagtcaacgt tgcggttcac ggctaaaccc tgggtgccaa acgctaaagt tgtggatccg 7380 ttgggcgata tcatcgcagg tacgaagccg ggcgataagg atcgaaaatg taaccgggat 7440 tatttccgtg attataaggc ccagtcatca tgggcgctgc gtatgcgttt taaacgaatt 7500 tacgaatggt acagggaagg taaaccgcag gatcctgatg agattattct catagaccca 7560 gaaatggaaa acgcgcaacg tctggaggca gaattaagtc aaccaacgta ttcaagtaac 7620 ggtgcgggta aaatcgtaat tgataaagca ccaaacggta ctaaatcacc aaacctgttc 7680 gacgccgttg ttatcgcatc atcgccgaaa cgcgtaatgg ttgaggaaga aggatttacc 7740 ggaaatgtaa accctattgg aacaccagaa tacggaagta ttttctaatg aacaaccccg 7800 gtttactccg gggttttttc gttgcggtaa acatctgcgc aaccatattt gttatcagga 7860 tggtaaacct gttcaacttt caacgacgcc tgacattcgt cccaagtaag aacgttatca 7920 ttaacaggtt caatcatcga cccgttaaga atgatcacta agacgtatcc gatcagcatt 7980 tgcgcaatgt ctcccgccag tccagaccgt gaaggtttac agatccgaga aaaagatgac 8040 tggaactttg taaccagacg tcatttttca tttctggttc ccgcaggtaa gaaaacacac 8100 taccgtttcg atctgttgca ataaaaccgt gactttttgg aaccattaaa acagtaccaa 8160 aataattaac cgctttatgt tctgcgattg attcaaacgt cattttacag tccggcgctt 8220 cctcgtggat atcccacgat ttaccgcaat acgagcactg atattcgtca ttacagcgaa 8280 tagcgtttac atggttcatt attcaacctc tctgattttt tcacctatga tttgtttcaa 8340 acgggtcaga cgacggcact gattgataaa tgcaccattt gaccacggtt gactaaaacg 8400 accagttgac acaggattca taagaccggg aattattact gaagcgtctg ctaaaactcg 8460 ttcaccatcc attgatattt caacgttaag gccattatca gggttgaaca tttgacaacc 8520 agtttcaaca cctgtaccca tgtaatgagc catacacgtc ataccctgga cagtcagaag 8580 ttgtttgtac tgttcgtaag tcattctaca gtctccggta caaaccattg tgaagcgagg 8640 taagcgcacc cagcgatctt gtgctcgtgt ttcggttcga aactagccag aatcactttg 8700 atatgtttgt gggcgtcttt gaaatttaca ccttttactg caacagcgta attttccaga 8760 ccattgtaaa accatttgct aatccatctg ttccacgggt tagagtcttt gaaaaactct 8820 tctgggatac tacccattgc cgggagaaat ttagcaaggt ttttaggacc aaaaacgata 8880 ttaccagagg tgatgttttc aatcggtttc atcttttact actcctgttc agttcatgca 8940 caaactataa ccgcacatct gcaatccgtc aagaattatt ttaaccccgt gcaaaactaa 9000 cctgtctgat ataacatacg ttaagaataa acccgtggag cctgtgaaga tggcagatga 9060 ccaatttgaa caactagccg ttgccggata cagtcgcaca ggcaaccagg ttaacgatga 9120 ctttttacct aaactcaacg gtaaacaggg tcgtcgtatc cttcgccaga tggcggagaa 9180 cgatgaaacg attggtggtg tattgttcgc catgaacagc gtttaccgtt ccgtacagtg 9240 gatttttgac ccatcagaca agaacgatcc gcaagctgtt aaatacgctg aatggctgca 9300 aaacaccatt gaaaaccaga tgggcgatcc gcagggtgcg ttacctgatg acacctggtc 9360 agcattcgtt cagacctgga ccgacaccga tgttttcggc tggggttggt atgacgtatg 9420 ggttaaagat ttaccagatg gttccgtggg tatcgcccgt ctggttccgg ttgctgctga 9480 aacgctcgac ggctgggaaa ttgaagaacc gacaggttat gtcactggta tttaccagcg 9540 tcaaccgtca accaatatca gtaaactgat cccccggtca agatcgctac acctgatttc 9600 atcaccgaac aaaggtaacc cggaaggttt atcactgctg cgcaccgcct atcgtccgtg 9660 gtattacaaa aaagtacagc ttgagatcga agcaattctg gcagagcgcg gaacaggttt 9720 cccggtcatc acagttaata gcgatattaa aaatgctgcg aacgatctga ccatcccgga 9780 agaaaaacgt aaagcagcac aggcgatgat tgataacttt gaaactatcg ttgccaatat 9840 taagcgcaat gaacagtctg gtctggttat ttactcaaaa ccctatgtca acggctttga 9900 cagtgagaca ggcgttacca catatggtgg tgagcaacag gttaaactgg aattcctgac 9960 ccctgaacag tctaatgccg tggatatcga ccggacaatc aaacgtctgg ataccagtat 10020 tgctcgtgca ttgctggctg acttcatgtt ttttggtaca ggtgggaata caggcaacca 10080 ggcaaatctg ggaagccgta cagaactgtg gatccgtgca atgcagtctc gcattgacag 10140 caacgttgaa tgtattaacc gccagttaat cccgcaactg tggacgttaa acgcgttccc 10200 ttcagaatac aaaccaacgt tacgtgctgg ctcaatcagt aaagacagta tcgaaacatt 10260 gaccactgcg cttacgcgtc tggcacaggc tggtgcgcca gtgttcccgg accctgtact 10320 tcaggagttc gtgtataaag aagctgggtt gccgacagcg ggtattgata aaacaggcga 10380 aggtttaccg tctattgaag attaaataaa aaggggtcta tagcagaccc caaattacca 10440 acgaccagaa cagaattaac atgattgcta tcagtaaata aactttctgg ttgtatgtca 10500 tatctacccc acgtagtttg caacgatttg atcgcagtca tccgtgttgc gggccagtcg 10560 ataaatttca gaagcaacct gtgaacgata atacatatcg acgttataat tatcattcac 10620 gtaattataa gccgcttcat aactaccgaa cattttgtga ttgctcacaa cttctttttt 10680 caccgaacca ttcattaacc agccgatcaa caacagcaac gcaccgatac cgggactggt 10740 taaaacagca atgaagaacc aggttccggg gttacgtccg gtacgtttag cgaaggcacc 10800 gaccagagcg ctaaacagga tccacaggat tacgaacatt tcaaacctcc ttaatcaggt 10860 attgatttaa cagtacacgt ccctgtgtaa tccgtcaaga attattttga aacgtcaaat 10920 acgggcggaa cacccatccc ggccattacg cgccgttgtt cgtacacctg acgcagtttc 10980 tgcaactgtt ctataccgat atcacaacca cggattatat cgtcgcaaag atcagtatag 11040 cttgcaccag cttgtggcgt ggttcgcgga tagtcaacca gcgacggatc cgtaatgatg 11100 acctttggga gaaacgccac cgtatcccca acgccatttt tcataatcgt cataagtcgc 11160 acccgtgata aagttcctga cctggttcaa ctttcgatcc gcaacactgg caaactaaac 11220 gccactcaaa accgggtgct gcttcaattt tacgataacc agcatcataa atacgcgcag 11280 catcttcaaa aaatgtacca cgaccgatca tacttgcaat ttcatggata gccgtttcac 11340 gttcgtcagg tagtggtttg aaatcatcgt cattaaccac aaacgattca gaaccatctt 11400 caggcttaac ccacacttcg ttaccgttga cgcccagtac gttaacagtg gtccattcgt 11460 tgccgttgtt ccactggcag acgataccaa caggtggtaa acctctaccg tcccatactt 11520 gtttcataag ttttccccaa taattgcagc acagttaacg atcgctaaac gggttgcttt 11580 ttcacgatct tctccgtgtg gagtaagttg tttatagcga acaccagtat ctggattgtt 11640 cactaaaact gcatagtctc taacatctaa gtctaaatac agatgtacca ttaaactgaa 11700 agcatcaccg ttatcaataa gcgggttcca caaacgacca ccgccgatat cgatcccttc 11760 gtttacgtca cgttcaccat acgcgatgta atacttaccc gcgatttcac cagcacgggc 11820 cgcattgatc agcaattcac gattagtcat catttacgcc ccgttgatcc aaaaccgcct 11880 ttacgttgac tttccacgcc gggtaactgt tccacttcaa ccacagttac aggttcaacg 11940 cgttctacca tcagttgaca gcagcgttcg ccatgttcca gcaagaacac cttgtgggaa 12000 tggttaacca gggtaatgaa gtattcgcca ggataatcgc ggtcaccgac acccacgcag 12060 ttaatcagcg tcataccgtt tttcaggctg aggccagaac gagggtaaaa tttgatacag 12120 tgatcagcat cgacagacat tttcaggcca gtggggatca gtgcgcgttc gcctgggtaa 12180 ataccaataa taccctcaat gggttttcgt tccagtttag cgcctgcagg cgggtagatt 12240 gttacggttt cagaccacag gcacgcgcga acatccatcc cggcgctatc agccgtttcc 12300 cgcgttggga tcacagccag gttagtgagt cgttgaatgt aaagattaga cattgcttgg 12360 ttcctcgttg tgtttcgaca cttgcaatac tgcgttctgt agtgtaatct gtcaagaatt 12420 atttataacc aacgaggaac gaacgatgaa tcttttcgac tggagtaaag cgcctgactg 12480 ggcaacctgt gttgttatac gatcaactaa taaatttagc actgactatc attggtcaga 12540 aaaaccaatg gatggtgctc gcatgatgag aattgaaaca ggtactagtt ttttaatgtc 12600 taaagtctta tggtggacag taattgaaca tcgtcctaca cgggtcaatg atataccaga 12660 gggtgacata ataaccactg tgtataaacc aatgtcacct gtagacctac atctgtcaca 12720 ttcatttacc ccagtagaac aaccatcaac tgcaccagaa ctgttgaatc aggccgcaca 12780 acttctgacc gaacgtggta aacagtacga caaatcaggt gaagaacgtt cagcggctgc 12840 aatcgtcgcg gcgtttaatg cgatcactaa acgcgattta acaccaggtg aaggctggtt 12900 attcatggtg ctattaaaag cagttcgttt ctattcaaat actgaaacgc cacaccgtga 12960 cagtctggaa gatatgatcg cctatgttgc gttgcacgct gaggaatatc tgaatgataa 13020 gtgagttgca ggcgtttcac cttatggtaa aacacagcat gattatcatt cactgtgacc 13080 gtgataaatc ggtattcact gatgacttac aatatacgga acagtgggtt aatgatttcg 13140 ataaacctaa agccacatgc cgtttaattg aacgtgtggc gcgtgacctg ggggaacagt 13200 tatgaagggt tttccaggtg tatattatag taccactggt ttttcagcag gcgttcatgt 13260 aaatcaaaag aaatgtcatt taggggtttt taaaactcca gagcgtgcaa gtgtatcagt 13320 gcgactgttt aaatactggt taagaaaagg ttttaaacct gatgaaatcc cacggtcatg 13380 tgtaacacca atgaatcgtg aaccggatta taaaccagtt gaaaattata aaatttcaac 13440 gatcattaaa aacaatggtg aatataaatt agacaccata gatctattaa atctcgcaag 13500 agaattacag tcactaaggg tttataaata tggtcggaca aaagcgctca gattctgaat 13560 tacttcgcga tctggaactt gattatgaac gtgcattagc agcagtagaa cacctggaag 13620 aacagatcag ggaagtgaag aaccgtttac aaggggtgac taaacgtgaa tttcagtcat 13680 aatttagaac gttctgcaga atatagcggt tatcctgcag atcatccgaa agtgatcggt 13740 gtacatgagt ttatcgatat agttgtaaca ttgcagttgt gtattgcgat gaataaagat 13800 aaaccaaata cggcgttaaa acgttgtgca caggtactga aacaacgaat gacaatgcca 13860 aacacaatca aaatgcttga cgttgttctt tcacaaccat tcccatcagg ctatgttgcc 13920 aaactccagc gcctgctgat cgcaaccgat cgtgaagttg gtcaacgcat gataaacctg 13980 tgatacaata agcctcagta accacgctga ggcttttcta tgaaagaccc atacccggac 14040 attgctgata aatatgacct gcggatccgt gaagcactga acctcgtgtg ggaaaacgtg 14100 cgccgtagtg agtcattagc taaccttgag tacattattg aaactcaggg tgttagcggg 14160 ttactcccca ttcttgatac tcttcccgat gagttgagcg cacagttacg gcccgttatc 14220 gaaaatgcga tagctgaatc aggtcgtgtg gtcgttcagg ttttgccgaa agcagcggtt 14280 acagcacccg tggttttcag cctggttaat ccccgtgttg gtgcatacat caataactac 14340 gttggacaga tgatccgcga agtaagcgat gaaacggtaa aagcggttca gattgctgtc 14400 aatcagggtg ttatcaccgg gcgtaacccg cgccagattg cccgtgattt tcgttccagt 14460 atcgggttaa ccagtcgcca ggaacaaact gttcaacggt tacgtgctgc gcttgaaaaa 14520 ggtgaagcag gctatgtgaa cagtttaacc acagttactg acagcgcaaa aaacgctgta 14580 agcgccggga aactgtctga aagccagatt gataagattg ttgaacaaac ccgcttacgc 14640 tacgtaaaac aacgcacaga gacaattgca cgtactgagt cattacgtgc aacatctgtt 14700 ggtcaggatc tggcaattcg tgaagggcag atcaccgggg ctatcagcaa cgaactgtta 14760 aagcgctggt tatatcgtca cgatacacgc actcgtgatg cacatattag cgccggggaa 14820 actaacgggt ggattccaat gaacagaccg ttttcaacac cgttagggcc gcttatgttc 14880 cctcgtgacc ctaacggaag cgcatcgaat acgattaact gcaggtgccg ggtacagtac 14940 agtttgccgg aagatatcgg ttcactgggt tgaacaggta cagcgcccga acatagccag 15000 actgattgga gacggatcag caggacttga gacagaatcc gtgtggtaaa cagtcccgcg 15060 ataaatcacg ctgaaaccat tctctttaat cagcatgagt tttcctgttc gtgcagtcat 15120 tcgaatactg ttacctgttc gtttctcgat cacaaaatca actttatcac cgactttcac 15180 aggtgttggt tcaccctgat agccgttaca tacgttacaa cgtttcatgg gcgcttacct 15240 ctgtaattac gaacggaaac ggcttttgtt tcatcaattt caatttcctg aatcttttta 15300 ccagcatgtt catcataatt atcacgaaag tcatcagcca gcgttgaaac cggattgctt 15360 ttccgaccac ctgctgcatg aagaacatca tttaccaagt cgggattttc cttaaaaatt 15420 acaccttctg tttgaccacg attccacacg attgtgtatt tgctcatttt taatttcctg 15480 aataagtttg aaagcatagt cagccatttt tcgatcgaac cacggcttct gtgtttttgc 15540 gtaacggtat gcattattgc cgtaaacaga gtgcgccccg taactgccaa actgacattt 15600 cggacactcc acccccgtgt taaatatcca ctcgcaagag gcgcatacgc gtagtttggc 15660 agtcatcagc gttactcctg cttttcacca cagaacgggc aataagacat tttcacgtta 15720 gtttctaatc gcgtgaagtt cttcgccagt tcgccgtttt tcttcggtgc acgatacgcc 15780 aggcgatatt tcagcatgac gtacatgttc ccggatgaca gccccagaca ctggttatcc 15840 cagcccactt tgtcaaatat gttggtactg acttctgcgc cctgcggcac tttttccatc 15900 agtcgttgtt gaagttcgtc accaagtttt ttcatgcatt cgcacattac cagccacctt 15960 tctttaaaag aatacgttta gtttcagggt gaggatgacg gtagttaacc agttgttccg 16020 gcatactcat aaatttattg tttttatctt tgaccgtgac aaaacaggaa tgaacaccaa 16080 acgcaccagt gttgattgtt tcgtcgtatt cgtggagaag ttcggccatt ttttcctgcc 16140 actcttttgg catctgcatc atagccacac ggggcataac aacaaacgcc gcataagata 16200 aaccgaacca cccgtgcagg tcttttcgat cgtcatattc catcgccttt accttttcag 16260 ttaagcaccc gttattgggt gtgataacta taccttcctg tctgcaatcc gtcaagaatt 16320 attttaaatc ttctttcatc ttaccaaact ggtaagccgt aactcagcgt catagatgac 16380 atagatagta tgaaagagtt atacagatct ggtaagccgt aacatagatt gcatagtttg 16440 cgcatactta tttttaacaa atttatcttc taacttactg tttttattat cttttacata 16500 tttatcatag atagtataga tttatataag aattataaaa gtaaggtaag taagggttag 16560 tagggtaaga tctaaaagat aaggaaaaca gcatgaaatg tatgatacta tgcacccgtg 16620 gttaactcgc gaggaaacac ccaatgatcg aagttaaagt taacaaggtc gatccacagt 16680 tacggatggt tttcggctgg ggttcgattt gtaaaaaacg gaatcaggaa acgggtcagt 16740 tagaaattta cactgacacc gataacgaac aattccctga agatgtaacg ttaaaagcat 16800 ggctggattt catgaacggc gatcagcgga tcatggataa catgcataac gagcaacccg 16860 tgggcaaagt ggtgttcgct tttccgatga ccgaagatat cgctgcaagt tttggactgg 16920 ttgaaaaact ggatcaaaca ggcgttattg ttggtacgct gatcaccgac gatgacattc 16980 tgaaaaaatt tcagtctggc gaatataccg ggtatagtat cggtggaact gcttactatg 17040 aggacgttga ataatgcgta ctgatggcac taaccattta cgccgggcgc ggtcaatgaa 17100 aattggcttt ctgtccggtg tgaccaaacc agcgcatgaa ggcgcaaacg cccttatgct 17160 taaatcccac ggtgaaacac ccggcgaagc cctgctgaag tctgcgttta gtgcggcgct 17220 tgctgaacag cagctggaac agcaggtgaa ccagtttctt tctaactcat gggtgcttaa 17280 tgaagcgctt cgcgagtcag cagaggatat tgcaaaagac gattcagtta ctgataaaca 17340 agcagcattg cgtgacgcag taaatgaata tattataaca atgcagcagg ccgctggtat 17400 ttcgcttaat aaagcgaatg gtggtaaaac agaaggtggt gaagtattcc cggcatccga 17460 ttacgcttat gtaccggact cggaaaaacc ttcaacctgg aaacttcgtt taacctccac 17520 gcccggcgga aaacctgatt cacgtattgt cggtgctgca ctggctgcat taggtccagg 17580 gtatcgcggt aataaggttg aaatccctga agctgattta gcaggtgtga aaagtaaggt 17640 tcgggccgcg tggaaagaat tgcacccgga tcaagaaatc ccccaggttt taaaaacggc 17700 agaggaaatt gaaatgtccg aactggaaaa atacaaagct ctggctgaga tgagcgatac 17760 ccacaaggcg tatcatgacg ctctgcctga aaccgatcag gaagcgttcc gtaaaatgga 17820 cgcaaccgcc cgtgacgctc tggtagttat ggcgaaacag gctgacgaat ctttcactac 17880 cgtagctggt caggaagtga aaaaatccgt agctggcgcg atgtatgacg ttctgaaaac 17940 tcaggacgaa cagatccgca aagcacaaac cgaagcggca ctggcgaaag ctaaagaagt 18000 agtgaatacc gactatgcgc atattccggg cgaagttgtt cagaaaaccg ctatggttat 18060 ggcgctggat aaactgccgg aagcagatcg caatttcctg gtagaaaaac tgaaacaggc 18120 cgataccctg tggaaagagc gtaaaacgcc tgccgcaccg aacggtggta aaggttctac 18180 tgcgtttgaa gatctgatca gcgaatacat gaagaataac ccaggcaaaa cccgtgcaca 18240 ggctatgcaa gctgttgcat cgaccaaaaa aggccaggaa gtgatcgaaa ccatgcgagg 18300 tgatgaataa tggctactaa cagcaaaatc tactggaact acgagcgccc gacccgtgct 18360 gttgccagcg tagcgatcgc tgctggtgtt ggtctggtgc ttgataccag tctgggcgac 18420 accaacgcgt gcgtaccgaa atataaactt cctgatgctg gcggtcgtat cgacggtgta 18480 gcactggacg atgtagcggc taatcagttc tttgatctgg ttaacgaaaa agaaaaattc 18540 gttccggtta aagcggctgc ggctttcggt gtcggtgttg aactcgcagt aactgccgct 18600 ggtaaattcc agactgcaac cacgggtcaa ctggtcgtgg caatttccca gacccaggcc 18660 accgctgcgg atcaggttgt tacggcttta gtccgtgcgc catacgctaa agcataatca 18720 ggagcaaatc agatgagcta taaacagaat ttccgcgacg ttggcgcccc ggatctattc 18780 ctgtccaact tttcagtagc ctactggcaa gatacctctc gctttgtcgg tactcgttat 18840 tttccagtag ttccggtaac tcaggctgca ggtaagtatc ttacctaccc gaaaggttat 18900 ttcggtcgcc cggtaaactc gaaacgtgct gaagatggtg ttgctaacac gatcggttat 18960 aaaaccaaaa accagggcta caccgtcgat gacgatgcga tccgtatttt tatctctgat 19020 aaaaaacgtg cgaacgtcgc aaacggtcaa caactggata tggaagcaac cggtgtcgtt 19080 accgacgcgc tgctgatcaa taaagagatc gatttcgtat ctaagttcct ggtgcctggc 19140 aagtgggcta ccgattatca gggtgttgat gcaacaccga ctggtaacca gttcctgaaa 19200 tggtctaacg ccaactctga tccgatcggt gatatcctgt cacatcgtgt ggcgttctct 19260 ctggctactg gcggtcgccg ctggaacaag gcgctgatga cgctggatgt gtacgatgcg 19320 ctgacccgta acccgtctgt aattgaccgc atcaacggcg cgtcaaccag ccagaatccg 19380 ggtattgtga cccaacaggc gcttgcagca ctgctggaag ttgacgaaat cgaaatcatg 19440 caatccgtgg ttaacatggc tgctgacggt ctggaagatg ccgaaggtaa cccgctgtcc 19500 gacttccagt ttgcggcaga aggtgtactg atgctgaact acgtcgaacc gaccgtaggt 19560 aacatgaaac cgatttcggc tgtaaccttt gcctggaatg agtttgcaag tctgggtatt 19620 gataatggcc cgtctatccg tacttatccg ggtgttgaag gtcgtcgcgg taactttgtt 19680 gaagcagagt ttgcgatcga tactgaaatg gttgcaccgg atatgggtat tctgttctac 19740 gacgctgttt aacagtctgc cgtaatcaca aaggggtggc taacgctgcc ccttttgctt 19800 atgtgaggtt tatcatgaaa aagaacgaat ttgatccgtc agccacatat cggtttacac 19860 gccctatgaa atggaacggt aaatatgttg gtacgggcac tttattaccc gaagatggta 19920 caccgatcgg aatcctgcgt tccctgttta agatgcgtca gattgaactg gctgacggtt 19980 ccgaaccgga acagcaaccg gaacagcaac cggaacagca accggaacag caaccggaac 20040 agcaaccgga acagcatggc gcagtagctg aaatccgtaa tgaaggttct ggctggtaca 20100 acgtctacat gggcgggatg ctgatcagcg agaagaaatt acgtaaagat gacgctgaaa 20160 aatggtgtga agaaaaaggt ttgacttaca atatttctta acgtattgtt agttcaaggc 20220 gacggtgatt agatagaact gcatagcaga cgctgttgaa aaccctagcc tttatagtcc 20280 agacgatatc tgagtgactt aaaaaacaga tgggagtcgg tggaatcccg gcacacaaca 20340 ggttagagca ttgagccgat aatcgtgaag agtcggcgtg cctggttagc cagtgctctt 20400 tccgttgtgg tgaagtataa gatggcagtg ctgatgaatc ggggacatca aaacccttga 20460 tccgggtctt atggggacgg aaacaacgcg acttcagcca ccacaacacc ccggatagtt 20520 ggctgagagg ccgaaagcga tcggttgcta accgatagat cggaaacggt ccacaggttc 20580 gaatcctgta ctatccgcca aattatgcga atcacaccga cgggaggtga tcgctatctt 20640 gctggcgggc aagccgcaaa gcgtgggtaa agcacgttgt gaaacgtcct gaactgcgta 20700 aagaattaac ccagagccaa gcaatcgtta gccgtctgtt taagacggct ttttttcgtg 20760 ctaaaataat gaaaactatt ctatacaggt gaccacatgg caatcacagt tgatggtatc 20820 cgcaatttaa ttaacgttcc tgatatcagt gatgaaacaa ttcagtggta catcgataac 20880 ggatatacta acccgttaag catctgtatc gccctttgtg attacatggc ttcactggtc 20940 agtaacgata ctgatattaa agttggccct atctcacttt ctggtagtga tgcagccaaa 21000 gcatggaacc tgcttaaaaa agatttcatt ttacgtttga atactggaac ggatccgggt 21060 ggttcagggt ttggtttagg gttcggcgtg ggtggtatta cattgactgg tcagggtatg 21120 ccacctgcta ttcaacgcgg gcagttcgat aacccgccga ttacgctgga gaatagcagt 21180 acgcgtatca acgaaggtga acagtaatgt ctgatcaacg tagccgtgtt ttagcaggtg 21240 tgactcgtgc actcgcagaa gtgggtgaag atctgactgt atcacgtact gtaaccacac 21300 caaaccccag caaccctacg ttacccggtg taacagaaac cacggttcat agttgccgtg 21360 gttatgttta cccgcttgaa aaatgggatc catcgaccat gacacgtaat acagtgacaa 21420 tggttattat ggacacgaaa tcatttgatc caccttttgt cccagagcgt ggcgatgttg 21480 tgactgatgg tcgtggtcgt gaatatcgac tgttagatcg tcaaaaccca cgattactgg 21540 gtgacgatat ggcgtttatc catcctacag gtgctgcata atggcacgta acgttaatga 21600 tataaatcgg atcactggtg tctttaaaga cataaaagct gatttacagg atttcacgaa 21660 tcgtgaagtg atccgatatg ttttaacgtt acgtaatatt ttaatcagtg aaccacctac 21720 aggtacacca gtagacacag gatgggcatc aaataactgg tggttcgatc aaggtcagcc 21780 agctaacagc ccatcaactt catctggtga tgtggcaacc agtaaagcgc gaattgaaca 21840 ggacactata acgatcagca gtattgttgt taatggtcaa tcgctgcata taacgaataa 21900 cgttccttat attggtattc tgaatagtgg tagtagttta caaacaccat caggatttgt 21960 agatcgtgct attttaacag ccggaattat ggtgaggttc aatcaatgaa tatctctgat 22020 gtatccgggg ttgtttataa tcgtgttctg gataatctcc ccgtggagat aacaccagat 22080 cgctttacga ttgcgtctgg taatcttcct gacgatacaa cagggaaacc cggacttatt 22140 ttaacgcata accccggccc gtgggcgatt acaaccctgg gtggggaggg tgtttgtcgt 22200 cggcgtttac gtaccggaaa tgtgttttta caggtgcgta ctcctgcaca atacggaatg 22260 gatacgttaa gtcttgatat tgctgaccga ctggcgcgtt tgtttgaggg gatctggcag 22320 gatcgcccgt tactttatac aggtgttgat gtaagatatg tgggacgtga taatgcctgg 22380 ttcctcgcga atacggttat cacttatgaa tttgaagaag tctattagcg aatgaggaac 22440 caaaatggct gagtcaattt ttaactgtaa tcaggccagc gctgcagacg ttaacgcaac 22500 ccgtctttct gtggctaaag tctgtgaacc tgtcagcggt acaccctgga ctgtacagca 22560 acctaacgaa atcagttcat actctgctga cattaccaaa actcaacgta ccccgattag 22620 cactgaccga tccgcgcgga aaggcactgt aaccaacatt gaagttgcac caggctttca 22680 gactgatatc actctggata cgttccgtta ctggggtgat ggttttcttt acagccgctg 22740 gatgggtgcc ggggctatcg atattgatgt aatcagcgtt gatagcgaca gttacaccgt 22800 tgcgacaatg gcaagcgcat tgccagccgg aacattggtt tatgctgctg ggtttatgat 22860 ggctgcaaat aacggtctga aaacggttgg ttccggcagt accactactg atattaacgt 22920 gactggtctg gtagctgagg catccccgcc agctactgca cgtttatacg tggtaggtac 22980 agtcgctgct gcaggtgaca ttgcggtaaa cgccaatggt cagatcacat caaccacgct 23040 ggattttacc acgctgggat tgattccggg tcagtacatt tacattgatg gtttcaccca 23100 gaccgttacc agtaagttag cgcgggttgt ttcggtaaca gatcatgtgc ttactctggc 23160 aagcagtgag tttgtaaccg aagtcggtac agggaaaacc gttagcattt acgtatccag 23220 ttttgtgcgt aacgttccgg ttgattcacc ggatttcgtg aaaactgaat acacgatgga 23280 agcgcgttat aacaccgaac cggaaattta cgaatatgcc cgtggtgtca gcgctaacca 23340 gatgaccatc aacgcgccat tgactgaaaa aatgacaatg gatctaacgt ttgtagcaca 23400 ggatttgtca gaacctgttg atacaccgtt accgggttca ggttattatg atttcgttga 23460 aaacgaagcg tataacactg ttactaacct caatcgtgtt cgcctgactg ggatcgatga 23520 aagtggtctt tcaacatatc tgaaagacac caccatcacg atcaacaaca acgtgtcagg 23580 tgaaaatacg ctgggccgca tgggtgccac gtttactaac ctgggtaacc tggaagtcac 23640 cattgatact gaagcagtca tgactgatgg cgcggtgctt gcggcgatcc gtaacaacac 23700 taccgttacg tttgaactgg ctggcgttaa tggtgatggt gcatttgtgg ttaacattcc 23760 tgctatgacg ctgggtgatg gttctaagaa cctggcaacg ggtgagaagg ttaaagtgac 23820 cgtatcagga accgcgcatg aggaagcggg tctggacttt atggtaggtt tcagtttgtt 23880 cccgtatctg ccaactctgt aaaagaactg ccccggacta accggggctt tatcttcact 23940 tgcgtaattc gtacagaact attactattt acctgtcatc taacataaca ggtaaacatc 24000 atgtccaagt ttgatcatct taaaaaagca ctttcaccgc tgatcctgaa agcatctgcc 24060 gaactgattc tgaacgaaaa tttcaaaatc accgtgctga acctgaacac cactaatcag 24120 gtgtataacg ccgcagttgc ggagtatatg aaaggtcgcg cagcgcttcc tgaagatttc 24180 tttgagcgtc tctggaaaca ggaatacttc ccacaggggg ttgaattcgt tgctaacgtc 24240 ctgatgctgg attgggtgtt attatcagaa gatgacacac ctgaaccgtt cagcccggaa 24300 gaagcgatcg aactgatgag cgatgatcgt ttcggtccgt ctatctacgc ccgcgtggtt 24360 cagttctcga ttaactccgc gatgtttaaa gacgactggg agaaacagat cacaaaaaac 24420 taattgactt cctccagtgg aaccgaaaaa cagacggtga tgatctggac tgggttgcac 24480 agggggctgc ggcgcgtggt aaggctgttc cggcagtagt tcagaatcgt cccgtgttgc 24540 gtcctgacgc gatattttac tggaatgctt accttgacct gatgacggct gaatggggta 24600 actgtgagcg ttatgcacgg tgttataacg ttgatgttca gttcctgtgg tcattactga 24660 ttaaattacg cgctgttggg tcaaagtagt cacggggtca cggttgagtt aaactattcg 24720 tatcaacgtt tcaggaggtt tgaccgtggc ccaatatcct atagatataa agttagatac 24780 cgggtctgct gaccgtgatc taaaaaatct taatactcag ttagatcaaa ctgagaaatc 24840 aactattgcg gctgcacagg ctgctaacca gttatctgct gcggatcaac aggtcgctaa 24900 agcatcccag caattagccc aacaacaagt acaacaggct gctaaagcgg ctgctgttgc 24960 gcgtgctact cgtgaggctg cacaggaaca atcacgctta ttagccacac agggggctgc 25020 ggcgcgtgct gctggtgaaa cggtcaataa ccaacagaag tttgcagatc ttgctaaaac 25080 aattaaacaa gcaactgctg atgaaaagaa agcaattgac gatctgacaa atagccttaa 25140 aaaactggat agccagcaga ataatacaaa ccagtcggca cagaaaacca atactgcatt 25200 tgacactatc gcaacaggtg ttaaaggttt tatcggttta caggtggtca gtaccgtagc 25260 tgaatggggt aaggcgttta tcgataccgc atcccaggtt gaacttttac agagtcgcat 25320 tcagctttat tcaaatacat ctgttgaagc aacacagatt tttcagcaac tagtacaaca 25380 ggctaaccgt gcgggtacag atattaatgc tgtagccaac agttttcagc gttttgcggc 25440 tgctggtaaa gatgccggga tcagtaatca ggttattctg cagttcaccg acaacctgca 25500 gaaaatggcg cgtatttctg gcgcatcttc acaggaagca tccgctgcta tctaccagct 25560 atcacaggcg tttgcatctg gtcgattaca gggtgacgaa ttcagatctg tttcggaaca 25620 gatgcctact gttctacaag tgttagcaaa acagttaggt gtaactacgg gtgaattaaa 25680 acaaatgggt tctgaaggac tcattacccg tgaccaaatg ttactgttaa ataacgccac 25740 cgacgatatt aacgcacagt ttgaccgtat gccgcgtaca gtcgatcagg ctgctaccgc 25800 attgcagaat aatctttccg tggctatcgc cgaactggat cagcagatcg gcgcgtctaa 25860 atttctggcg aaattcctcg atttactggc aggcggtgta tccggggtta ctgacctggt 25920 caaagccgct ggtgaaattg ataaaatggc gcaggctaca aataacctga atgccgttac 25980 cagtcaacgt gaatcgaacc tgaaagagat cgcggatctt gagaaacaga ttcagaatgg 26040 ttacaccact caatctatcg gtgggtatac caaatttgtt aacagcactg ctgatgcaca 26100 aaaacggctg actgagctta aaaaattaga tgttcagtta acaaaacagc aggcagacgc 26160 acagcgacag gtaacacagg ctaccccact gggtaaaggt gttgctgaaa atctcgcgtc 26220 acaggcaagc cagttagcat cgctgaacaa aagtgtcacg gctgctggtc gtcctgatgc 26280 agatgcagcc aaacagatta aaaacctgca ggaacagttt acctatacta aagcgcttgc 26340 cgatggtaac tacgaactgg ccgctgctca aaaactgggt aataaagcca ccaaagacca 26400 gatttcttct tacgctgcgt tactgaaaca gcaggcagag tataagcaag gtcttaaaga 26460 cgataaaaaa gcccagtcag aggccgcagc ggctgctaaa cgtgcacaga aagaactgga 26520 acgtaatcag gctgcgaatg aaaaatattt aaaaacactc aacaataaag ttactgcagg 26580 tcaatatgat gttcagttgg cccgtgagca ggttcaatta agtctcacgc agggtgcatc 26640 agttgatcag cttacggcag cgtatcagaa gtcctatcag gtacagcagc agttaacgct 26700 acagtcacaa caggcagaag cacaatcacg cctgaataaa gatgctacgg acgctgaacg 26760 taaagctgta gatgaacagg ttgcagcgct tcagcgccag caggaggcta aacgccttgc 26820 tgcacaggtt tcccaggttc aaagcgatgt taccagtacg cttaacccag ttcagggaca 26880 aatggaccag attaaccagc aggaagcaca gcgtttaact gttgctgaac aggcacgcca 26940 acaggatctg attaacgaac agcaatacca ggatctgaaa acgcagatca tgatggcggg 27000 tgaacaacag cgcaatgatg taatgactgc taataatgcg atgttgctgg gtgcaactgg 27060 cgatcttttt ggtggtctgg ctgatgtttt aaagaatgcg caaggtgaac agtcaagcat 27120 ctataaaacg atgtttgctg caagtaaagc atttgccatt gcgcaggcgt ctgttcttct 27180 gtggcaaaac gtcagtaaag caatggcgat tggtttccct cagaacatcc catttattgc 27240 gggtgcttta gcacagggta catctatttt aactagcctg tcgtccgtgg ctgcaactgg 27300 gtttgcaacg ggtggtttag tcactggtcc gggtacaggg cagagtgata gcattaacgc 27360 acgtttaagt aatggtgaat tcgtcagtac caaacaagca acaagtcgtt atcgtgatac 27420 actggaatca atgaaccgtg gcacatatac accgggttct gagggtggat caggaactaa 27480 cgtacaagtt cataactatg ctggtgagcg tgtacaggtt aagcaaggat taacccgtga 27540 tgatgtagtt ctgatcatcg gtgaagaatt cccgcgtcag tctgccgcac aatggaataa 27600 cccgtacagc cagactaaca aatcattcag atcgaattac gatgtgaaca ggaaacttta 27660 atcatggcaa atactgacga cttaccacgg cttgaatatg ggggtgaaat ggttcgcccc 27720 gcccgtgata attataatta taaccctcca tggggtgcga ctaaatcaga tattgccggg 27780 acactatcgc ggctgggacg tagcgctttc ggtggtccgg ctgatgtttc ctgtactgtt 27840 cagttgcata gtccagcaat gcttcagtgg tgggacgatt tttataacct tgaaattgca 27900 gaaggtacga aacgcttcgt gatggaactg tttgttaacg gttttattca ggaacatgtc 27960 gtacagatcg tatcacgacc agcagcagtt acagtaggct ggaaaggaag tattgacctg 28020 cagttgcagg cagtaccaat tatcgatcgc tgtgctatgg catcccgctt gctcatcact 28080 aaatgtcagg gtgatcactc atcttgctat attaatgact tgattgaatt aggtttatct 28140 ctcaataacg cctggacacc agaatgaaag acgaactgaa agaactattg acagtcgcca 28200 caacgggtaa aggagtggtt gacggcataa aacttaatca tagttcctgg ccgcagccgc 28260 tttatatcac cagtgtttac cccggcttta cggcagtaca tgaagatggt ctggaatatg 28320 attacgaata tattcctatg tctgttaaaa aagcgaacaa gcaaaacgac ttatcacagg 28380 attatagttt cactattcag gatctgaacg aggttgtcgg ggtttatctg gacctgatac 28440 cgcttgatag tgaagaaaaa ccatcggtgg agttgcgaac cttcgtgtat cgtgaggacg 28500 gatctatttc tgatattcag gatggtccat atgtgctcga atctggtgat atcaccacag 28560 agccgcaggg gtgtacgttt acagctacac caccgataac gaatttttca ggaacaggcg 28620 agttatacac gtttgaactt ttcccttcat tgctggcata tacatcatga tcggtgatcg 28680 ttatgatgtt gataaatgga attgcacaca tgaagtcagt cagtggtaca gattaaataa 28740 ctatcctcat caattacaga gtatcaacag tagtgaatgg ggtgtatcgt tcgtcagatg 28800 gatgcgtaag cgttttacac cactggtcaa gcctgaacag ggtgcattag ttttaatgaa 28860 aaatcgctgt tctggtgggc ttcatgttgg tgtatgggat agcggtatgg ttcatcattg 28920 ctatcagcct cccggtaata caccaggaca aactataaga acacctctaa gtataataaa 28980 atgttctcat aaagacgtga ctttctggag aatgaaaaat gtctaaagtt gtttatcaca 29040 cagtgccgat tgaaaaagct gaaaatgttg attttggtga atggttgctg aaacgctggc 29100 ctgttggatc cgttcgcccc cgtggattac tgatttttaa aaatgacgaa aacattactc 29160 atgaatgggt gaataacccg tcagttttaa acgatcctga tgcaacttat catatttacg 29220 aattaccacg cggcggtatt gtaagcgcca ttacaggtgt gattggcgct atcctcaacc 29280 ctattttaaa aatattcacg ccgcagggta acgtttcgaa tgctacaata aacagtaaaa 29340 taaagtcgtc gaacaactcg ttacagggtc gttcgaacga ttcccgtccc ggtgaacgaa 29400 ttgcggatat tcgtggtatg gtcagagcat acccggatct gttaatgaac tacaatattt 29460 ttaaagacgg cactgagttt gaatgtcagt ttctttgtct gggcgctggg tcatatgtta 29520 ccgatgaaat cagcgatggt gtaacgccca ttacaaacgt atctggttct cagatttcaa 29580 tttatgaacc aggaactgcg cctgggtatg gttcaccttc aaaggttatc aacggggtta 29640 ttgatattgc atcattcccc gtggttatcg ctaaagaatc gaatgaagtt gatggcgctg 29700 aactattccc gccgaactat gccgatgtta gttccgggaa tgtaacctat acaatatatt 29760 ctactggtca aatagatgcc gtcagcaatg atgatgataa ccctattaac tggtctgatc 29820 gtgtagcgat tggtgatgat tttgtaatat caggttttat ttcactagaa gaacaaatag 29880 tgggtggtgt accaacaggt ttatattatc tacatgattt aagtggtaca tatcaggtta 29940 ctggaacatc tgatgacggt gtattactag acgtgtctgg aaattcgaac tggtcttttc 30000 tttcttccac tggacaggca ccttatacga ctgtttacga tgttggtggt ggtctgtact 30060 cattaagtgc ttcatctggc ggtactaaaa ttacttataa accgagtatg gatacaaccc 30120 gcccttatag tgtcggcccg tacttaatga ttaattcacc gaaaattctg gtgaatgctt 30180 acgctcaaaa cggtatttat cgtcgtcgct attacattac cccgtttgat gtaactttgc 30240 gtgtaaccgt atctaattat gataatccgt cagatcctga atatacattc gactttgtag 30300 ttaagggatc gacaagtgct acaggcgcgt ctttattatt tgataatcct tatccagatg 30360 cagcgtttat caggatgcaa cgtatcacag atacaacatt aaacgaaagt atttcaacaa 30420 tcgatactgt taaatggcgc gatatgtatg gtatcactga tatttcaccg cgcagttatg 30480 gtaatgtcac aaccattcat tctgtaacta aagcaacgtc agcagcttta aaactaaaag 30540 aaagaaaatt aaacatgttg gctaccagaa tttataatgg tagtccaagc agtaattttg 30600 ccgatgttgt tatgtcaatg catcttgatc cgcacttcgg acgtcgtgat ctatccacaa 30660 tcgatgttga tgctttatat gccgtacaac agcagttact tgattacttt ggtgatcctc 30720 gtgctattca ggttggatat acgttcgacg ataacgggac cacctatgaa gaagcgttgc 30780 aaaccatttg taatacggtc aacgtaaccc catatcaggt gggtagcgtg ctttactttt 30840 ggcctgagtt accacaatca gtatctgcaa tgcaatttgg gcacgcgttt aaagtgcccg 30900 atactgataa acgtacccgt gcatttgcac cacctaaaga atacacgggt gttcaggtta 30960 aatactttga ccacgatgaa aaatcatatc tttacgttac gatcggcgaa gaaactaacc 31020 tgaataaaat agatttagtt gcctgccagt caaaatatct ggctacaatc cgtgctaatc 31080 gtgagatgaa taaactacgt tatcagcgta ttacccacga atgcaccgcg cttagtatcg 31140 ggttacaggc tactcccgga atgcgcgtgg atatgatcga taataccaga atgaaacaac 31200 atgaaggtgt gatagttgat gttgatggtt taacactgac gttaagtgat cctgttgatt 31260 ttgttacagg taatacatat tcaatcacga taacaggtcg tttaggcacg cttgaaaaca 31320 tcccagtttc acccggtgat gatgaattta ccgttgtatt acagtcagca ccgacagaag 31380 aaatatacac cgggtggtta caggatcgga ccaattatat catcagaacg gatgatgaac 31440 gtagtaagct ggcaatgctg gtacagacta tggaaccttc aggcgctgac aacaactatc 31500 aggtaggttt aacgtgcatc aactacgatg cacgttatta tcaggacgat gtttaattag 31560 attttgaaga tgtattgttt aataatacat cttcaatcct gtccagacgt ctgcgttgat 31620 atgcagtttc catagcatta cattcatcca tcaccagtct ccactggtcg acggcttcag 31680 ttgcctcctg gataaccccg taaccggctt ctttaacaag aacttgcgtt tccggagtta 31740 ctacatttcc atccgcatca tattcagctg gtacggtctc ataaacagca tcccatgatt 31800 caacaatagc gtcctgtgct tcctggtaaa catgtacaat taacccccac tcagtagcat 31860 cttcaccagc agcttcaaat gcttcaagga tatcctgggc aatatatcct acatgccacc 31920 gtgcagcctc ttcccctttc ccagcaacgg cccaatcgta cttataccgc ttgatgctga 31980 tagtgcccca tatatccagg atgttatcag gaatactttc ctgaacaggc ttatgtctcc 32040 tgtcagatac aacggtaaca gcattctgcg tatagatatt gttccatggt aacgctgctg 32100 taccaagatt ataggtagct gccgcagcag gctgtacacc gcgcgttgtt gctgtccggg 32160 tgagcgtcaa acctccggca gtcaccatcc ctgtagcggt gagcgtactg gccgatacgt 32220 tgttaaagtt cacatcgcct ttggtgctgt atgccggtaa taaactttgg tttataacca 32280 gcgtatcccc ggcagccccc actaccgcat cgagcacata cttgttagtc gcggttccat 32340 tgctattcat cactcgcgca tatacgcggg tagcgcctgt atatgccgtg gaagagccag 32400 acgccacata tgcagggatc cccattgcga tatacggaag gctgcctgat ggcacagtaa 32460 tcgtagtgcg cccgtttgcg gaatccactg agtctactgt cacattaaag gtctgctgat 32520 actggctacc caacgtcatc ccgctggtga tgatttgcgg gatcggattt cctgtcgcgc 32580 ccagcgtcgc attgtacttg tagtcgttgg agtgtttatc gactgatatc cacggataaa 32640 cgatgtcacc tggtttaaac agcccaccac ccggagactt gatgtagcca ttggtgtagt 32700 taccgaatac gccagccata ccagattccg gcttgtagga taatccggta gggaatacag 32760 gtacaccacc agtaaaagcc tgaatagctt tcagtacgat tggcttacca gatgcaaccg 32820 tgataaccag gttctgctgt ggtgtgaacg tgcctacgcc gtcgttcgcg ttccacttga 32880 cgttcgggat gatcgccagc ttatagccgt taccgaagtc gatacagcct tctccgcgcg 32940 acatcaccag gttcccgtca actgacggcg tttccagccc tgcaattgat tgccagataa 33000 caaaatttac cgggtcaaag ctccccgtta agtctttgta ccagatacag atattagacc 33060 tgtatgcagg tgagtgcatt gggacataca acgttcccga gtttacctgt aacccatacg 33120 gactgataaa ctcttttgtc tctttgtaat cccttagatg gtcaaaatcc acactcccgg 33180 ctgcaccgcc atacagcccg taggttccat atttaaagtc atatccacca tgcaggaaag 33240 ctcctacatc atgaacaggc gcaccaatac gcgtaaagtt tatgccgtta tatgagaagt 33300 tgttgtcgtt gtataactct gggtacaccc agttgccgtt ggcgtcatag tgtccaaaac 33360 acccatcctc gaaagtgata tacgtccatg aggaaaccgg tttgtactgg tgtgcgatcc 33420 catcaatgat aaggcccagc gccttcgaat aggttgggtc acccatctgc ttactaacaa 33480 cgaagagatt aggggtgtgt tccaggtagt tgttagtgaa agaatggcca cggcagttgg 33540 tgtaaattac acccttacct gggcgttttg tttcatcaga aatctgcccg tggctaacgg 33600 tcaggttcac cccagacatt ctgaaacccg cgccagtgac taccaggaag tagtctggtc 33660 gtttagcatc tggtccttca atccaggcag caccatcaca caggcttcct ccttcccatg 33720 tggaccagtc agtcataatt tgggccaaac cttcacgacc ccaatcgagg aaaacgtttt 33780 tgcaatacaa cccgtagaag ttaccaaaag taacaccagc atcactagat gttggcaagt 33840 cggttgtaat caggccggaa ttgataaccc cactgtttgc cgggcgggca accaatggaa 33900 gctggaagcc gcgcgcgtgg atattctcaa gggtgacata ctccgggtta atcaggaaga 33960 atgccgagcc agcagaacat acagattctg aaagagaaac tttgtggtca ccaataattt 34020 tagcattaga aattttggta tacccggcag ctaccgcacc ccaatactcc tgcttcccaa 34080 ttgccgcgta aacttcgtcg atatcttcat acgagtgctc gaagccatta agccactcac 34140 ctgtaactga gcgcttatat tcgttagcag catatacgta tatcaccgac cccgcacaat 34200 cgtaatcggc gaacttgcgg aatttagcac ctttcttgga gattcggtaa ctgcccccgg 34260 ttattttaat ataaactttc tgagcaacta ccggcgctaa caggtcatcg ttagacagtg 34320 aatatgtgtc tgttgggctg attgtgtaca gtatgccgtt aatagcttgc ccaaggcagg 34380 tggtgcttgc cgcacttaca tctgaaatga ggctggagtt atctccgcca gtgacacata 34440 ccgcaccatt gcttcgggca tcaacgtcgc ttccgacatt cactttcagc tgatattcga 34500 caccgttggc gttgtaaatc ttcgcctgag tgataaggtg ggttcctgct tttgatgcgt 34560 cagtgtttcc ggtagctacc catgtaccct cccctccatc attaggagaa taaaatccac 34620 gaacacgaat ggatgagtac gtgtcggttg aactgagtac agctgataca gatggcagcc 34680 actggcctaa ctggtactgc acttgctgtc ggatatcatt atctccgata gctacaagat 34740 gaagtgaatc gctcgcccag gaagtagaat cattcccggt tgtcgtaaac ggaacgtcag 34800 tattggcagc aagtcggtac gctactccat tgtatacggt tacctggctg cgatttgtaa 34860 atgtaactgg cccatcaata taatcattca gccacgaata gcctgatgct gcgagcatat 34920 cgttgaattc gtctctttgt tctgtaatct gagaaacaaa ctcgttttcc tgggagatca 34980 actgatcatt aaatcttgtt tgttgttgat caagttgttg attaaattct gtttcacgct 35040 catcttgcgc agtctgaaac tgtgcttcca ttccgtcaag tgtcaagttc gttacttgct 35100 caccacggat agtatcagtt acagttaaag catgtgcacc attagcatct ttgcttttag 35160 caacatgttc aatgtgctgg actgcttgtt tacctgtttt aaggtcgtca gcattgatat 35220 aatcactgca attagccatc ttttaaccct cgtgggagtg tggaacaatg tccgataatc 35280 cggtattgaa atattggcct atcataacat ttattgtaac tggtgcggta ggtttcggcg 35340 tactccagca gcaggttaac gcaacggcta aagatgtagc tgacgcaaag gtaaacgcca 35400 gcaacgcata caacctcgca aaacgtattg aatcccgtgt tgatgttcac gatgtaaaat 35460 tagagtatca ggctgttcag aatactcaaa tcctttccag cgtcaaagaa cttacccagt 35520 ctactaacga tctaaaagtc gttatcgaag gtcttaaaaa tcaacgccgt acagaaggtg 35580 acagaagatg agcacaggta acgcatctgt tgataaaatc attgatacaa ctattggtca 35640 cgagggcggt tattcaaata atagcgccga tcgtggtggt gcaacaatgt ggggcattac 35700 agagactgta gcacgtgcac atggctacaa aggtgatatg catttattac cacgggcaac 35760 tgctgtaagc atttatgagg ctgattactg gttcggtcct cgttttgatc tggtacaaaa 35820 agtttcaccg ttaattgcgg ctgaactttt tgatactggc gttaacatgg gtccgtcagt 35880 cccatgcaag ttttttcaac ggtggttgaa cgttttcaat aatcagcaaa aactttaccc 35940 tgatttaatc gcagatggtc agatcggacc acgaactatc aacgccctta aacagtactt 36000 aaccgtccgt ggtaaagatg ctgaaaaagt catgctgcgt gcgctgaact gttcacaagg 36060 taatcgttac ttggaactgt cagaggcacg ggaagcgaat gaaacgttta cttatggttg 36120 gttacttaat cgcgtggggt cactctgatg gatatgttaa gcatgtttcg taatgcagcg 36180 ggtggtatct cgttaagccg tgcgcaggct gcgctgggtt tcctcgtggt aaccgggatc 36240 ctgatttacc aggcggttga tcagacgtta gataacaccg tgctgttaat gtacttcggt 36300 ttctgcatcg gccagtatgt tggcgctaag aagatcgccg ttgataagga tatcaaagaa 36360 cagaaaattg atgcggggtt gaacccatga gtattcgcag cgttgttatc acgataattg 36420 cgcttttact ggctttagca gcaggtggta taacctgtta taaggccggg tataaagcgc 36480 gagtgaatga agaaaaacag gaaaagttaa acgatgctca acaggagcag ttacgtttaa 36540 aagcacagca acagttggct gataacgttt tacgtggtct tgctgactgg tcacaaaata 36600 ctaaaatcgt ggaaattcgt catgaaaaaa ctaatactgt ttttcgtaat gagtgtctta 36660 ctcctgaata tcagcgcttg tacaacgaac gagttaccga agcagaaagc cgtttatcag 36720 gccgcactgg ttcagaagtg tcagaccgaa aacctgccac ggctaaacgg tctgacggga 36780 actgattcaa ctgatgtgaa tgatttgtgg ttggatattt atttcaaatg cgcttataca 36840 cacaacgcat tagtagacag ccttcagtaa ttcttcaacg ctcacttcaa cccatgacac 36900 cgggacagga tattcagtcc gatacatgaa cagggacgtt ccaatcagac cgttaggatc 36960 cgttttaatt ccctgcattg cgataagcgg caagaactgt tcacgcgttt gtggcaaccg 37020 tgcaaagcgc cccgtgggac gtttcgccgg gtccataggg ttaaactcaa cgattgttga 37080 cataagcaat cctctgttta gctatttcac aataatgtgg gtccatttcg aaaccgataa 37140 aatcaaaacc ctcaattgca caggctttac cagttgaacc actgcctgtg aatggatcca 37200 gaactttacc gcctggtggt gtaacgagac gtaccagcca ctgcatcagc gctgtaggtt 37260 ttaccgtagg atggttatta cgtgcgccag atgtacgccc ggcacctgca cgagggctgt 37320 ttaacccgtc agtatcaggt tcacggtctg tcatttcagc agcggtcacc atcgctaaca 37380 taacaccttc atcacggtct gatttgctcg ctttagcaca gtagaagaac cgcgcagcac 37440 tccctgaatc actgtagaac tgacctggta aacgatcgtt gaatttacca tagataccgt 37500 tagtaacttc actttgttca gtccctttga cgggtgcagc agcgccagct ttcgccggga 37560 acaggcttac aacttcatct gaaccatcgt ggataaagtt tgcgggccat cggccttgtg 37620 tgtcaggctg gttagcagtt gacggattat aattatcaga caaacctgtt attgacggcc 37680 taccgtttgc agaggattta aaatcgccat tcaattctgt tcgacaatca tcaatattca 37740 tcccacccgt accgaacttc aggacgtttt cagcaacatt tcctgccagt ggtttacgtg 37800 caacgcaaat tggctcgtga gcaggtttca aagctgttcc ccatccttgc cattgttttg 37860 cttcgtcggt gactggtgct agaatatcag gaaccccacc gacatatgtt ccgtaatcat 37920 tatctcccgc atctgaacca aatgatcggc tattgtgtct tgcgctctta ccgatcactt 37980 cactacgttc agcgcctgcc gctttatcaa tagccttact cacgtctaac gatttaggga 38040 aaccagaacc gtaaacccaa tcaatttgat cgcggatttc aaatcctgct aaacggattg 38100 cgagcgttcc caggtcatag gtacgtgttc cgaaaaacgc caacaggtga ccacctggtt 38160 tcaggacacg gaaaacttct ttccagattg atggacctgg tacaaagcta tcccacgttt 38220 tacccatgaa accaccacct gtatgaacat agtcatcacc gtttaaccaa tggcgtaaaa 38280 cttcgttcat atcaggttgt ttactgagtc cgtaaggcgg atccgtcacg actgcatcga 38340 tactattatc agcgatcatc atacgcatac cgattagaca ttcgagatta atcaccatgt 38400 gggatactct ccacgctgta ataaacgggg atccttaatc gttcagcctc tgcgatttca 38460 gcaatagtcc catgcgaacg acggtaatca ggaagcacca gaacagcgtc acagcggcgc 38520 ataacttcca gtgtccctga caggtagtat tcaggctgaa tgttgcgtaa cccgccgtca 38580 aagtcccata gttcggtgtt cttgtgtggg ataaccggga accattcagg acgctctaac 38640 gtcagacgct tacccatttg ttcagcacgg gacacgttac gggaggtttt aagcgcacat 38700 tcagcacggt aaggcccggc aatatagcaa agtttcatta tttgttttcc tgcatttgta 38760 agaatacgat catcgcagcg cggagtgggt ttacgtcagt gacagcactg tcacttgcat 38820 aaaaacaaac gtcaaaatct ccggtaatcc catcaattac ggtatcaacc ggtgccgcaa 38880 tccatttatc attaagtgat acgatgctta tcttgttagc aacaataatc ggccatgcat 38940 ccgctgggtt gttgcaataa tcccttgaaa aaccaccgta accattatgc atatagacaa 39000 tggatgtatt ttgtggaaac gacttatttt cgcattctgg tgattttcgc aaatcatgcc 39060 aaaaaacatc acaaatcatc ttgttaatat caaagtcact caacttactg taatcagtca 39120 tgacgtttca ttccttccaa catatcccag atgatagcca cacggcgcgg gttagtgctg 39180 atcgaatgca gggtttcgca cccgtggtga tagccccaac gaacagataa ttctgataac 39240 aggtaaccgc gagtattagc cagttctgcc agttcacccg gcgcgaaaat agttgtgttc 39300 ggttctgtca gaacatgcga tccgaaaatt gcgtcagtga tgcgccacgg tttcatgagg 39360 tcgtcaacca tgtaccagtt actgatactg atttcagaaa caccccagcg tgcagccagt 39420 ttcaaacgtt cctggcgcgg cgggaaaaca ggcattcgtg gtaaacgcag ttcggtaagt 39480 tctgcaggct caaacagcgc gtcatcggtc aaacggaatt caccacggtc atcgatatag 39540 aaaccacggg atttcccgtc gcggataaaa ccatcaacgc gattgtaaac tttacccggc 39600 gtaaacacgc caatggtgga accagaaatg aatttatgtg aagtatgcat tgtttatcgc 39660 ctcagtaagt tttaaataat tctatacggt ttaccgtaat ggcgcaacca gcttttcagc 39720 ctcttttatg taaaactcat agttcagcgt tgtccggttg aagcgctgca tgttgttaca 39780 ttctgtcact gtccagcctt tgcatactgc catgtgtcgt tctggtgcgt taggatccag 39840 tttaagattt ttagccagtg gtggcatgac tttaactaaa ggtgcaccat cagtgctgac 39900 gtaataacgt gtaatgtttt gaacctgctg atcgccacac attaatttgc tgttgcgggg 39960 aactttcgtt accagcatga aatcgtgaat atcttcatgt gttgttataa acttacgaat 40020 atctttgcca tataccagtg cggcttcagc agcttttgcg acaacctgca tactgtggtt 40080 ttgatgccaa cccaaatcac catttttatt ctgttcagtc ttagttgtgt ggcaatacgc 40140 acctttgcgt ttaacctttt ttccaccttc atacactgca atatagttat tcacatcacg 40200 gataaacatc acatcataaa ttgcttcttc taattccagc cgtgtaagtt tttcccaagc 40260 gtgacgaacc tgttcaactt gtctagtgaa aacacgagga acataaacag taagaccatc 40320 agtatttgcc tgaatcattg aaagaccagg gattttcatc aactcttcgg ctaacatgca 40380 aagtagtaac tgaccgttga tagtaatcgc catcgtataa gctggatcat aaaatggact 40440 atacacatta ttactgtcac catagacacc gttcagtgcg agtttaagca ttgcgttttc 40500 cggtgtgcct tttggataac cagaacgcat atcgtaaaca tttttataaa taatgcagaa 40560 ctgtttaccc aaatgttctg gaaaaagctc attactgatc gccaggttag ggtaaaaact 40620 tgcaacgtcc agatcgataa tcacatagtt ttcagttgaa cggatggttt gtgattcaat 40680 agatccgtgg atgccacctg taccaaaatc aaatgaaaag ccgttaatag tagcgctcag 40740 atcagtaaat acacctttag tttctgtaat gacttgctga cgtaaccagt ttaagacacg 40800 gttgaattca ggctgttcaa aatgaatgta agggaatata acatcgttaa gtgcaataga 40860 tgatctgata gtttgccgtg gtcttttgcc tggtcctggg tgataacatt caatgccgga 40920 tttttcaagt tccataatga aataatcttt gccgatttta gtatcattat ggttcatgaa 40980 atttcgatta tacttctcgg aaagttcacg gcgaaaatct atcaactttt tactgtgacc 41040 atgaaacatc aaagtagctt taaggtcgtg tatcaaatac tgacgaagtt tatcaatttg 41100 ttcatcagtc aaataagtac ccggtgagaa tggcagatct tcaatatttt ccattctcat 41160 attgaactca agcgttttta aacttgttct ttttgcctgg ttatcaaagt ggtgaatctt 41220 ataaagatcg atttgtggaa caatccagtc actttcccac accatgtgag caaaacgatt 41280 atcatcgcca cagttaatga tagcatcacc tttacgataa atatcagcat tagtgatgta 41340 catgatatta ttgagtatcg aatgttgaac agggtagtca taaccaatgt tgttataacc 41400 cacttcttca gcaccatgtt cacgaagaaa ttcagtgaac atataatacg cctgacgatc 41460 atcgcggcga tgcgagattt caaatatata aggcgttccc gttaaagcgt gaatagcacc 41520 aaataaccac acgttagggt aattttcaat atcgtaaatg taagcgtctg acatagtaaa 41580 tcctgataag taaatggggc gctatggccc catgtctgtt taaagcggta tgtcgtccca 41640 gttccagtaa ctatcagtaa ccgttacccg tgagaaaccc tggcgcggga gtggtcataa 41700 ccatgtaacc ctgatcaatc attgcctgat ctgtccagcc acctgcaaca aactgttcat 41760 aagttgcacc acccgctttt tcagtcatca ctttcacagg tgctgccgct ggtgtaggcg 41820 ctgctacagg tgctgccgct ggtgtaggcg ctgctacagg tgctgccgct ggtgtaggcg 41880 ctggtgtagg cgctgctaca ggtgtaggcg ctgcgccgat cgcagtagcg cctgctggca 41940 ttgctggtac agcaccaaac acagaagcag gagccggacc agaaatgatt tcttcacctg 42000 cgtatagcag ttgcgccatt tccatattga tatacatccc cgcctgattg ccagtacgac 42060 cattaggaga cgttgagccg ctaatacggt aatagtagcc ttttttggcc tgatttttat 42120 cgatcacagg ctggaattgt gcgttataca acgggcaagc atcgatcgcc acgttgcgtg 42180 aaaatccgat tacccagtga ccagggtaac ccgtttttcc agcatgtttt ggatcgtcac 42240 cattcgtgat tttccatgca aaagttggtt gttgcgtttc accatttaca tagtgtgcgc 42300 cagcagcttt caaaattgcc tggaatacca cacccagttc accttgttct tcccaccagt 42360 tcgcggcggt tttaggaaac gccaggccaa cccaccagtt gtatttttca ggtgcgagcg 42420 gtttgttttc atgatcgctg gtattcatat caaagaacga gccaccaact agacgaccaa 42480 ccggagtgac gaatttttca acaatcttag ccatgttact taccttttat aacggacgtg 42540 cgccagcggg catcgtcgca ggagtattaa aaatggattc agccattgtg ctaaaaccag 42600 ttcgagcatc ggtatcaggc actaacgcaa actgaccttc aggtttcgtt gtgcacatat 42660 caaccagttc tttcggtaat gttttttcca gagtagccag agttttcaat ttacgttcgt 42720 aaagcgtatc agggttgaca ccaaacatag gcgcaatacc aatcagtttc ccttcatcgg 42780 ttaactgacg tttcgtttgt ttcggagcca gtttaaaacc gggtaacggt ttaccttgtc 42840 gaacgaaatg caaaccctga atgtgcaacg ctgtttttgc atcgcttgcc cgtgaataaa 42900 gttcctccag aagcagtaaa cgttgtccca cttcttcagg ggttaatgat ggtggtgcat 42960 ccagaacggt agccaattct gtgatcctct cataaagagc cgggcataaa ccacgggccg 43020 ggcaataatg acaatgttca ccaacaacca acggtgcatc aattttgtga gcatcagcga 43080 aacctttttt aaaccgatcc gcccactcca ttaacacgcc gcgtgaaaac tgccagcgcc 43140 ttacaggccc gtcaggatgc cacgcacggg gttgaataac ggtgaatacc acttgtttaa 43200 ctgaactaat acaccgttga tcaagcgcat agtaaacacc ctgtgagtta ccaacagcat 43260 caatcgcctt atgcccgtat ttgtaatccc agatatacag ggtatcagtt aaaaaatcgt 43320 accagcgata atcacagatc ccgtattgcc ccggcaacaa ccagtcaatg tggatgcgaa 43380 cttctgaaaa cagcggatcg acttttgcac caactgataa aatatcagca atgaattcat 43440 cagcatgttc atgcatatca tcagttacgg taataccgtt tggtgcaaca caaggcatta 43500 gtggtgactt acctttaatc ttttgttcaa gcacccagtg agccgcttta ccttcatgct 43560 tgctttgact taaaggttcg tcaaagtcga tccgctgtga cagttgaacg ctacccggac 43620 aagataacca acgtttagaa ccactggcac taaaggtagc gttgcgtgtc atcagaagga 43680 tccgcccata tttttgctga cttctgcctg acccagaata ttttcagcat cagcaggtgt 43740 ctggttgata cgctcgatca ggtcgattgc agatttcagt tgtgcaggat cagacaacgc 43800 catgatattc tgcgtgttat acagtgccag gatacgctga ctaatcggcg cggcgcgatc 43860 gccggtgatc tggccgaaca tctgcatcag tgcagactgc aacacctgac tgttgtaaac 43920 tttcgctggt tctgattcca ctggcggaac gttagccgga gcagccggaa cggtgttcac 43980 tggtgctgct ggaaccgggt tagcgggtgc aacaggtaca gcaggagtcg gatcgactgg 44040 cgcaacataa cccggcgcaa gttcagcggg tccggtataa cgtccggctg ctgcggcttc 44100 tgcgatcagt tcgcgtttca ctttgtccag gaaaacttca tccagttttt tacgctgacg 44160 ccacaggcca tcgcctttat tgatagattt gctgtcagtg tgaatacgcg gatcgtggcg 44220 cagaccccat gcgtcgaatt cgtcggtgct ggtttcacct tcttcaccgt catcagatcc 44280 ggtaactggc gctgctggtg taacgatcgg taagttggga tgctgtgcag cgattagtgc 44340 ctctttggcg acaccatcac cagcaactgt cataagcggc gcggcaccag tagcaatagc 44400 atttgccaga ttgttgatcg cagtttccag acccggagcg gtgataagca atttaacttc 44460 aaacatagtt ggttccttgt gtggttgatt ggttgctacg tggctaaggt tacgagtcag 44520 gttgcaatgt gtcaagaatt attttatgat tatttcacat tcaaaacgga gataaaccga 44580 tgattactga tctgtatagt ttcattcgtc ataacgtatt tttcgatcgc gtaacaggta 44640 agtatgtttt cagaggtcgt gagtttaaac gaaacggaca agcacagaaa gccgcgcgtg 44700 acgcatacgt taaggagaac cgcgcgtgag tcaacaaccg ttacgttact atcagcagga 44760 tgcggttaac ggtgtgaatg ctgaatggga cgctggtaaa aaagatgtga tcctggtaat 44820 gcctaccggg agcggtaaaa cgcgaacgat ggctgaactg gttaaggttg acgggataaa 44880 agtcattcag gcgcaccgta aagaactggt tagtcagata gcaatggcta ttgctgcaca 44940 gggattacca caccgtttca tcgcgcaaaa agacgctatt aaatttgcta ctggtcagca 45000 gatgaaaaag ctgggttaca gcacctacgc acccggcgca gatatcgtta ttgccagtgc 45060 acccacgctg cgaacaaaaa aatacgaacg ttggcacgat agcgtaaccc gtgttttttg 45120 tgatgaagcc catcatctgg tacgcggcac catgtgggga acctgtcgtg agcttttccc 45180 aaaatcttta ggattaggcg taactgcatc accgatccgt gcagatggta aagggcttgg 45240 acgtcatgcg tctggctatg ctgatgcgat ggtgattggt ccggcaatgc gtgaattaat 45300 caaccagcag cacctggcag attatcgcct gattatggct gaaacagata ttgacctgac 45360 agcggatatg atttccagca ccacggggga ttacaagcca tctgcgttga aaaaggcaat 45420 ggaagattca accatcgttg gtgatacagt gagtacctgg aaaatgtacg ccgacggtat 45480 gctgacggtg gttttcaccg ttgatgttga cgcggctata acactggcac aggaattcag 45540 ggacgcgggt attcctgctg aggcaatcag ttcgcgtaat accgatcagg aacgcgccga 45600 tattctggac cgtttcgaaa aacgcaaaac cctgattatg tgcaacaatg atctgttcgg 45660 ggaaggttac gattgtcccg caatggaatg tgctgtaatg gacagaccca cagaatccta 45720 ttcgttgttt atccagcaaa tgggacgccc gttacgctat gttccgggta aaaaagcact 45780 catcattgat aaagtgggta acgtccggcg ctttattgct cgtgggtttc ctttacccga 45840 tcaacattac aactggtcgt tagacgaccg tgatcgtaaa tcatcgagcg gtggggcaag 45900 taatacaacc tgtacgaata aaggggatgc tgcaaaaggt attgaaccct gtctgaaacc 45960 ataccctgca gggcttgctg cctgccctta ctgtggtcat gtgccggaaa aagcattacg 46020 ttctggtcct gatcgggttg agggtaattt acgcgaacta acccctgaag aactcgaaga 46080 actgcgccgg gcagtggtga ttattgaccg tgacccagca gccgttaaag accagatgtt 46140 acacgctggc gcacccgctg ttgcagctta cagcgcaatg aaaaatattc aggcgatgaa 46200 tgatgcacaa cgtaagttac gttccatgat aaccacatgg gctgggttac agcgtgataa 46260 aggtatttca cctgatgatg cttatcgtat gttttatcag gtatttggcg ttgatgtact 46320 cagcgcacag gcgttacaca ctcgggaagc aaacgagttg tcagcacggg ttgcaggaac 46380 tatgatttaa tggtaatctg tttagaatta ttttaaacat aaggttgaac gaatgcagga 46440 tctgatgatt gatattgaaa catgtggcac gaaacccggt tgtgcggtgc tttccattgg 46500 tgctgtatat ttcgatcgca aaggtaatat cggtgaacag ttttacgcat cgatgggttt 46560 tagcgcgttg tcatacggta atgctgatgt tgacataatg cgttggtggt cgcagcagtc 46620 tgaacaggcg cgtactgatg cgtttggcgg gactgatgac ccacgtgaag tagcacaacg 46680 ttttgcaaaa ttcattcgtt ctgatgcgct tccctggggt aacggatctg tatttgatat 46740 taccatttta gaagcatggt ttgatgcggt aggtatccgc tgcccgtgga aattctggaa 46800 tgttcgcgat gtgcgcacgg cggtggattt gctgggtatc aatactaaac tgtttatccg 46860 tgatggtgtt tttcataacg cgctggatga ttgccttcat cagatcaaat atctcaccag 46920 cgggactaaa catttatgac accacttgaa caatgggcga aacgccacgg tgtcagccag 46980 atggcactat atgaactgta tggtctgttt cagccggacg ggaaaccgca tgaagatggt 47040 gttagcgagt cagcaacgtc taaagaatgc gaactgatcg cggcccgtgc gggtcagcgt 47100 ctctggcgaa acaacaatgg cgctttacag aatgaaaaag gtcagtgggt tcgctacggt 47160 ttgggtaaca ccagcaagaa gatcaacgat gttatgaaat ccagtgacta tatcgggatc 47220 aaaacgttga ttatcacccc tgctgatgtt ggtcgtaaaa ttggaatgtt tatcgcggct 47280 gaaatgaaag agccaaactg gcacatgacc cccagtgata aacgcgcaca ggcgcaggcc 47340 acttttggta cagttgtagt taacgcaggt ggtgaatttc gtttcatcac ccacccctca 47400 cagtttgaac aatggatgaa agaatgaata acgaacgcgt aaaccgtctg caaaaattga 47460 tcgatactca cgggattgaa aacgttgcta aacgtatgaa cgtaagtgag atccacatta 47520 aacgtaatct tctcacaggt cattcagcaa tcaacctggt aaaactcatg gctgctgaac 47580 gtcagttcgg agcgtagatc atgatggaga gaaaatcact tccatcacag gattacataa 47640 aaaaatgttt cgtatacaac gaagatactg gtgatcttgt ttggaaatac agaccgcaaa 47700 accattttaa aaattccgtt ggttttaaaa acttcaacaa tcagaacgtg ggtaaaatcg 47760 cgggttcaat agttacaacc aaagagggta atcgttacag aagtgttaag ataaatggtg 47820 ttttttattt tgcgcacaga ttggttttca agctcttata caatgaagaa cctgattaca 47880 tcgatcattt aaatgggaac ggcattgata accgtaaagt gaatttagaa aaatcaactg 47940 ctcataaaaa caataaaaat caaacactta ataaaagaaa taaagaaaat aaaatgggtg 48000 tttattggcg tgaggaccac ggtcgttttt gtgcgtcaat tggttataaa ggaaaacaaa 48060 ttcacatagg ttcttttatg agcaaaaaag aagccgtaaa ggcccgtgaa aaagctgaaa 48120 aagaactctt attttcttcg aatcacggga gacttagaac atgaaaggtc tgctgaaccg 48180 taaacagtgg atttgttgga ggctggaaca cgttgaaggt cgcccaaaac ctaccaaagt 48240 accttacagc ccaattcacg ggtataaggc cagtacaaca aaccctgctg actggtctga 48300 ctatcatact gcgctgggta tggcgcaaat gtatggtatg tcaggtgtcg gtttcgtgtt 48360 cactgaaaac gatccttatt ttttcattga cgtcgataac tgtctggtag accaggctac 48420 cgctacatgg tcgccactgg cgcatgaatt tgtaaaccgt ttccccggcg cttatacgga 48480 agtaagccag tcaggaacag gtttacatat catctgtgcc tacaccagtt taccggaagg 48540 tttcaacagc cttaacgatc agaaaaccgg acttgaaatg tactggcgcg atcgttttgt 48600 cgccatgacg ttaacaggga acggtgaagt tgacgttgat tatacacagg gcgttcatga 48660 ctcaatcgcc cggtatggtc gtattcgttc cgatcgttca gcacactgga ccagtgcacc 48720 ctgtgacgaa tggtccgggc cggaagatga tgaagaactg atcgcaatgg cgttaaagtc 48780 gtcaagtgcg gcttcagttt ttgggaataa agcatcgttt gcggatctgt ggactgcgaa 48840 tgttgaaaaa ctgtctgtca gttacgccag tgatcaggga aaagactaca acgcgtcagc 48900 cgctgatgct gctttgtgtt cacaccttgc tttctggacg ggtaaaaact gtgaacgaat 48960 ggagcggtta tttaataaat ccgcgctggt tcgtggtaaa tggaccgatc gccaggatta 49020 ccgggaaaca accatattag gcgcggttga acgttgcgat accgtttatc gtgcgcaacc 49080 agcactgaca caggaactga ttaatgctgt tacgccagcg cctacagtag ctgttactgg 49140 tggtgttccg gcatatatga ctatcagacc tggtgaaggt gcatatggtg ctaaccatac 49200 cgttaacgcg tcaacgttcg ttaataacta ttatccgaac aacacgctta tttttgtaca 49260 gcagcaaccg taccgcttta acggtcgcgt ctgggagcgg gtgacagaag atgaattaaa 49320 acatcagtta tctatggcaa tgctggcgag cgaaccaaaa gctgatgtga ttaatggcac 49380 atataaagtt ttaagctatc tgtttacccg tgccgatcgt gagttaggca cctggccggg 49440 cgttgatgtt tcacactata tcgtgtgtca aaacgggatc cttgacgttc acacgagaaa 49500 atgtgaaccg cacaatcctg atttcttcac taccagtatt ttaccataca gttacgatcc 49560 gtttgcacag gcacccgttt ttcaggaatt tctgaatacg acactggaag gcgatcagga 49620 acgtattgca ctgttgcagg agtggttggg ttatatgctt gttaactcct atgactatca 49680 gaaagcaatg ctgatgatcg gtgcaccacg ttccggtaaa ggtacaatcg gccagattat 49740 acaggcgctg gtaggtgaag aagcgtatgc agggatcacg ctcgaaggtc tggcgaatga 49800 tgcaatactt gaaactgttc tggataaatc agtgttgttt atcggtgatg ctcacagtgt 49860 ttccgggcct gaccgtaaca ggatccttga ccgctttaag tcaataactg gtgctgatgc 49920 gatacctgtt aaccgtaaat ataaaggtgc gtggaacggt cgtttaccag gtcgtatgac 49980 acttgccgcg aacaatattc cggcttttgc ggatgattcc ggggcaatgg ctaaccgtct 50040 gctgatcctg ccgtttaacg tgtcgttcct caatcgtgaa gatatcacct taaaatcacg 50100 actgatgaag gaattaccgg ggatctgcaa ctgggctatc gaaggtctgg aacgtttacg 50160 taaaaataac cgcttcacag aacctgcagc gagtatcgca gaacgtcagg aaatcatgga 50220 ccagcaggca ccgttaatgg cttttgtgcg tgactgctgc gaactgctgc ctgatagcgc 50280 tactcacact gaagaacttt tctgtagata taaaatgtgg aagatgcagg agggaggcgc 50340 aaccatgact aaaaccgcat ttagtcgggc gtttaagtca atgcttcgtg ggcgagtggt 50400 taaagatgtg gtatcagtca atggtcagcg tgctaacggc ttcaggggtg tccgtttact 50460 ctctttccag tcagcggcta atgtgctgcc gttcccgcct gtcagtaata gttaaaataa 50520 ttcttgacgg attacaagga agtgatccat actctgtaca tcaactgaac aggggttaag 50580 aaaatggtta acgttaagtg catcaaagat aacgaaggtt actggaccga aggtgaaatt 50640 tatcaggctg aaacagaacc gggtggtttt ttaagaattg gtgacgataa cgacaaaaat 50700 gctgattggt gtttagtgcc attatcatat gatgaaaatg aaaaagccac ttatttatta 50760 gctggcttag atgctgaatt tattgatcta tgaaacgtcg ccgtaagcag tatacatgcc 50820 gatgcagcgc ctatggtttc ccacaccgtt ttagtggtgg gcgctgtcag gggttatggt 50880 tggtcgaacc taataattat tgccccgcgt gtaatttgct tactggttct ggttgccagg 50940 ttattaacgg tgttgaacac ccgcgcgaat gtccgttagt tcaggatttt tgcacttatc 51000 acgaggttaa attatgaagc cgcgttatcg attaatgaaa ttatcagaat gtgcgaacgg 51060 gacgcgattt tatttctatc gttctaaatt gatgtggcct tatacgctaa ttgctatcaa 51120 tcgtaagaaa tacgaaggtg tttatcacat agggcatggt tttaatatta acgttcggat 51180 gtttagaaca tcgttgaata cacaagtttg ggctaaggtg gattaaatgg aatggaaacg 51240 tattaaacga agttacggat cgaacccatt atatctgtat ttgaataaac ttcatgttgc 51300 tacagtttca tgggattttg ggcattctaa aaataacccc aatactcatc gtgctaatgt 51360 gcatttaccg ggtatgaaac aagaattttc tacttctaca caccccagtg aacaaatagc 51420 aaaagacgct gttgaaacta ttgttaaacg ctgggtagat gctgccggac tggagtttaa 51480 ataatgagtg gtcgtcgaac tcgttcgtta cgctgtagca agtgttatga acaatacggt 51540 tataacggtc tggtcgaagt tactggtgag aacggaaacg cttttacctg ccgttgtaaa 51600 acctgtggtc acacttatca aacaacatca gcggctgcac gccgtgcctg gagatatcgt 51660 gaaaagagaa tttgatcgtt atgtggtaat caagaatagt catgcagaac aagcactaac 51720 cgatgatgaa cgtaaagaac tttatcggtt aggtgtgaag tgcgcaaaat ggcgtcggga 51780 taacggcaaa aaacctttcg agtgtgttgt agttgaacac gactggcctg aatatgaacc 51840 tgtctggaaa gcgattgaac aacgtgttga tggtccacac cctttaccag taatgaataa 51900 agatgttcgg tgtttagttg acgctattag tcaggcagcg ttagctgatg atatttctgc 51960 tggtatattt ggtcctgttt ttagtcagct tattttccag ttagcagaaa taaagcgcaa 52020 atcacaatta ctcgatcagt tacgcgatct gatgggttac gttcaaaacg gaacagatgg 52080 aattatcact ttgttccagg atgatgctac tttaacttat tgggttactc atcgaacagc 52140 aggtaaaaaa gaacatgact ggcaagaaca tgctgcatca ctagaacaag ctattcgtaa 52200 tgcgtatgat aaacatgggg ataactaaga tgcttgaacg tatcgttatt tcgattattt 52260 ttctgatctc cgtggcgctg gtttcatcga atctggcgtt tattactcaa cagttcgtac 52320 tggctttaac gggcgtaatt gcagcgttag ccagtatcgc cgcgtgcatg tggggcgcta 52380 aacatgaata aggtagtctg gtcacttttc gacggttccg ggatcatggg tttgccgtgg 52440 gctgaggctg gttatcaggt gtactgtttc aatgcggata agggtaatca cggtgaatat 52500 aaaattaaaa tgtatcaccc taacctgcat tatgttgatc agtggattga tccagatttt 52560 gctattaaac gtgaaatcct cggaacgccg ttaccgtcta ttatttttgg tttccctgat 52620 tgcacgctat ttgctcaaag tggatcacaa catgaacgat cgcagggagc gctacaatac 52680 gcgctaatgc tggcaaaact gatccgtgaa ttgggtgaaa gatataacgt accgtggatg 52740 attgaaaacc cggtgggtgc tttgtcacga ccagaaatga tgggtaaagc aaatgcttat 52800 tttcatccgt gggaatatgg cggtcatatg agtattgacg atcgaccata tcacccaaaa 52860 atgccgatgt ttgatgggta tacgaaaaaa acatgtttgt ggttcggcaa tggttttaaa 52920 atgcctgaaa agtgtccggg gccgattaac attggtttct tctggggctg gaaattcctc 52980 ggtggtaact ctacacggac taagcaatta cgatcactta ccccacgggg ctttgctcgt 53040 gctgtgttca aggctaacca tcatgacgca tcttgaaaaa ttacgatcgc tgatggggta 53100 ttaccagtcc ggtagcgatc agataatcag tcttgcccag gatcctcata cggggcttta 53160 ctgggttagt tgtaaacgtg cctggtatga atgcggcgca acactggaag ccgcgattga 53220 taccgcttat gaaaaacatg gggtgccttc ttatgagtga acaatacgtt tatcgataca 53280 atgatgttaa ccgggttggt gatggtaatc cgacaccata tggtaaatgg cataacgtat 53340 ttgctcgcca gtatttacag ttaggtaagt ttaaaacaaa cagtcagggt aatctgcaac 53400 atattgaaac aggtgataca gattatcaaa actatcttgt accaccatct gaggtgagca 53460 aaccatgaaa cgactgatat tactgacgac tcttacgctc gccgctgcag tgaacggtgc 53520 ggagttaaaa cgctgtgacc tgacgatcac ccggctgaac tcgacagaca gcattacgcg 53580 gcccggtggc gcaactgttg ttgatgatgt agatcggttc gtggtgatga ccagcgattt 53640 tacaagctgg agcctgaaac tgaaccgtta cgggttcggg aagtcgaaag acggtaaacg 53700 gatgttcgta aaagacaacg gcaactacac cgcgaaagaa acgctgatca ccttatctgc 53760 aacaaactgt catcccttct gaactgctgg cggggcgctc aaccccgctg catatctgta 53820 tagaattgca taatcacatc gtctggtaca gcatcaaaat cacactcaga gttcatcatc 53880 atggcgaacg gtcgaacgta ttcgcggatc tcctgtgtta cacccatcgc attaaacggc 53940 gtgcctgtac cttcataatg ctctgtcagt gtcaccattg tttccagcac atcagaaggc 54000 cattcccgat cgatatggtt gtgtagccag ttttccgtga tgttgtaccc ggtaacgttc 54060 cggcgcaggg tgtacagcgc gttgttgaag ttcccgcaca tggtttcaaa ccgtttccag 54120 acgtcataac cataacggat cactgcatcc ttatgactca ttacccgtgg tgatccgtcg 54180 ccctgggaca ctggtaaacc gttctggatc acgtcatcca taaagttcag aacatccggg 54240 taccagccgt tatcgatccg gttcagtacc catgattcag tgacccggcg attcagtgac 54300 ccggcgttac gcagcacatc aactgcctta aacgtcccgc cgcagatatc cctgaaacgt 54360 tcccagacgt catagccgta gatcacccgt tcaacttctt tatccatcat ccgcaactgc 54420 tgaaaataat tatcgctgaa ccgacgatga ggaagcgccg cacgcagcat atcaacactg 54480 accgttttgt tcagtacgat ttctgctttc ggtgtttgcg ccgggatgac cacggggacc 54540 agatccagtt ccccgcccgt taccgtagta aggattaaat ttaaagtttc tgcccgtggt 54600 aaccgtttcc cggtcatcca ttctgtgaac cgacccctgt ttacgctgca acccatcatt 54660 tttagataac ttactgcgtt gtctgccgat ccaaaatgac tggcgaattt ttcaaacaag 54720 ttcatgttgt ttcaccttac cagatatata acgagaactt tacgccttat atgaaacaag 54780 gtcaactctt atatgcaaca gtttcaaagt tggccttgtt tacgctggta aggtgaaaca 54840 gaaaagttgt tacatctggt aagctgaaac aaagatctat 54880 <210> 2 <211> 107 <212> PRT <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF57 <400> 2 Met Ser Asp Asn Pro Val Leu Lys Tyr Trp Pro Ile Ile Thr Phe Ile 1 5 10 15 Val Thr Gly Ala Val Gly Phe Gly Val Leu Gln Gln Gln Val Asn Ala 20 25 30 Thr Ala Lys Asp Val Ala Asp Ala Lys Val Asn Ala Ser Asn Ala Tyr 35 40 45 Asn Leu Ala Lys Arg Ile Glu Ser Arg Val Asp Val His Asp Val Lys 50 55 60 Leu Glu Tyr Gln Ala Val Gln Asn Thr Gln Ile Leu Ser Ser Val Lys 65 70 75 80 Glu Leu Thr Gln Ser Thr Asn Asp Leu Lys Val Val Ile Glu Gly Leu 85 90 95 Lys Asn Gln Arg Arg Thr Glu Gly Asp Arg Arg 100 105 <210> 3 <211> 80 <212> PRT <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF59 <400> 3 Met Asp Met Leu Ser Met Phe Arg Asn Ala Ala Gly Gly Ile Ser Leu 1 5 10 15 Ser Arg Ala Gln Ala Ala Leu Gly Phe Leu Val Val Thr Gly Ile Leu 20 25 30 Ile Tyr Gln Ala Val Asp Gln Thr Leu Asp Asn Thr Val Leu Leu Met 35 40 45 Tyr Phe Gly Phe Cys Ile Gly Gln Tyr Val Gly Ala Lys Lys Ile Ala 50 55 60 Val Asp Lys Asp Ile Lys Glu Gln Lys Ile Asp Ala Gly Leu Asn Pro 65 70 75 80 <210> 4 <211> 324 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF57 <400> 4 atgtccgata atccggtatt gaaatattgg cctatcataa catttattgt aactggtgcg 60 gtaggtttcg gcgtactcca gcagcaggtt aacgcaacgg ctaaagatgt agctgacgca 120 aaggtaaacg ccagcaacgc atacaacctc gcaaaacgta ttgaatcccg tgttgatgtt 180 cacgatgtaa aattagagta tcaggctgtt cagaatactc aaatcctttc cagcgtcaaa 240 gaacttaccc agtctactaa cgatctaaaa gtcgttatcg aaggtcttaa aaatcaacgc 300 cgtacagaag gtgacagaag atga 324 <210> 5 <211> 243 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF59 <400> 5 atggatatgt taagcatgtt tcgtaatgca gcgggtggta tctcgttaag ccgtgcgcag 60 gctgcgctgg gtttcctcgt ggtaaccggg atcctgattt accaggcggt tgatcagacg 120 ttagataaca ccgtgctgtt aatgtacttc ggtttctgca tcggccagta tgttggcgct 180 aagaagatcg ccgttgataa ggatatcaaa gaacagaaaa ttgatgcggg gttgaaccca 240 tga 243 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> Novel bacteriophage specific for Klebsiella genus bacteria <130> PDPB187324 <160> 5 <170> KoPatentIn 3.0 <210> 1 <211> 54880 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP <400> 1 gtaaaccata caagcacatt tggtaagctg taactaaaat ccttatttat taataactta 60 ctactttata acatagataa catagataac atagataata taaaaaagta taaaccctat 120 aaagataggc tagttaaact ggtaagctgt aacaaggtaa actaggaggg atttaaaagt 180 tatagggaaa tagtatgtaa actatgattt tctatgtttt caacaactta aagtatgttg 240 tagacaccgg gtggtaattt gtgcaaaata acccaaaagt gtaagaggaa actagcttat 300 gaaaatttca gaccgtgcta aacgtgcaag tctggagtta actaccaacc aacttagatt 360 tgctaatctg tggctagatc gtgcgaataa cggcctcagt aatgctcagt gcgttttaga 420 ggcttaccca ggacataaag acttaaacgc cgcacaggtc actgcacacc gtctgttgtc 480 gaatacgaag gtgttaaact acctcgacgc gatgggtagt catgcgctgg aatctgttgg 540 tgaatcgttg tcatctcgtg tcgaatggtg gaagcgtgcg gcaagcaccg ctgaagaatt 600 actggagcca ttttgcaaac gcgttgtgat cccaggcgag gacgatgacg aatgcaaaca 660 cctgtgggtg aacagcactg acgatatccc gaaccacctg caacaatacg tggtgcgtta 720 caaacgttat ctattgggcg ggtacacgct ggagacgcgt gaactgttcg atcctaagac 780 gcgggcgaaa gcatcagaga acttggataa aatcaccggg aacagtgttg agcgtgtgga 840 attgtcagga acggtgggta atgtggttca gagtgttccc gaaggtgcca gcattgaaga 900 tatcgcgcag ttatatcaga aggcgctgaa gtagcaggtt agaccgcctc aaattcagcc 960 ggaaaccgtt tgcgttttga cgatcggcgg ttaggtagtg taaaggtaca ggttgatata 1020 agaaagcccc ttacggggcg tttacgataa aatttaaagc acctgtttta ccagtgcgtt 1080 caacnttaca ttttcaacga tgactggggc gattttctta aattcgttaa tcattttctt 1140 gtctccggta gttcgttttc tatgaactaa caatacactt ccctgtgtaa tccgtcaaga 1200 attattttaa atattcatcg tcaccaggaa cacagaacat ttcccagggc atcttttcag 1260 ttacttccag ttccagatcg ccgcgtgtgt tttcagcgat aatcttcacg ggtacaccgt 1320 cataggtttt catttgtttc tggcctccat catcgcatca gcataggcgt aagcaccttt 1380 tgcgtaatag gaaaacgctt catccggggt attaaatatc ggctgatttt cggatgaatg 1440 agcgatcaac ccctgtaaag cagcaattgc aaactggtca cgaacggtca gtgttttctg 1500 gttaatttct tccagagttt ccgctgactg aaagtgggaa agacagtttt gaccttcaat 1560 agatttataa ccctgagagt gtttatgttc ggcatcacta cgtttcatcg ttgagcctcc 1620 ccgcccagac cagttacaag ctgtttgatc agcgactgca gttcacctgt catcagtgta 1680 aaatcagcgt cgaaccgcgc taacacatct tcatgatcga tatcgtcgtt ctgttcaatc 1740 agttcgtcgc agaacttcag gcgcgttaaa atcgcatcat tagttagtgt gaacgtgatc 1800 cgctgttgcc agtccagcgc cagtttagta acaacttttc cggcttcgat gtgcgttgcg 1860 atttcatcgc ttaccagatc ctgtttctta actttcgcaa taccaccatc agccaggatc 1920 gctttcagtt ccgccgcatc accgatcgcg aagtaatcgc cagggacttt accgagcttg 1980 atccattcag tcatcgtcag ttcaacaggg ttttcaatcg tgagcgggat aaccgggagg 2040 ctacccagac ttttacgcag cagtgcaagc gcgtcctctg ctttacgagc gctggacgca 2100 tcgacaacaa tcaacccgtt cataacatcg atccacaact gcgtacggct gtctttggta 2160 aatgcccgtg gtaataacga atgcaacact tcgtctttca ggctgtcttt ctctgttttc 2220 ttcagcttac gaccctgttc actttccagt ttagcaatac gcgcattcag ttcctgttta 2280 ataaccggac cgggcaggat tttttcctga cgttgcacgg ttaacagata ctgagtgtgt 2340 gaccgatgcg ccagggtctg gctgaaagca gtcgccggaa cccatccagt gcgtgccata 2400 tcgttagaac cgcacggcgt aaactggaac ggcaacaact gttgttcgat ggttaccagt 2460 tgtgccatca gcgacatagg gttaccgatg cgatagataa ttgcattttt gaagaagttc 2520 ataattattc ctgttcgtta aaagtagcga caatacgcgg taaatggttt tgaatttcca 2580 gtgaccaaac accacgtact ttggttaatt tccacgttac accgtctttt tcgtcatccg 2640 ggatagatac accatcatct ttataaacgg cattgtacgt tttacccacc gtaaaccacg 2700 gacaagattt atccacggtt aaacaggtga atccggttgg aaagcgtttc atggtgtcga 2760 taatcctctt agtttgtaat tcaaccgcac acagaacatt tcccaagaac ggtcgttaaa 2820 tttaaaacat gggtcaaatg aaccataagc ccagaaattg acatactgac cgcatgtttc 2880 acagtgcgta tcaatttcag cagcattatt cgcgactgtg tcggtaatgg tgtctttaaa 2940 ccgtgcacca ccacaatcag gacagcgaac acattcacca tctttgctgt aattgctgcg 3000 gatcgaccac aactttttca ccttcaatat cctctttaat aaccggtaca attctgcagc 3060 ggcagttgat cattcgttca cgaccgttat catcaaccgc tgccgggatg taagttacgc 3120 ctggttcaag ttcaatcgtg ggcgaccagt cgaaacggtt catttattat cccatttcac 3180 atgagcaatg attaaaccca atgcaaacat tccgcaatgt cccacaatca atgaccatac 3240 gggaacatca atttttgcac aggtcattga aatcggaagc gctaatataa aaaccgacaa 3300 tacgatcgtt aaacttttca ttttcggttc cttcttttcc gtgcatcgcg ccgggactgt 3360 gcaacaccag ttttacggcg cggctgtttg gtcggtaact gttgggttat ttgtggttgt 3420 gctgcccagt tttcatgatt actagcaact gaaccaacaa tactgagaaa gtggtataac 3480 cacggtgtat gtctcatacg ttcagcaccg caaaatcagg cgacaggctg cggtgatcgt 3540 gctgcccgga ccaggtgaaa gaaaaggtgt aatcgcactg ttcaccattg aacaggaagg 3600 ggatttgaaa ccccgtatcg tcggtaatgc gaacttttac ggggtattca gcttgtgggt 3660 cgatggcgac aatctggccg aaaggttttg ttttccgacg tgcgagaacg tcgattagtt 3720 gtggattggt gatttccaca tgttgaccaa catgatagat agacattttg ttgactccgg 3780 gttgtgtgta caaccagaag tctatcgggt aattcgtaat ccgtcaagaa ttattttaaa 3840 ccgtcctgta ctgtctatcg cgtaacagat accgttactg taaacggtgg tggtctgagt 3900 aatcctttga taatcggtgc attggctgcg aacacgtaaa tcatacgcag actgtatgac 3960 gaaccaggca accattattg ctaaaagttt taacacaaat ctgaacattt ccgcaccctc 4020 cagtgtttcc cccagagtag tgcggatttc tggggtggct atggggttaa tctgatttaa 4080 cagtgatacc agcagttttg aggactctgg tgcaatcctg aacaccctga cggtaacagt 4140 cagcacggct tgcatctttc ggtattacga tgaatgaagt atccggcaac tcaaccatta 4200 actgttcccg actggctttc cagccttccc acattacagc catcgtcaag aaccagaggt 4260 ttccgcattc actctttttg ttgtcgaaaa accaatcaat aaattctttc gacatgccgt 4320 ttcgttcagc caattcgtaa cgatcatctt tcatagtttg tgcaccttaa aattacagcc 4380 ggaatagcga tgtttaccgc acagtttaca gcggtgttct tcagtcgcgt agttgcgttc 4440 gtccccgtga atggttctga acagatacca ctgatgtttg caaaaaagac gcttaatgaa 4500 gttcatattt aatcatccac atgataaatt acatactttg catcattcga agtatcaacg 4560 gtcttaccgc agcgcgtatt tgaagtattg aatattcagg aaacaagcgt tccatttcag 4620 accatacttc atttgcatta tttttaacgc gacaaagacg gaccatcgcc atctgcattt 4680 cagcttcatc gtcttgtatt ttactcacta tcagtaaccc ctctttgact ggtattcaat 4740 tttgttcagc gtgttttgca cgatctgcca tgagcgcatc atgaacaacg acgcatactg 4800 tgataacaag acacaacgcg gctgaacact gtacgcggtg atcgtgtcca tatcatcagg 4860 tgtcaggagg aaacgccagg gtgagttatt catgttcaag ccgctccagc agttcgcgga 4920 tgttctgtag aacgtgttgc tttgtctgcg tcgttacaca aacaccatca gtacgcccga 4980 acgtattcag caccgtttga agtacctggt acatctgttc gttgtgtgta atagacgttt 5040 caacaaacca tgcagatcta accaaaacac catgaatcca gtgtaaatca gcatcacggt 5100 ctgctttctt cattttctca ctgctgatgg ctttactgat gtgacattta actaactcgt 5160 cgtgcagttc taatgcttct tttacggtaa aaccaccgtg cataattctt tcagtattca 5220 tcacaaaccc catattaatt taatgagcag ccagagagcg agtatcatta atgaaataaa 5280 agctggtccg tacatgattg cgaatgagtg tttcagtcgc cagacagacg gtatgtaaaa 5340 acaaataacg ccttgaaata aacaaacggc gaaaagtgtt cctaataatt tatccaatag 5400 ttcaaccatg ttactcaccc cgctgtactt tcaacctggt tagggaaatt taaaacttca 5460 tcgaagactg caccaatacg atctgcgctg ggaatgaaat caccacttcc attatcaaca 5520 gcatcacata tttcatgata acgggtcgca tcgaatagtg ttacctcaca atcaccaata 5580 gtggcaaatg caatacgatg tgatgggcat tgagctaata atttatttaa ttttttaacc 5640 catgcgcgtt cttctttagt aagtgttccc aataatttat ccaagagttc aaccatttta 5700 gtcgcctcgt tattagatgg tgacaaaata tctcttcaac ccgtcgcaac tagtctcaca 5760 atccccgcag gaaccactat caatcagata gtgcatcgtg tgtgatttcg tggagtgagt 5820 tacgctttat actcaccgta gcgcctgaca atcagcggta tcttcagccg gacattaccg 5880 ggttactaca tacttggtca ggtattttgt ctatgtgtaa gactatagcc gcacatctgc 5940 aatccgtcaa gaattatttt aaccaatacc agctacgata acccgtggta aactgtacag 6000 aactgttgga aacggaacct tacaatgatt aaattcactg gtaacattca caagtacccg 6060 cgctggcggg acgcttacgc agaggacgaa cggatctggc gcaagggtga acaacgacct 6120 gattaccgtc agtgttacct tgaccgtatc aacctgttaa accgtatgcg cacggatcgg 6180 gcgattgtcc cgatactgaa aaaatattat gaaactaacc cggtggcgtt catcctcgac 6240 tgggcgttta cttatgaccc gcgtaacgtt ggtacggaat acccgccgaa tatgccgttc 6300 tgcctatttg agcgccagat cgatatgatt cagttcgttt atgaagcgct cgaagataag 6360 gagaaagggt tatgggaaaa atcccgcgac tatggcgcaa cgtgggtagc ctgtggttta 6420 tccgtgtggg cctggcttta tcgtcctggt tcgtcggtag gttggggatc gcgtaaagaa 6480 acactggtcg ataaactggg ggatcctgac agcatatttg aaaaaatcag gcagattatc 6540 cgcgctttac cacctgaatt acgcccggtt ggataccgtg aaaaagatca cctgacgttc 6600 atgaaatgta ttaacccgga aaacggatcg acgataactg gtgaggcagg ggataatatt 6660 gggcgcggtg gtcgtaagtc gatttatttt ctggatgagg ctgcacacgt tgatcgccct 6720 gaactgatcg aagcatcgtt atcagctaac accaacgttc gtatcgatat cagttctgtt 6780 aatggtgtcg gtaacgtttt ttaccgtaat cgtaaagcag gtctggaatg ggaaccaggt 6840 aaaaagatcc cccgtggtaa attgcgtgtc atggttctgg actggcgcga tcacccggcg 6900 aaaaatgatg aatggtacga acgggaaaag aaatcatttg ctgaaaaagg tctgcaacat 6960 attttcgcac aggaagttga ccgcgattac gccgcagcag ttcagggcgt gctgattaaa 7020 gctgactggg tgcgtgctgc gtttgatgcg ttccgcgatg tggaatggcg taaagcaaat 7080 ggtctgctca ctccacacgg taaacgtgtt gccggacagg atgccgcaga tggcggtgaa 7140 gatgcgagcg ccctggcgat aatgcacggc gtatttataa cctacctgca gcttgaccac 7200 cgtagcgcgg aactggcagc acctggaatg ctgcttaacg cgaacgtgca acagtgcgat 7260 gaatactggt atgaatcgat cggtgtcggt acaggcgtaa aagtagcggc gcacaatatg 7320 aagtcaacgt tgcggttcac ggctaaaccc tgggtgccaa acgctaaagt tgtggatccg 7380 ttgggcgata tcatcgcagg tacgaagccg ggcgataagg atcgaaaatg taaccgggat 7440 tatttccgtg attataaggc ccagtcatca tgggcgctgc gtatgcgttt taaacgaatt 7500 tacgaatggt acagggaagg taaaccgcag gatcctgatg agattattct catagaccca 7560 gaaatggaaa acgcgcaacg tctggaggca gaattaagtc aaccaacgta ttcaagtaac 7620 ggtgcgggta aaatcgtaat tgataaagca ccaaacggta ctaaatcacc aaacctgttc 7680 gacgccgttg ttatcgcatc atcgccgaaa cgcgtaatgg ttgaggaaga aggatttacc 7740 ggaaatgtaa accctattgg aacaccagaa tacggaagta ttttctaatg aacaaccccg 7800 gtttactccg gggttttttc gttgcggtaa acatctgcgc aaccatattt gttatcagga 7860 tggtaaacct gttcaacttt caacgacgcc tgacattcgt cccaagtaag aacgttatca 7920 ttaacaggtt caatcatcga cccgttaaga atgatcacta agacgtatcc gatcagcatt 7980 tgcgcaatgt ctcccgccag tccagaccgt gaaggtttac agatccgaga aaaagatgac 8040 tggaactttg taaccagacg tcatttttca tttctggttc ccgcaggtaa gaaaacacac 8100 taccgtttcg atctgttgca ataaaaccgt gactttttgg aaccattaaa acagtaccaa 8160 aataattaac cgctttatgt tctgcgattg attcaaacgt cattttacag tccggcgctt 8220 cctcgtggat atcccacgat ttaccgcaat acgagcactg atattcgtca ttacagcgaa 8280 tagcgtttac atggttcatt attcaacctc tctgattttt tcacctatga tttgtttcaa 8340 acgggtcaga cgacggcact gattgataaa tgcaccattt gaccacggtt gactaaaacg 8400 accagttgac acaggattca taagaccggg aattattact gaagcgtctg ctaaaactcg 8460 ttcaccatcc attgatattt caacgttaag gccattatca gggttgaaca tttgacaacc 8520 agtttcaaca cctgtaccca tgtaatgagc catacacgtc ataccctgga cagtcagaag 8580 ttgtttgtac tgttcgtaag tcattctaca gtctccggta caaaccattg tgaagcgagg 8640 taagcgcacc cagcgatctt gtgctcgtgt ttcggttcga aactagccag aatcactttg 8700 atatgtttgt gggcgtcttt gaaatttaca ccttttactg caacagcgta attttccaga 8760 ccattgtaaa accatttgct aatccatctg ttccacgggt tagagtcttt gaaaaactct 8820 tctgggatac tacccattgc cgggagaaat ttagcaaggt ttttaggacc aaaaacgata 8880 ttaccagagg tgatgttttc aatcggtttc atcttttact actcctgttc agttcatgca 8940 caaactataa ccgcacatct gcaatccgtc aagaattatt ttaaccccgt gcaaaactaa 9000 cctgtctgat ataacatacg ttaagaataa acccgtggag cctgtgaaga tggcagatga 9060 ccaatttgaa caactagccg ttgccggata cagtcgcaca ggcaaccagg ttaacgatga 9120 ctttttacct aaactcaacg gtaaacaggg tcgtcgtatc cttcgccaga tggcggagaa 9180 cgatgaaacg attggtggtg tattgttcgc catgaacagc gtttaccgtt ccgtacagtg 9240 gatttttgac ccatcagaca agaacgatcc gcaagctgtt aaatacgctg aatggctgca 9300 aaacaccatt gaaaaccaga tgggcgatcc gcagggtgcg ttacctgatg acacctggtc 9360 agcattcgtt cagacctgga ccgacaccga tgttttcggc tggggttggt atgacgtatg 9420 ggttaaagat ttaccagatg gttccgtggg tatcgcccgt ctggttccgg ttgctgctga 9480 aacgctcgac ggctgggaaa ttgaagaacc gacaggttat gtcactggta tttaccagcg 9540 tcaaccgtca accaatatca gtaaactgat cccccggtca agatcgctac acctgatttc 9600 atcaccgaac aaaggtaacc cggaaggttt atcactgctg cgcaccgcct atcgtccgtg 9660 gtattacaaa aaagtacagc ttgagatcga agcaattctg gcagagcgcg gaacaggttt 9720 cccggtcatc acagttaata gcgatattaa aaatgctgcg aacgatctga ccatcccgga 9780 agaaaaacgt aaagcagcac aggcgatgat tgataacttt gaaactatcg ttgccaatat 9840 taagcgcaat gaacagtctg gtctggttat ttactcaaaa ccctatgtca acggctttga 9900 cagtgagaca ggcgttacca catatggtgg tgagcaacag gttaaactgg aattcctgac 9960 ccctgaacag tctaatgccg tggatatcga ccggacaatc aaacgtctgg ataccagtat 10020 tgctcgtgca ttgctggctg acttcatgtt ttttggtaca ggtgggaata caggcaacca 10080 ggcaaatctg ggaagccgta cagaactgtg gatccgtgca atgcagtctc gcattgacag 10140 caacgttgaa tgtattaacc gccagttaat cccgcaactg tggacgttaa acgcgttccc 10200 ttcagaatac aaaccaacgt tacgtgctgg ctcaatcagt aaagacagta tcgaaacatt 10260 gaccactgcg cttacgcgtc tggcacaggc tggtgcgcca gtgttcccgg accctgtact 10320 tcaggagttc gtgtataaag aagctgggtt gccgacagcg ggtattgata aaacaggcga 10380 aggtttaccg tctattgaag attaaataaa aaggggtcta tagcagaccc caaattacca 10440 acgaccagaa cagaattaac atgattgcta tcagtaaata aactttctgg ttgtatgtca 10500 tatctacccc acgtagtttg caacgatttg atcgcagtca tccgtgttgc gggccagtcg 10560 ataaatttca gaagcaacct gtgaacgata atacatatcg acgttataat tatcattcac 10620 gtaattataa gccgcttcat aactaccgaa cattttgtga ttgctcacaa cttctttttt 10680 caccgaacca ttcattaacc agccgatcaa caacagcaac gcaccgatac cgggactggt 10740 taaaacagca atgaagaacc aggttccggg gttacgtccg gtacgtttag cgaaggcacc 10800 gaccagagcg ctaaacagga tccacaggat tacgaacatt tcaaacctcc ttaatcaggt 10860 attgatttaa cagtacacgt ccctgtgtaa tccgtcaaga attattttga aacgtcaaat 10920 acgggcggaa cacccatccc ggccattacg cgccgttgtt cgtacacctg acgcagtttc 10980 tgcaactgtt ctataccgat atcacaacca cggattatat cgtcgcaaag atcagtatag 11040 cttgcaccag cttgtggcgt ggttcgcgga tagtcaacca gcgacggatc cgtaatgatg 11100 acctttggga gaaacgccac cgtatcccca acgccatttt tcataatcgt cataagtcgc 11160 acccgtgata aagttcctga cctggttcaa ctttcgatcc gcaacactgg caaactaaac 11220 gccactcaaa accgggtgct gcttcaattt tacgataacc agcatcataa atacgcgcag 11280 catcttcaaa aaatgtacca cgaccgatca tacttgcaat ttcatggata gccgtttcac 11340 gttcgtcagg tagtggtttg aaatcatcgt cattaaccac aaacgattca gaaccatctt 11400 caggcttaac ccacacttcg ttaccgttga cgcccagtac gttaacagtg gtccattcgt 11460 tgccgttgtt ccactggcag acgataccaa caggtggtaa acctctaccg tcccatactt 11520 gtttcataag ttttccccaa taattgcagc acagttaacg atcgctaaac gggttgcttt 11580 ttcacgatct tctccgtgtg gagtaagttg tttatagcga acaccagtat ctggattgtt 11640 cactaaaact gcatagtctc taacatctaa gtctaaatac agatgtacca ttaaactgaa 11700 agcatcaccg ttatcaataa gcgggttcca caaacgacca ccgccgatat cgatcccttc 11760 gtttacgtca cgttcaccat acgcgatgta atacttaccc gcgatttcac cagcacgggc 11820 cgcattgatc agcaattcac gattagtcat catttacgcc ccgttgatcc aaaaccgcct 11880 ttacgttgac tttccacgcc gggtaactgt tccacttcaa ccacagttac aggttcaacg 11940 cgttctacca tcagttgaca gcagcgttcg ccatgttcca gcaagaacac cttgtgggaa 12000 tggttaacca gggtaatgaa gtattcgcca ggataatcgc ggtcaccgac acccacgcag 12060 ttaatcagcg tcataccgtt tttcaggctg aggccagaac gagggtaaaa tttgatacag 12120 tgatcagcat cgacagacat tttcaggcca gtggggatca gtgcgcgttc gcctgggtaa 12180 ataccaataa taccctcaat gggttttcgt tccagtttag cgcctgcagg cgggtagatt 12240 gttacggttt cagaccacag gcacgcgcga acatccatcc cggcgctatc agccgtttcc 12300 cgcgttggga tcacagccag gttagtgagt cgttgaatgt aaagattaga cattgcttgg 12360 ttcctcgttg tgtttcgaca cttgcaatac tgcgttctgt agtgtaatct gtcaagaatt 12420 atttataacc aacgaggaac gaacgatgaa tcttttcgac tggagtaaag cgcctgactg 12480 ggcaacctgt gttgttatac gatcaactaa taaatttagc actgactatc attggtcaga 12540 aaaaccaatg gatggtgctc gcatgatgag aattgaaaca ggtactagtt ttttaatgtc 12600 taaagtctta tggtggacag taattgaaca tcgtcctaca cgggtcaatg atataccaga 12660 gggtgacata ataaccactg tgtataaacc aatgtcacct gtagacctac atctgtcaca 12720 ttcatttacc ccagtagaac aaccatcaac tgcaccagaa ctgttgaatc aggccgcaca 12780 acttctgacc gaacgtggta aacagtacga caaatcaggt gaagaacgtt cagcggctgc 12840 aatcgtcgcg gcgtttaatg cgatcactaa acgcgattta acaccaggtg aaggctggtt 12900 attcatggtg ctattaaaag cagttcgttt ctattcaaat actgaaacgc cacaccgtga 12960 cagtctggaa gatatgatcg cctatgttgc gttgcacgct gaggaatatc tgaatgataa 13020 gtgagttgca ggcgtttcac cttatggtaa aacacagcat gattatcatt cactgtgacc 13080 gtgataaatc ggtattcact gatgacttac aatatacgga acagtgggtt aatgatttcg 13140 ataaacctaa agccacatgc cgtttaattg aacgtgtggc gcgtgacctg ggggaacagt 13200 tatgaagggt tttccaggtg tatattatag taccactggt ttttcagcag gcgttcatgt 13260 aaatcaaaag aaatgtcatt taggggtttt taaaactcca gagcgtgcaa gtgtatcagt 13320 gcgactgttt aaatactggt taagaaaagg ttttaaacct gatgaaatcc cacggtcatg 13380 tgtaacacca atgaatcgtg aaccggatta taaaccagtt gaaaattata aaatttcaac 13440 gatcattaaa aacaatggtg aatataaatt agacaccata gatctattaa atctcgcaag 13500 agaattacag tcactaaggg tttataaata tggtcggaca aaagcgctca gattctgaat 13560 tacttcgcga tctggaactt gattatgaac gtgcattagc agcagtagaa cacctggaag 13620 aacagatcag ggaagtgaag aaccgtttac aaggggtgac taaacgtgaa tttcagtcat 13680 aatttagaac gttctgcaga atatagcggt tatcctgcag atcatccgaa agtgatcggt 13740 gtacatgagt ttatcgatat agttgtaaca ttgcagttgt gtattgcgat gaataaagat 13800 aaaccaaata cggcgttaaa acgttgtgca caggtactga aacaacgaat gacaatgcca 13860 aacacaatca aaatgcttga cgttgttctt tcacaaccat tcccatcagg ctatgttgcc 13920 aaactccagc gcctgctgat cgcaaccgat cgtgaagttg gtcaacgcat gataaacctg 13980 tgatacaata agcctcagta accacgctga ggcttttcta tgaaagaccc atacccggac 14040 attgctgata aatatgacct gcggatccgt gaagcactga acctcgtgtg ggaaaacgtg 14100 cgccgtagtg agtcattagc taaccttgag tacattattg aaactcaggg tgttagcggg 14160 ttactcccca ttcttgatac tcttcccgat gagttgagcg cacagttacg gcccgttatc 14220 gaaaatgcga tagctgaatc aggtcgtgtg gtcgttcagg ttttgccgaa agcagcggtt 14280 acagcacccg tggttttcag cctggttaat ccccgtgttg gtgcatacat caataactac 14340 gttggacaga tgatccgcga agtaagcgat gaaacggtaa aagcggttca gattgctgtc 14400 aatcagggtg ttatcaccgg gcgtaacccg cgccagattg cccgtgattt tcgttccagt 14460 atcgggttaa ccagtcgcca ggaacaaact gttcaacggt tacgtgctgc gcttgaaaaa 14520 ggtgaagcag gctatgtgaa cagtttaacc acagttactg acagcgcaaa aaacgctgta 14580 agcgccggga aactgtctga aagccagatt gataagattg ttgaacaaac ccgcttacgc 14640 tacgtaaaac aacgcacaga gacaattgca cgtactgagt cattacgtgc aacatctgtt 14700 ggtcaggatc tggcaattcg tgaagggcag atcaccgggg ctatcagcaa cgaactgtta 14760 aagcgctggt tatatcgtca cgatacacgc actcgtgatg cacatattag cgccggggaa 14820 actaacgggt ggattccaat gaacagaccg ttttcaacac cgttagggcc gcttatgttc 14880 cctcgtgacc ctaacggaag cgcatcgaat acgattaact gcaggtgccg ggtacagtac 14940 agtttgccgg aagatatcgg ttcactgggt tgaacaggta cagcgcccga acatagccag 15000 actgattgga gacggatcag caggacttga gacagaatcc gtgtggtaaa cagtcccgcg 15060 ataaatcacg ctgaaaccat tctctttaat cagcatgagt tttcctgttc gtgcagtcat 15120 tcgaatactg ttacctgttc gtttctcgat cacaaaatca actttatcac cgactttcac 15180 aggtgttggt tcaccctgat agccgttaca tacgttacaa cgtttcatgg gcgcttacct 15240 ctgtaattac gaacggaaac ggcttttgtt tcatcaattt caatttcctg aatcttttta 15300 ccagcatgtt catcataatt atcacgaaag tcatcagcca gcgttgaaac cggattgctt 15360 ttccgaccac ctgctgcatg aagaacatca tttaccaagt cgggattttc cttaaaaatt 15420 acaccttctg tttgaccacg attccacacg attgtgtatt tgctcatttt taatttcctg 15480 aataagtttg aaagcatagt cagccatttt tcgatcgaac cacggcttct gtgtttttgc 15540 gtaacggtat gcattattgc cgtaaacaga gtgcgccccg taactgccaa actgacattt 15600 cggacactcc acccccgtgt taaatatcca ctcgcaagag gcgcatacgc gtagtttggc 15660 agtcatcagc gttactcctg cttttcacca cagaacgggc aataagacat tttcacgtta 15720 gtttctaatc gcgtgaagtt cttcgccagt tcgccgtttt tcttcggtgc acgatacgcc 15780 aggcgatatt tcagcatgac gtacatgttc ccggatgaca gccccagaca ctggttatcc 15840 cagcccactt tgtcaaatat gttggtactg acttctgcgc cctgcggcac tttttccatc 15900 agtcgttgtt gaagttcgtc accaagtttt ttcatgcatt cgcacattac cagccacctt 15960 tctttaaaag aatacgttta gtttcagggt gaggatgacg gtagttaacc agttgttccg 16020 gcatactcat aaatttattg tttttatctt tgaccgtgac aaaacaggaa tgaacaccaa 16080 acgcaccagt gttgattgtt tcgtcgtatt cgtggagaag ttcggccatt ttttcctgcc 16140 actcttttgg catctgcatc atagccacac ggggcataac aacaaacgcc gcataagata 16200 aaccgaacca cccgtgcagg tcttttcgat cgtcatattc catcgccttt accttttcag 16260 ttaagcaccc gttattgggt gtgataacta taccttcctg tctgcaatcc gtcaagaatt 16320 attttaaatc ttctttcatc ttaccaaact ggtaagccgt aactcagcgt catagatgac 16380 atagatagta tgaaagagtt atacagatct ggtaagccgt aacatagatt gcatagtttg 16440 cgcatactta tttttaacaa atttatcttc taacttactg tttttattat cttttacata 16500 tttatcatag atagtataga tttatataag aattataaaa gtaaggtaag taagggttag 16560 tagggtaaga tctaaaagat aaggaaaaca gcatgaaatg tatgatacta tgcacccgtg 16620 gttaactcgc gaggaaacac ccaatgatcg aagttaaagt taacaaggtc gatccacagt 16680 tacggatggt tttcggctgg ggttcgattt gtaaaaaacg gaatcaggaa acgggtcagt 16740 tagaaattta cactgacacc gataacgaac aattccctga agatgtaacg ttaaaagcat 16800 ggctggattt catgaacggc gatcagcgga tcatggataa catgcataac gagcaacccg 16860 tgggcaaagt ggtgttcgct tttccgatga ccgaagatat cgctgcaagt tttggactgg 16920 ttgaaaaact ggatcaaaca ggcgttattg ttggtacgct gatcaccgac gatgacattc 16980 tgaaaaaatt tcagtctggc gaatataccg ggtatagtat cggtggaact gcttactatg 17040 aggacgttga ataatgcgta ctgatggcac taaccattta cgccgggcgc ggtcaatgaa 17100 aattggcttt ctgtccggtg tgaccaaacc agcgcatgaa ggcgcaaacg cccttatgct 17160 taaatcccac ggtgaaacac ccggcgaagc cctgctgaag tctgcgttta gtgcggcgct 17220 tgctgaacag cagctggaac agcaggtgaa ccagtttctt tctaactcat gggtgcttaa 17280 tgaagcgctt cgcgagtcag cagaggatat tgcaaaagac gattcagtta ctgataaaca 17340 agcagcattg cgtgacgcag taaatgaata tattataaca atgcagcagg ccgctggtat 17400 ttcgcttaat aaagcgaatg gtggtaaaac agaaggtggt gaagtattcc cggcatccga 17460 ttacgcttat gtaccggact cggaaaaacc ttcaacctgg aaacttcgtt taacctccac 17520 gcccggcgga aaacctgatt cacgtattgt cggtgctgca ctggctgcat taggtccagg 17580 gtatcgcggt aataaggttg aaatccctga agctgattta gcaggtgtga aaagtaaggt 17640 tcgggccgcg tggaaagaat tgcacccgga tcaagaaatc ccccaggttt taaaaacggc 17700 agaggaaatt gaaatgtccg aactggaaaa atacaaagct ctggctgaga tgagcgatac 17760 ccacaaggcg tatcatgacg ctctgcctga aaccgatcag gaagcgttcc gtaaaatgga 17820 cgcaaccgcc cgtgacgctc tggtagttat ggcgaaacag gctgacgaat ctttcactac 17880 cgtagctggt caggaagtga aaaaatccgt agctggcgcg atgtatgacg ttctgaaaac 17940 tcaggacgaa cagatccgca aagcacaaac cgaagcggca ctggcgaaag ctaaagaagt 18000 agtgaatacc gactatgcgc atattccggg cgaagttgtt cagaaaaccg ctatggttat 18060 ggcgctggat aaactgccgg aagcagatcg caatttcctg gtagaaaaac tgaaacaggc 18120 cgataccctg tggaaagagc gtaaaacgcc tgccgcaccg aacggtggta aaggttctac 18180 tgcgtttgaa gatctgatca gcgaatacat gaagaataac ccaggcaaaa cccgtgcaca 18240 ggctatgcaa gctgttgcat cgaccaaaaa aggccaggaa gtgatcgaaa ccatgcgagg 18300 tgatgaataa tggctactaa cagcaaaatc tactggaact acgagcgccc gacccgtgct 18360 gttgccagcg tagcgatcgc tgctggtgtt ggtctggtgc ttgataccag tctgggcgac 18420 accaacgcgt gcgtaccgaa atataaactt cctgatgctg gcggtcgtat cgacggtgta 18480 gcactggacg atgtagcggc taatcagttc tttgatctgg ttaacgaaaa agaaaaattc 18540 gttccggtta aagcggctgc ggctttcggt gtcggtgttg aactcgcagt aactgccgct 18600 ggtaaattcc agactgcaac cacgggtcaa ctggtcgtgg caatttccca gacccaggcc 18660 accgctgcgg atcaggttgt tacggcttta gtccgtgcgc catacgctaa agcataatca 18720 ggagcaaatc agatgagcta taaacagaat ttccgcgacg ttggcgcccc ggatctattc 18780 ctgtccaact tttcagtagc ctactggcaa gatacctctc gctttgtcgg tactcgttat 18840 tttccagtag ttccggtaac tcaggctgca ggtaagtatc ttacctaccc gaaaggttat 18900 ttcggtcgcc cggtaaactc gaaacgtgct gaagatggtg ttgctaacac gatcggttat 18960 aaaaccaaaa accagggcta caccgtcgat gacgatgcga tccgtatttt tatctctgat 19020 aaaaaacgtg cgaacgtcgc aaacggtcaa caactggata tggaagcaac cggtgtcgtt 19080 accgacgcgc tgctgatcaa taaagagatc gatttcgtat ctaagttcct ggtgcctggc 19140 aagtgggcta ccgattatca gggtgttgat gcaacaccga ctggtaacca gttcctgaaa 19200 tggtctaacg ccaactctga tccgatcggt gatatcctgt cacatcgtgt ggcgttctct 19260 ctggctactg gcggtcgccg ctggaacaag gcgctgatga cgctggatgt gtacgatgcg 19320 ctgacccgta acccgtctgt aattgaccgc atcaacggcg cgtcaaccag ccagaatccg 19380 ggtattgtga cccaacaggc gcttgcagca ctgctggaag ttgacgaaat cgaaatcatg 19440 caatccgtgg ttaacatggc tgctgacggt ctggaagatg ccgaaggtaa cccgctgtcc 19500 gacttccagt ttgcggcaga aggtgtactg atgctgaact acgtcgaacc gaccgtaggt 19560 aacatgaaac cgatttcggc tgtaaccttt gcctggaatg agtttgcaag tctgggtatt 19620 gataatggcc cgtctatccg tacttatccg ggtgttgaag gtcgtcgcgg taactttgtt 19680 gaagcagagt ttgcgatcga tactgaaatg gttgcaccgg atatgggtat tctgttctac 19740 gacgctgttt aacagtctgc cgtaatcaca aaggggtggc taacgctgcc ccttttgctt 19800 atgtgaggtt tatcatgaaa aagaacgaat ttgatccgtc agccacatat cggtttacac 19860 gccctatgaa atggaacggt aaatatgttg gtacgggcac tttattaccc gaagatggta 19920 caccgatcgg aatcctgcgt tccctgttta agatgcgtca gattgaactg gctgacggtt 19980 ccgaaccgga acagcaaccg gaacagcaac cggaacagca accggaacag caaccggaac 20040 agcaaccgga acagcatggc gcagtagctg aaatccgtaa tgaaggttct ggctggtaca 20100 acgtctacat gggcgggatg ctgatcagcg agaagaaatt acgtaaagat gacgctgaaa 20160 aatggtgtga agaaaaaggt ttgacttaca atatttctta acgtattgtt agttcaaggc 20220 gacggtgatt agatagaact gcatagcaga cgctgttgaa aaccctagcc tttatagtcc 20280 agacgatatc tgagtgactt aaaaaacaga tgggagtcgg tggaatcccg gcacacaaca 20340 ggttagagca ttgagccgat aatcgtgaag agtcggcgtg cctggttagc cagtgctctt 20400 tccgttgtgg tgaagtataa gatggcagtg ctgatgaatc ggggacatca aaacccttga 20460 tccgggtctt atggggacgg aaacaacgcg acttcagcca ccacaacacc ccggatagtt 20520 ggctgagagg ccgaaagcga tcggttgcta accgatagat cggaaacggt ccacaggttc 20580 gaatcctgta ctatccgcca aattatgcga atcacaccga cgggaggtga tcgctatctt 20640 gctggcgggc aagccgcaaa gcgtgggtaa agcacgttgt gaaacgtcct gaactgcgta 20700 aagaattaac ccagagccaa gcaatcgtta gccgtctgtt taagacggct ttttttcgtg 20760 ctaaaataat gaaaactatt ctatacaggt gaccacatgg caatcacagt tgatggtatc 20820 cgcaatttaa ttaacgttcc tgatatcagt gatgaaacaa ttcagtggta catcgataac 20880 ggatatacta acccgttaag catctgtatc gccctttgtg attacatggc ttcactggtc 20940 agtaacgata ctgatattaa agttggccct atctcacttt ctggtagtga tgcagccaaa 21000 gcatggaacc tgcttaaaaa agatttcatt ttacgtttga atactggaac ggatccgggt 21060 ggttcagggt ttggtttagg gttcggcgtg ggtggtatta cattgactgg tcagggtatg 21120 ccacctgcta ttcaacgcgg gcagttcgat aacccgccga ttacgctgga gaatagcagt 21180 acgcgtatca acgaaggtga acagtaatgt ctgatcaacg tagccgtgtt ttagcaggtg 21240 tgactcgtgc actcgcagaa gtgggtgaag atctgactgt atcacgtact gtaaccacac 21300 caaaccccag caaccctacg ttacccggtg taacagaaac cacggttcat agttgccgtg 21360 gttatgttta cccgcttgaa aaatgggatc catcgaccat gacacgtaat acagtgacaa 21420 tggttattat ggacacgaaa tcatttgatc caccttttgt cccagagcgt ggcgatgttg 21480 tgactgatgg tcgtggtcgt gaatatcgac tgttagatcg tcaaaaccca cgattactgg 21540 gtgacgatat ggcgtttatc catcctacag gtgctgcata atggcacgta acgttaatga 21600 tataaatcgg atcactggtg tctttaaaga cataaaagct gatttacagg atttcacgaa 21660 tcgtgaagtg atccgatatg ttttaacgtt acgtaatatt ttaatcagtg aaccacctac 21720 aggtacacca gtagacacag gatgggcatc aaataactgg tggttcgatc aaggtcagcc 21780 agctaacagc ccatcaactt catctggtga tgtggcaacc agtaaagcgc gaattgaaca 21840 ggacactata acgatcagca gtattgttgt taatggtcaa tcgctgcata taacgaataa 21900 cgttccttat attggtattc tgaatagtgg tagtagttta caaacaccat caggatttgt 21960 agatcgtgct attttaacag ccggaattat ggtgaggttc aatcaatgaa tatctctgat 22020 gtatccgggg ttgtttataa tcgtgttctg gataatctcc ccgtggagat aacaccagat 22080 cgctttacga ttgcgtctgg taatcttcct gacgatacaa cagggaaacc cggacttatt 22140 ttaacgcata accccggccc gtgggcgatt acaaccctgg gtggggaggg tgtttgtcgt 22200 cggcgtttac gtaccggaaa tgtgttttta caggtgcgta ctcctgcaca atacggaatg 22260 gatacgttaa gtcttgatat tgctgaccga ctggcgcgtt tgtttgaggg gatctggcag 22320 gatcgcccgt tactttatac aggtgttgat gtaagatatg tgggacgtga taatgcctgg 22380 ttcctcgcga atacggttat cacttatgaa tttgaagaag tctattagcg aatgaggaac 22440 caaaatggct gagtcaattt ttaactgtaa tcaggccagc gctgcagacg ttaacgcaac 22500 ccgtctttct gtggctaaag tctgtgaacc tgtcagcggt acaccctgga ctgtacagca 22560 acctaacgaa atcagttcat actctgctga cattaccaaa actcaacgta ccccgattag 22620 cactgaccga tccgcgcgga aaggcactgt aaccaacatt gaagttgcac caggctttca 22680 gactgatatc actctggata cgttccgtta ctggggtgat ggttttcttt acagccgctg 22740 gatgggtgcc ggggctatcg atattgatgt aatcagcgtt gatagcgaca gttacaccgt 22800 tgcgacaatg gcaagcgcat tgccagccgg aacattggtt tatgctgctg ggtttatgat 22860 ggctgcaaat aacggtctga aaacggttgg ttccggcagt accactactg atattaacgt 22920 gactggtctg gtagctgagg catccccgcc agctactgca cgtttatacg tggtaggtac 22980 agtcgctgct gcaggtgaca ttgcggtaaa cgccaatggt cagatcacat caaccacgct 23040 ggattttacc acgctgggat tgattccggg tcagtacatt tacattgatg gtttcaccca 23100 gaccgttacc agtaagttag cgcgggttgt ttcggtaaca gatcatgtgc ttactctggc 23160 aagcagtgag tttgtaaccg aagtcggtac agggaaaacc gttagcattt acgtatccag 23220 ttttgtgcgt aacgttccgg ttgattcacc ggatttcgtg aaaactgaat acacgatgga 23280 agcgcgttat aacaccgaac cggaaattta cgaatatgcc cgtggtgtca gcgctaacca 23340 gatgaccatc aacgcgccat tgactgaaaa aatgacaatg gatctaacgt ttgtagcaca 23400 ggatttgtca gaacctgttg atacaccgtt accgggttca ggttattatg atttcgttga 23460 aaacgaagcg tataacactg ttactaacct caatcgtgtt cgcctgactg ggatcgatga 23520 aagtggtctt tcaacatatc tgaaagacac caccatcacg atcaacaaca acgtgtcagg 23580 tgaaaatacg ctgggccgca tgggtgccac gtttactaac ctgggtaacc tggaagtcac 23640 cattgatact gaagcagtca tgactgatgg cgcggtgctt gcggcgatcc gtaacaacac 23700 taccgttacg tttgaactgg ctggcgttaa tggtgatggt gcatttgtgg ttaacattcc 23760 tgctatgacg ctgggtgatg gttctaagaa cctggcaacg ggtgagaagg ttaaagtgac 23820 cgtatcagga accgcgcatg aggaagcggg tctggacttt atggtaggtt tcagtttgtt 23880 cccgtatctg ccaactctgt aaaagaactg ccccggacta accggggctt tatcttcact 23940 tgcgtaattc gtacagaact attactattt acctgtcatc taacataaca ggtaaacatc 24000 atgtccaagt ttgatcatct taaaaaagca ctttcaccgc tgatcctgaa agcatctgcc 24060 gaactgattc tgaacgaaaa tttcaaaatc accgtgctga acctgaacac cactaatcag 24120 gtgtataacg ccgcagttgc ggagtatatg aaaggtcgcg cagcgcttcc tgaagatttc 24180 tttgagcgtc tctggaaaca ggaatacttc ccacaggggg ttgaattcgt tgctaacgtc 24240 ctgatgctgg attgggtgtt attatcagaa gatgacacac ctgaaccgtt cagcccggaa 24300 gaagcgatcg aactgatgag cgatgatcgt ttcggtccgt ctatctacgc ccgcgtggtt 24360 cagttctcga ttaactccgc gatgtttaaa gacgactggg agaaacagat cacaaaaaac 24420 taattgactt cctccagtgg aaccgaaaaa cagacggtga tgatctggac tgggttgcac 24480 agggggctgc ggcgcgtggt aaggctgttc cggcagtagt tcagaatcgt cccgtgttgc 24540 gtcctgacgc gatattttac tggaatgctt accttgacct gatgacggct gaatggggta 24600 actgtgagcg ttatgcacgg tgttataacg ttgatgttca gttcctgtgg tcattactga 24660 ttaaattacg cgctgttggg tcaaagtagt cacggggtca cggttgagtt aaactattcg 24720 tatcaacgtt tcaggaggtt tgaccgtggc ccaatatcct atagatataa agttagatac 24780 cgggtctgct gaccgtgatc taaaaaatct taatactcag ttagatcaaa ctgagaaatc 24840 aactattgcg gctgcacagg ctgctaacca gttatctgct gcggatcaac aggtcgctaa 24900 agcatcccag caattagccc aacaacaagt acaacaggct gctaaagcgg ctgctgttgc 24960 gcgtgctact cgtgaggctg cacaggaaca atcacgctta ttagccacac agggggctgc 25020 ggcgcgtgct gctggtgaaa cggtcaataa ccaacagaag tttgcagatc ttgctaaaac 25080 aattaaacaa gcaactgctg atgaaaagaa agcaattgac gatctgacaa atagccttaa 25140 aaaactggat agccagcaga ataatacaaa ccagtcggca cagaaaacca atactgcatt 25200 tgacactatc gcaacaggtg ttaaaggttt tatcggttta caggtggtca gtaccgtagc 25260 tgaatggggt aaggcgttta tcgataccgc atcccaggtt gaacttttac agagtcgcat 25320 tcagctttat tcaaatacat ctgttgaagc aacacagatt tttcagcaac tagtacaaca 25380 ggctaaccgt gcgggtacag atattaatgc tgtagccaac agttttcagc gttttgcggc 25440 tgctggtaaa gatgccggga tcagtaatca ggttattctg cagttcaccg acaacctgca 25500 gaaaatggcg cgtatttctg gcgcatcttc acaggaagca tccgctgcta tctaccagct 25560 atcacaggcg tttgcatctg gtcgattaca gggtgacgaa ttcagatctg tttcggaaca 25620 gatgcctact gttctacaag tgttagcaaa acagttaggt gtaactacgg gtgaattaaa 25680 acaaatgggt tctgaaggac tcattacccg tgaccaaatg ttactgttaa ataacgccac 25740 cgacgatatt aacgcacagt ttgaccgtat gccgcgtaca gtcgatcagg ctgctaccgc 25800 attgcagaat aatctttccg tggctatcgc cgaactggat cagcagatcg gcgcgtctaa 25860 atttctggcg aaattcctcg atttactggc aggcggtgta tccggggtta ctgacctggt 25920 caaagccgct ggtgaaattg ataaaatggc gcaggctaca aataacctga atgccgttac 25980 cagtcaacgt gaatcgaacc tgaaagagat cgcggatctt gagaaacaga ttcagaatgg 26040 ttacaccact caatctatcg gtgggtatac caaatttgtt aacagcactg ctgatgcaca 26100 aaaacggctg actgagctta aaaaattaga tgttcagtta acaaaacagc aggcagacgc 26160 acagcgacag gtaacacagg ctaccccact gggtaaaggt gttgctgaaa atctcgcgtc 26220 acaggcaagc cagttagcat cgctgaacaa aagtgtcacg gctgctggtc gtcctgatgc 26280 agatgcagcc aaacagatta aaaacctgca ggaacagttt acctatacta aagcgcttgc 26340 cgatggtaac tacgaactgg ccgctgctca aaaactgggt aataaagcca ccaaagacca 26400 gatttcttct tacgctgcgt tactgaaaca gcaggcagag tataagcaag gtcttaaaga 26460 cgataaaaaa gcccagtcag aggccgcagc ggctgctaaa cgtgcacaga aagaactgga 26520 acgtaatcag gctgcgaatg aaaaatattt aaaaacactc aacaataaag ttactgcagg 26580 tcaatatgat gttcagttgg cccgtgagca ggttcaatta agtctcacgc agggtgcatc 26640 agttgatcag cttacggcag cgtatcagaa gtcctatcag gtacagcagc agttaacgct 26700 acagtcacaa caggcagaag cacaatcacg cctgaataaa gatgctacgg acgctgaacg 26760 taaagctgta gatgaacagg ttgcagcgct tcagcgccag caggaggcta aacgccttgc 26820 tgcacaggtt tcccaggttc aaagcgatgt taccagtacg cttaacccag ttcagggaca 26880 aatggaccag attaaccagc aggaagcaca gcgtttaact gttgctgaac aggcacgcca 26940 acaggatctg attaacgaac agcaatacca ggatctgaaa acgcagatca tgatggcggg 27000 tgaacaacag cgcaatgatg taatgactgc taataatgcg atgttgctgg gtgcaactgg 27060 cgatcttttt ggtggtctgg ctgatgtttt aaagaatgcg caaggtgaac agtcaagcat 27120 ctataaaacg atgtttgctg caagtaaagc atttgccatt gcgcaggcgt ctgttcttct 27180 gtggcaaaac gtcagtaaag caatggcgat tggtttccct cagaacatcc catttattgc 27240 gggtgcttta gcacagggta catctatttt aactagcctg tcgtccgtgg ctgcaactgg 27300 gtttgcaacg ggtggtttag tcactggtcc gggtacaggg cagagtgata gcattaacgc 27360 acgtttaagt aatggtgaat tcgtcagtac caaacaagca acaagtcgtt atcgtgatac 27420 actggaatca atgaaccgtg gcacatatac accgggttct gagggtggat caggaactaa 27480 cgtacaagtt cataactatg ctggtgagcg tgtacaggtt aagcaaggat taacccgtga 27540 tgatgtagtt ctgatcatcg gtgaagaatt cccgcgtcag tctgccgcac aatggaataa 27600 cccgtacagc cagactaaca aatcattcag atcgaattac gatgtgaaca ggaaacttta 27660 atcatggcaa atactgacga cttaccacgg cttgaatatg ggggtgaaat ggttcgcccc 27720 gcccgtgata attataatta taaccctcca tggggtgcga ctaaatcaga tattgccggg 27780 acactatcgc ggctgggacg tagcgctttc ggtggtccgg ctgatgtttc ctgtactgtt 27840 cagttgcata gtccagcaat gcttcagtgg tgggacgatt tttataacct tgaaattgca 27900 gaaggtacga aacgcttcgt gatggaactg tttgttaacg gttttattca ggaacatgtc 27960 gtacagatcg tatcacgacc agcagcagtt acagtaggct ggaaaggaag tattgacctg 28020 cagttgcagg cagtaccaat tatcgatcgc tgtgctatgg catcccgctt gctcatcact 28080 aaatgtcagg gtgatcactc atcttgctat attaatgact tgattgaatt aggtttatct 28140 ctcaataacg cctggacacc agaatgaaag acgaactgaa agaactattg acagtcgcca 28200 caacgggtaa aggagtggtt gacggcataa aacttaatca tagttcctgg ccgcagccgc 28260 tttatatcac cagtgtttac cccggcttta cggcagtaca tgaagatggt ctggaatatg 28320 attacgaata tattcctatg tctgttaaaa aagcgaacaa gcaaaacgac ttatcacagg 28380 attatagttt cactattcag gatctgaacg aggttgtcgg ggtttatctg gacctgatac 28440 cgcttgatag tgaagaaaaa ccatcggtgg agttgcgaac cttcgtgtat cgtgaggacg 28500 gatctatttc tgatattcag gatggtccat atgtgctcga atctggtgat atcaccacag 28560 agccgcaggg gtgtacgttt acagctacac caccgataac gaatttttca ggaacaggcg 28620 agttatacac gtttgaactt ttcccttcat tgctggcata tacatcatga tcggtgatcg 28680 ttatgatgtt gataaatgga attgcacaca tgaagtcagt cagtggtaca gattaaataa 28740 ctatcctcat caattacaga gtatcaacag tagtgaatgg ggtgtatcgt tcgtcagatg 28800 gatgcgtaag cgttttacac cactggtcaa gcctgaacag ggtgcattag ttttaatgaa 28860 aaatcgctgt tctggtgggc ttcatgttgg tgtatgggat agcggtatgg ttcatcattg 28920 ctatcagcct cccggtaata caccaggaca aactataaga acacctctaa gtataataaa 28980 atgttctcat aaagacgtga ctttctggag aatgaaaaat gtctaaagtt gtttatcaca 29040 cagtgccgat tgaaaaagct gaaaatgttg attttggtga atggttgctg aaacgctggc 29100 ctgttggatc cgttcgcccc cgtggattac tgatttttaa aaatgacgaa aacattactc 29160 atgaatgggt gaataacccg tcagttttaa acgatcctga tgcaacttat catatttacg 29220 aattaccacg cggcggtatt gtaagcgcca ttacaggtgt gattggcgct atcctcaacc 29280 ctattttaaa aatattcacg ccgcagggta acgtttcgaa tgctacaata aacagtaaaa 29340 taaagtcgtc gaacaactcg ttacagggtc gttcgaacga ttcccgtccc ggtgaacgaa 29400 ttgcggatat tcgtggtatg gtcagagcat acccggatct gttaatgaac tacaatattt 29460 ttaaagacgg cactgagttt gaatgtcagt ttctttgtct gggcgctggg tcatatgtta 29520 ccgatgaaat cagcgatggt gtaacgccca ttacaaacgt atctggttct cagatttcaa 29580 tttatgaacc aggaactgcg cctgggtatg gttcaccttc aaaggttatc aacggggtta 29640 ttgatattgc atcattcccc gtggttatcg ctaaagaatc gaatgaagtt gatggcgctg 29700 aactattccc gccgaactat gccgatgtta gttccgggaa tgtaacctat acaatatatt 29760 ctactggtca aatagatgcc gtcagcaatg atgatgataa ccctattaac tggtctgatc 29820 gtgtagcgat tggtgatgat tttgtaatat caggttttat ttcactagaa gaacaaatag 29880 tgggtggtgt accaacaggt ttatattatc tacatgattt aagtggtaca tatcaggtta 29940 ctggaacatc tgatgacggt gtattactag acgtgtctgg aaattcgaac tggtcttttc 30000 tttcttccac tggacaggca ccttatacga ctgtttacga tgttggtggt ggtctgtact 30060 cattaagtgc ttcatctggc ggtactaaaa ttacttataa accgagtatg gatacaaccc 30120 gcccttatag tgtcggcccg tacttaatga ttaattcacc gaaaattctg gtgaatgctt 30180 acgctcaaaa cggtatttat cgtcgtcgct attacattac cccgtttgat gtaactttgc 30240 gtgtaaccgt atctaattat gataatccgt cagatcctga atatacattc gactttgtag 30300 ttaagggatc gacaagtgct acaggcgcgt ctttattatt tgataatcct tatccagatg 30360 cagcgtttat caggatgcaa cgtatcacag atacaacatt aaacgaaagt atttcaacaa 30420 tcgatactgt taaatggcgc gatatgtatg gtatcactga tatttcaccg cgcagttatg 30480 gtaatgtcac aaccattcat tctgtaacta aagcaacgtc agcagcttta aaactaaaag 30540 aaagaaaatt aaacatgttg gctaccagaa tttataatgg tagtccaagc agtaattttg 30600 ccgatgttgt tatgtcaatg catcttgatc cgcacttcgg acgtcgtgat ctatccacaa 30660 tcgatgttga tgctttatat gccgtacaac agcagttact tgattacttt ggtgatcctc 30720 gtgctattca ggttggatat acgttcgacg ataacgggac cacctatgaa gaagcgttgc 30780 aaaccatttg taatacggtc aacgtaaccc catatcaggt gggtagcgtg ctttactttt 30840 ggcctgagtt accacaatca gtatctgcaa tgcaatttgg gcacgcgttt aaagtgcccg 30900 atactgataa acgtacccgt gcatttgcac cacctaaaga atacacgggt gttcaggtta 30960 aatactttga ccacgatgaa aaatcatatc tttacgttac gatcggcgaa gaaactaacc 31020 tgaataaaat agatttagtt gcctgccagt caaaatatct ggctacaatc cgtgctaatc 31080 gtgagatgaa taaactacgt tatcagcgta ttacccacga atgcaccgcg cttagtatcg 31140 ggttacaggc tactcccgga atgcgcgtgg atatgatcga taataccaga atgaaacaac 31200 atgaaggtgt gatagttgat gttgatggtt taacactgac gttaagtgat cctgttgatt 31260 ttgttacagg taatacatat tcaatcacga taacaggtcg tttaggcacg cttgaaaaca 31320 tcccagtttc acccggtgat gatgaattta ccgttgtatt acagtcagca ccgacagaag 31380 aaatatacac cgggtggtta caggatcgga ccaattatat catcagaacg gatgatgaac 31440 gtagtaagct ggcaatgctg gtacagacta tggaaccttc aggcgctgac aacaactatc 31500 aggtaggttt aacgtgcatc aactacgatg cacgttatta tcaggacgat gtttaattag 31560 attttgaaga tgtattgttt aataatacat cttcaatcct gtccagacgt ctgcgttgat 31620 atgcagtttc catagcatta cattcatcca tcaccagtct ccactggtcg acggcttcag 31680 ttgcctcctg gataaccccg taaccggctt ctttaacaag aacttgcgtt tccggagtta 31740 ctacatttcc atccgcatca tattcagctg gtacggtctc ataaacagca tcccatgatt 31800 caacaatagc gtcctgtgct tcctggtaaa catgtacaat taacccccac tcagtagcat 31860 cttcaccagc agcttcaaat gcttcaagga tatcctgggc aatatatcct acatgccacc 31920 gtgcagcctc ttcccctttc ccagcaacgg cccaatcgta cttataccgc ttgatgctga 31980 tagtgcccca tatatccagg atgttatcag gaatactttc ctgaacaggc ttatgtctcc 32040 tgtcagatac aacggtaaca gcattctgcg tatagatatt gttccatggt aacgctgctg 32100 taccaagatt ataggtagct gccgcagcag gctgtacacc gcgcgttgtt gctgtccggg 32160 tgagcgtcaa acctccggca gtcaccatcc ctgtagcggt gagcgtactg gccgatacgt 32220 tgttaaagtt cacatcgcct ttggtgctgt atgccggtaa taaactttgg tttataacca 32280 gcgtatcccc ggcagccccc actaccgcat cgagcacata cttgttagtc gcggttccat 32340 tgctattcat cactcgcgca tatacgcggg tagcgcctgt atatgccgtg gaagagccag 32400 acgccacata tgcagggatc cccattgcga tatacggaag gctgcctgat ggcacagtaa 32460 tcgtagtgcg cccgtttgcg gaatccactg agtctactgt cacattaaag gtctgctgat 32520 actggctacc caacgtcatc ccgctggtga tgatttgcgg gatcggattt cctgtcgcgc 32580 ccagcgtcgc attgtacttg tagtcgttgg agtgtttatc gactgatatc cacggataaa 32640 cgatgtcacc tggtttaaac agcccaccac ccggagactt gatgtagcca ttggtgtagt 32700 taccgaatac gccagccata ccagattccg gcttgtagga taatccggta gggaatacag 32760 gtacaccacc agtaaaagcc tgaatagctt tcagtacgat tggcttacca gatgcaaccg 32820 tgataaccag gttctgctgt ggtgtgaacg tgcctacgcc gtcgttcgcg ttccacttga 32880 cgttcgggat gatcgccagc ttatagccgt taccgaagtc gatacagcct tctccgcgcg 32940 acatcaccag gttcccgtca actgacggcg tttccagccc tgcaattgat tgccagataa 33000 caaaatttac cgggtcaaag ctccccgtta agtctttgta ccagatacag atattagacc 33060 tgtatgcagg tgagtgcatt gggacataca acgttcccga gtttacctgt aacccatacg 33120 gactgataaa ctcttttgtc tctttgtaat cccttagatg gtcaaaatcc acactcccgg 33180 ctgcaccgcc atacagcccg taggttccat atttaaagtc atatccacca tgcaggaaag 33240 ctcctacatc atgaacaggc gcaccaatac gcgtaaagtt tatgccgtta tatgagaagt 33300 tgttgtcgtt gtataactct gggtacaccc agttgccgtt ggcgtcatag tgtccaaaac 33360 acccatcctc gaaagtgata tacgtccatg aggaaaccgg tttgtactgg tgtgcgatcc 33420 catcaatgat aaggcccagc gccttcgaat aggttgggtc acccatctgc ttactaacaa 33480 cgaagagatt aggggtgtgt tccaggtagt tgttagtgaa agaatggcca cggcagttgg 33540 tgtaaattac acccttacct gggcgttttg tttcatcaga aatctgcccg tggctaacgg 33600 tcaggttcac cccagacatt ctgaaacccg cgccagtgac taccaggaag tagtctggtc 33660 gtttagcatc tggtccttca atccaggcag caccatcaca caggcttcct ccttcccatg 33720 tggaccagtc agtcataatt tgggccaaac cttcacgacc ccaatcgagg aaaacgtttt 33780 tgcaatacaa cccgtagaag ttaccaaaag taacaccagc atcactagat gttggcaagt 33840 cggttgtaat caggccggaa ttgataaccc cactgtttgc cgggcgggca accaatggaa 33900 gctggaagcc gcgcgcgtgg atattctcaa gggtgacata ctccgggtta atcaggaaga 33960 atgccgagcc agcagaacat acagattctg aaagagaaac tttgtggtca ccaataattt 34020 tagcattaga aattttggta tacccggcag ctaccgcacc ccaatactcc tgcttcccaa 34080 ttgccgcgta aacttcgtcg atatcttcat acgagtgctc gaagccatta agccactcac 34140 ctgtaactga gcgcttatat tcgttagcag catatacgta tatcaccgac cccgcacaat 34200 cgtaatcggc gaacttgcgg aatttagcac ctttcttgga gattcggtaa ctgcccccgg 34260 ttattttaat ataaactttc tgagcaacta ccggcgctaa caggtcatcg ttagacagtg 34320 aatatgtgtc tgttgggctg attgtgtaca gtatgccgtt aatagcttgc ccaaggcagg 34380 tggtgcttgc cgcacttaca tctgaaatga ggctggagtt atctccgcca gtgacacata 34440 ccgcaccatt gcttcgggca tcaacgtcgc ttccgacatt cactttcagc tgatattcga 34500 caccgttggc gttgtaaatc ttcgcctgag tgataaggtg ggttcctgct tttgatgcgt 34560 cagtgtttcc ggtagctacc catgtaccct cccctccatc attaggagaa taaaatccac 34620 gaacacgaat ggatgagtac gtgtcggttg aactgagtac agctgataca gatggcagcc 34680 actggcctaa ctggtactgc acttgctgtc ggatatcatt atctccgata gctacaagat 34740 gaagtgaatc gctcgcccag gaagtagaat cattcccggt tgtcgtaaac ggaacgtcag 34800 tattggcagc aagtcggtac gctactccat tgtatacggt tacctggctg cgatttgtaa 34860 atgtaactgg cccatcaata taatcattca gccacgaata gcctgatgct gcgagcatat 34920 cgttgaattc gtctctttgt tctgtaatct gagaaacaaa ctcgttttcc tgggagatca 34980 actgatcatt aaatcttgtt tgttgttgat caagttgttg attaaattct gtttcacgct 35040 catcttgcgc agtctgaaac tgtgcttcca ttccgtcaag tgtcaagttc gttacttgct 35100 caccacggat agtatcagtt acagttaaag catgtgcacc attagcatct ttgcttttag 35160 caacatgttc aatgtgctgg actgcttgtt tacctgtttt aaggtcgtca gcattgatat 35220 aatcactgca attagccatc ttttaaccct cgtgggagtg tggaacaatg tccgataatc 35280 cggtattgaa atattggcct atcataacat ttattgtaac tggtgcggta ggtttcggcg 35340 tactccagca gcaggttaac gcaacggcta aagatgtagc tgacgcaaag gtaaacgcca 35400 gcaacgcata caacctcgca aaacgtattg aatcccgtgt tgatgttcac gatgtaaaat 35460 tagagtatca ggctgttcag aatactcaaa tcctttccag cgtcaaagaa cttacccagt 35520 ctactaacga tctaaaagtc gttatcgaag gtcttaaaaa tcaacgccgt acagaaggtg 35580 acagaagatg agcacaggta acgcatctgt tgataaaatc attgatacaa ctattggtca 35640 cgagggcggt tattcaaata atagcgccga tcgtggtggt gcaacaatgt ggggcattac 35700 agagactgta gcacgtgcac atggctacaa aggtgatatg catttattac cacgggcaac 35760 tgctgtaagc atttatgagg ctgattactg gttcggtcct cgttttgatc tggtacaaaa 35820 agtttcaccg ttaattgcgg ctgaactttt tgatactggc gttaacatgg gtccgtcagt 35880 cccatgcaag ttttttcaac ggtggttgaa cgttttcaat aatcagcaaa aactttaccc 35940 tgatttaatc gcagatggtc agatcggacc acgaactatc aacgccctta aacagtactt 36000 aaccgtccgt ggtaaagatg ctgaaaaagt catgctgcgt gcgctgaact gttcacaagg 36060 taatcgttac ttggaactgt cagaggcacg ggaagcgaat gaaacgttta cttatggttg 36120 gttacttaat cgcgtggggt cactctgatg gatatgttaa gcatgtttcg taatgcagcg 36180 ggtggtatct cgttaagccg tgcgcaggct gcgctgggtt tcctcgtggt aaccgggatc 36240 ctgatttacc aggcggttga tcagacgtta gataacaccg tgctgttaat gtacttcggt 36300 ttctgcatcg gccagtatgt tggcgctaag aagatcgccg ttgataagga tatcaaagaa 36360 cagaaaattg atgcggggtt gaacccatga gtattcgcag cgttgttatc acgataattg 36420 cgcttttact ggctttagca gcaggtggta taacctgtta taaggccggg tataaagcgc 36480 gagtgaatga agaaaaacag gaaaagttaa acgatgctca acaggagcag ttacgtttaa 36540 aagcacagca acagttggct gataacgttt tacgtggtct tgctgactgg tcacaaaata 36600 ctaaaatcgt ggaaattcgt catgaaaaaa ctaatactgt ttttcgtaat gagtgtctta 36660 ctcctgaata tcagcgcttg tacaacgaac gagttaccga agcagaaagc cgtttatcag 36720 gccgcactgg ttcagaagtg tcagaccgaa aacctgccac ggctaaacgg tctgacggga 36780 actgattcaa ctgatgtgaa tgatttgtgg ttggatattt atttcaaatg cgcttataca 36840 cacaacgcat tagtagacag ccttcagtaa ttcttcaacg ctcacttcaa cccatgacac 36900 cgggacagga tattcagtcc gatacatgaa cagggacgtt ccaatcagac cgttaggatc 36960 cgttttaatt ccctgcattg cgataagcgg caagaactgt tcacgcgttt gtggcaaccg 37020 tgcaaagcgc cccgtgggac gtttcgccgg gtccataggg ttaaactcaa cgattgttga 37080 cataagcaat cctctgttta gctatttcac aataatgtgg gtccatttcg aaaccgataa 37140 aatcaaaacc ctcaattgca caggctttac cagttgaacc actgcctgtg aatggatcca 37200 gaactttacc gcctggtggt gtaacgagac gtaccagcca ctgcatcagc gctgtaggtt 37260 ttaccgtagg atggttatta cgtgcgccag atgtacgccc ggcacctgca cgagggctgt 37320 ttaacccgtc agtatcaggt tcacggtctg tcatttcagc agcggtcacc atcgctaaca 37380 taacaccttc atcacggtct gatttgctcg ctttagcaca gtagaagaac cgcgcagcac 37440 tccctgaatc actgtagaac tgacctggta aacgatcgtt gaatttacca tagataccgt 37500 tagtaacttc actttgttca gtccctttga cgggtgcagc agcgccagct ttcgccggga 37560 acaggcttac aacttcatct gaaccatcgt ggataaagtt tgcgggccat cggccttgtg 37620 tgtcaggctg gttagcagtt gacggattat aattatcaga caaacctgtt attgacggcc 37680 taccgtttgc agaggattta aaatcgccat tcaattctgt tcgacaatca tcaatattca 37740 tcccacccgt accgaacttc aggacgtttt cagcaacatt tcctgccagt ggtttacgtg 37800 caacgcaaat tggctcgtga gcaggtttca aagctgttcc ccatccttgc cattgttttg 37860 cttcgtcggt gactggtgct agaatatcag gaaccccacc gacatatgtt ccgtaatcat 37920 tatctcccgc atctgaacca aatgatcggc tattgtgtct tgcgctctta ccgatcactt 37980 cactacgttc agcgcctgcc gctttatcaa tagccttact cacgtctaac gatttaggga 38040 aaccagaacc gtaaacccaa tcaatttgat cgcggatttc aaatcctgct aaacggattg 38100 cgagcgttcc caggtcatag gtacgtgttc cgaaaaacgc caacaggtga ccacctggtt 38160 tcaggacacg gaaaacttct ttccagattg atggacctgg tacaaagcta tcccacgttt 38220 tacccatgaa accaccacct gtatgaacat agtcatcacc gtttaaccaa tggcgtaaaa 38280 cttcgttcat atcaggttgt ttactgagtc cgtaaggcgg atccgtcacg actgcatcga 38340 tactattatc agcgatcatc atacgcatac cgattagaca ttcgagatta atcaccatgt 38400 gggatactct ccacgctgta ataaacgggg atccttaatc gttcagcctc tgcgatttca 38460 gcaatagtcc catgcgaacg acggtaatca ggaagcacca gaacagcgtc acagcggcgc 38520 ataacttcca gtgtccctga caggtagtat tcaggctgaa tgttgcgtaa cccgccgtca 38580 aagtcccata gttcggtgtt cttgtgtggg ataaccggga accattcagg acgctctaac 38640 gtcagacgct tacccatttg ttcagcacgg gacacgttac gggaggtttt aagcgcacat 38700 tcagcacggt aaggcccggc aatatagcaa agtttcatta tttgttttcc tgcatttgta 38760 agaatacgat catcgcagcg cggagtgggt ttacgtcagt gacagcactg tcacttgcat 38820 aaaaacaaac gtcaaaatct ccggtaatcc catcaattac ggtatcaacc ggtgccgcaa 38880 tccatttatc attaagtgat acgatgctta tcttgttagc aacaataatc ggccatgcat 38940 ccgctgggtt gttgcaataa tcccttgaaa aaccaccgta accattatgc atatagacaa 39000 tggatgtatt ttgtggaaac gacttatttt cgcattctgg tgattttcgc aaatcatgcc 39060 aaaaaacatc acaaatcatc ttgttaatat caaagtcact caacttactg taatcagtca 39120 tgacgtttca ttccttccaa catatcccag atgatagcca cacggcgcgg gttagtgctg 39180 atcgaatgca gggtttcgca cccgtggtga tagccccaac gaacagataa ttctgataac 39240 aggtaaccgc gagtattagc cagttctgcc agttcacccg gcgcgaaaat agttgtgttc 39300 ggttctgtca gaacatgcga tccgaaaatt gcgtcagtga tgcgccacgg tttcatgagg 39360 tcgtcaacca tgtaccagtt actgatactg atttcagaaa caccccagcg tgcagccagt 39420 ttcaaacgtt cctggcgcgg cgggaaaaca ggcattcgtg gtaaacgcag ttcggtaagt 39480 tctgcaggct caaacagcgc gtcatcggtc aaacggaatt caccacggtc atcgatatag 39540 aaaccacggg atttcccgtc gcggataaaa ccatcaacgc gattgtaaac tttacccggc 39600 gtaaacacgc caatggtgga accagaaatg aatttatgtg aagtatgcat tgtttatcgc 39660 ctcagtaagt tttaaataat tctatacggt ttaccgtaat ggcgcaacca gcttttcagc 39720 ctcttttatg taaaactcat agttcagcgt tgtccggttg aagcgctgca tgttgttaca 39780 ttctgtcact gtccagcctt tgcatactgc catgtgtcgt tctggtgcgt taggatccag 39840 tttaagattt ttagccagtg gtggcatgac tttaactaaa ggtgcaccat cagtgctgac 39900 gtaataacgt gtaatgtttt gaacctgctg atcgccacac attaatttgc tgttgcgggg 39960 aactttcgtt accagcatga aatcgtgaat atcttcatgt gttgttataa acttacgaat 40020 atctttgcca tataccagtg cggcttcagc agcttttgcg acaacctgca tactgtggtt 40080 ttgatgccaa cccaaatcac catttttatt ctgttcagtc ttagttgtgt ggcaatacgc 40140 acctttgcgt ttaacctttt ttccaccttc atacactgca atatagttat tcacatcacg 40200 gataaacatc acatcataaa ttgcttcttc taattccagc cgtgtaagtt tttcccaagc 40260 gtgacgaacc tgttcaactt gtctagtgaa aacacgagga acataaacag taagaccatc 40320 agtatttgcc tgaatcattg aaagaccagg gattttcatc aactcttcgg ctaacatgca 40380 aagtagtaac tgaccgttga tagtaatcgc catcgtataa gctggatcat aaaatggact 40440 atacacatta ttactgtcac catagacacc gttcagtgcg agtttaagca ttgcgttttc 40500 cggtgtgcct tttggataac cagaacgcat atcgtaaaca tttttataaa taatgcagaa 40560 ctgtttaccc aaatgttctg gaaaaagctc attactgatc gccaggttag ggtaaaaact 40620 tgcaacgtcc agatcgataa tcacatagtt ttcagttgaa cggatggttt gtgattcaat 40680 agatccgtgg atgccacctg taccaaaatc aaatgaaaag ccgttaatag tagcgctcag 40740 atcagtaaat acacctttag tttctgtaat gacttgctga cgtaaccagt ttaagacacg 40800 gttgaattca ggctgttcaa aatgaatgta agggaatata acatcgttaa gtgcaataga 40860 tgatctgata gtttgccgtg gtcttttgcc tggtcctggg tgataacatt caatgccgga 40920 tttttcaagt tccataatga aataatcttt gccgatttta gtatcattat ggttcatgaa 40980 atttcgatta tacttctcgg aaagttcacg gcgaaaatct atcaactttt tactgtgacc 41040 atgaaacatc aaagtagctt taaggtcgtg tatcaaatac tgacgaagtt tatcaatttg 41100 ttcatcagtc aaataagtac ccggtgagaa tggcagatct tcaatatttt ccattctcat 41160 attgaactca agcgttttta aacttgttct ttttgcctgg ttatcaaagt ggtgaatctt 41220 ataaagatcg atttgtggaa caatccagtc actttcccac accatgtgag caaaacgatt 41280 atcatcgcca cagttaatga tagcatcacc tttacgataa atatcagcat tagtgatgta 41340 catgatatta ttgagtatcg aatgttgaac agggtagtca taaccaatgt tgttataacc 41400 cacttcttca gcaccatgtt cacgaagaaa ttcagtgaac atataatacg cctgacgatc 41460 atcgcggcga tgcgagattt caaatatata aggcgttccc gttaaagcgt gaatagcacc 41520 aaataaccac acgttagggt aattttcaat atcgtaaatg taagcgtctg acatagtaaa 41580 tcctgataag taaatggggc gctatggccc catgtctgtt taaagcggta tgtcgtccca 41640 gttccagtaa ctatcagtaa ccgttacccg tgagaaaccc tggcgcggga gtggtcataa 41700 ccatgtaacc ctgatcaatc attgcctgat ctgtccagcc acctgcaaca aactgttcat 41760 aagttgcacc acccgctttt tcagtcatca ctttcacagg tgctgccgct ggtgtaggcg 41820 ctgctacagg tgctgccgct ggtgtaggcg ctgctacagg tgctgccgct ggtgtaggcg 41880 ctggtgtagg cgctgctaca ggtgtaggcg ctgcgccgat cgcagtagcg cctgctggca 41940 ttgctggtac agcaccaaac acagaagcag gagccggacc agaaatgatt tcttcacctg 42000 cgtatagcag ttgcgccatt tccatattga tatacatccc cgcctgattg ccagtacgac 42060 cattaggaga cgttgagccg ctaatacggt aatagtagcc ttttttggcc tgatttttat 42120 cgatcacagg ctggaattgt gcgttataca acgggcaagc atcgatcgcc acgttgcgtg 42180 aaaatccgat tacccagtga ccagggtaac ccgtttttcc agcatgtttt ggatcgtcac 42240 cattcgtgat tttccatgca aaagttggtt gttgcgtttc accatttaca tagtgtgcgc 42300 cagcagcttt caaaattgcc tggaatacca cacccagttc accttgttct tcccaccagt 42360 tcgcggcggt tttaggaaac gccaggccaa cccaccagtt gtatttttca ggtgcgagcg 42420 gtttgttttc atgatcgctg gtattcatat caaagaacga gccaccaact agacgaccaa 42480 ccggagtgac gaatttttca acaatcttag ccatgttact taccttttat aacggacgtg 42540 cgccagcggg catcgtcgca ggagtattaa aaatggattc agccattgtg ctaaaaccag 42600 ttcgagcatc ggtatcaggc actaacgcaa actgaccttc aggtttcgtt gtgcacatat 42660 caaccagttc tttcggtaat gttttttcca gagtagccag agttttcaat ttacgttcgt 42720 aaagcgtatc agggttgaca ccaaacatag gcgcaatacc aatcagtttc ccttcatcgg 42780 ttaactgacg tttcgtttgt ttcggagcca gtttaaaacc gggtaacggt ttaccttgtc 42840 gaacgaaatg caaaccctga atgtgcaacg ctgtttttgc atcgcttgcc cgtgaataaa 42900 gttcctccag aagcagtaaa cgttgtccca cttcttcagg ggttaatgat ggtggtgcat 42960 ccagaacggt agccaattct gtgatcctct cataaagagc cgggcataaa ccacgggccg 43020 ggcaataatg acaatgttca ccaacaacca acggtgcatc aattttgtga gcatcagcga 43080 aacctttttt aaaccgatcc gcccactcca ttaacacgcc gcgtgaaaac tgccagcgcc 43140 ttacaggccc gtcaggatgc cacgcacggg gttgaataac ggtgaatacc acttgtttaa 43200 ctgaactaat acaccgttga tcaagcgcat agtaaacacc ctgtgagtta ccaacagcat 43260 caatcgcctt atgcccgtat ttgtaatccc agatatacag ggtatcagtt aaaaaatcgt 43320 accagcgata atcacagatc ccgtattgcc ccggcaacaa ccagtcaatg tggatgcgaa 43380 cttctgaaaa cagcggatcg acttttgcac caactgataa aatatcagca atgaattcat 43440 cagcatgttc atgcatatca tcagttacgg taataccgtt tggtgcaaca caaggcatta 43500 gtggtgactt acctttaatc ttttgttcaa gcacccagtg agccgcttta ccttcatgct 43560 tgctttgact taaaggttcg tcaaagtcga tccgctgtga cagttgaacg ctacccggac 43620 aagataacca acgtttagaa ccactggcac taaaggtagc gttgcgtgtc atcagaagga 43680 tccgcccata tttttgctga cttctgcctg acccagaata ttttcagcat cagcaggtgt 43740 ctggttgata cgctcgatca ggtcgattgc agatttcagt tgtgcaggat cagacaacgc 43800 catgatattc tgcgtgttat acagtgccag gatacgctga ctaatcggcg cggcgcgatc 43860 gccggtgatc tggccgaaca tctgcatcag tgcagactgc aacacctgac tgttgtaaac 43920 tttcgctggt tctgattcca ctggcggaac gttagccgga gcagccggaa cggtgttcac 43980 tggtgctgct ggaaccgggt tagcgggtgc aacaggtaca gcaggagtcg gatcgactgg 44040 cgcaacataa cccggcgcaa gttcagcggg tccggtataa cgtccggctg ctgcggcttc 44100 tgcgatcagt tcgcgtttca ctttgtccag gaaaacttca tccagttttt tacgctgacg 44160 ccacaggcca tcgcctttat tgatagattt gctgtcagtg tgaatacgcg gatcgtggcg 44220 cagaccccat gcgtcgaatt cgtcggtgct ggtttcacct tcttcaccgt catcagatcc 44280 ggtaactggc gctgctggtg taacgatcgg taagttggga tgctgtgcag cgattagtgc 44340 ctctttggcg acaccatcac cagcaactgt cataagcggc gcggcaccag tagcaatagc 44400 atttgccaga ttgttgatcg cagtttccag acccggagcg gtgataagca atttaacttc 44460 aaacatagtt ggttccttgt gtggttgatt ggttgctacg tggctaaggt tacgagtcag 44520 gttgcaatgt gtcaagaatt attttatgat tatttcacat tcaaaacgga gataaaccga 44580 tgattactga tctgtatagt ttcattcgtc ataacgtatt tttcgatcgc gtaacaggta 44640 agtatgtttt cagaggtcgt gagtttaaac gaaacggaca agcacagaaa gccgcgcgtg 44700 acgcatacgt taaggagaac cgcgcgtgag tcaacaaccg ttacgttact atcagcagga 44760 tgcggttaac ggtgtgaatg ctgaatggga cgctggtaaa aaagatgtga tcctggtaat 44820 gcctaccggg agcggtaaaa cgcgaacgat ggctgaactg gttaaggttg acgggataaa 44880 agtcattcag gcgcaccgta aagaactggt tagtcagata gcaatggcta ttgctgcaca 44940 gggattacca caccgtttca tcgcgcaaaa agacgctatt aaatttgcta ctggtcagca 45000 gatgaaaaag ctgggttaca gcacctacgc acccggcgca gatatcgtta ttgccagtgc 45060 acccacgctg cgaacaaaaa aatacgaacg ttggcacgat agcgtaaccc gtgttttttg 45120 tgatgaagcc catcatctgg tacgcggcac catgtgggga acctgtcgtg agcttttccc 45180 aaaatcttta ggattaggcg taactgcatc accgatccgt gcagatggta aagggcttgg 45240 acgtcatgcg tctggctatg ctgatgcgat ggtgattggt ccggcaatgc gtgaattaat 45300 caaccagcag cacctggcag attatcgcct gattatggct gaaacagata ttgacctgac 45360 agcggatatg atttccagca ccacggggga ttacaagcca tctgcgttga aaaaggcaat 45420 ggaagattca accatcgttg gtgatacagt gagtacctgg aaaatgtacg ccgacggtat 45480 gctgacggtg gttttcaccg ttgatgttga cgcggctata acactggcac aggaattcag 45540 ggacgcgggt attcctgctg aggcaatcag ttcgcgtaat accgatcagg aacgcgccga 45600 tattctggac cgtttcgaaa aacgcaaaac cctgattatg tgcaacaatg atctgttcgg 45660 ggaaggttac gattgtcccg caatggaatg tgctgtaatg gacagaccca cagaatccta 45720 ttcgttgttt atccagcaaa tgggacgccc gttacgctat gttccgggta aaaaagcact 45780 catcattgat aaagtgggta acgtccggcg ctttattgct cgtgggtttc ctttacccga 45840 tcaacattac aactggtcgt tagacgaccg tgatcgtaaa tcatcgagcg gtggggcaag 45900 taatacaacc tgtacgaata aaggggatgc tgcaaaaggt attgaaccct gtctgaaacc 45960 ataccctgca gggcttgctg cctgccctta ctgtggtcat gtgccggaaa aagcattacg 46020 ttctggtcct gatcgggttg agggtaattt acgcgaacta acccctgaag aactcgaaga 46080 actgcgccgg gcagtggtga ttattgaccg tgacccagca gccgttaaag accagatgtt 46140 acacgctggc gcacccgctg ttgcagctta cagcgcaatg aaaaatattc aggcgatgaa 46200 tgatgcacaa cgtaagttac gttccatgat aaccacatgg gctgggttac agcgtgataa 46260 aggtatttca cctgatgatg cttatcgtat gttttatcag gtatttggcg ttgatgtact 46320 cagcgcacag gcgttacaca ctcgggaagc aaacgagttg tcagcacggg ttgcaggaac 46380 tatgatttaa tggtaatctg tttagaatta ttttaaacat aaggttgaac gaatgcagga 46440 tctgatgatt gatattgaaa catgtggcac gaaacccggt tgtgcggtgc tttccattgg 46500 tgctgtatat ttcgatcgca aaggtaatat cggtgaacag ttttacgcat cgatgggttt 46560 tagcgcgttg tcatacggta atgctgatgt tgacataatg cgttggtggt cgcagcagtc 46620 tgaacaggcg cgtactgatg cgtttggcgg gactgatgac ccacgtgaag tagcacaacg 46680 ttttgcaaaa ttcattcgtt ctgatgcgct tccctggggt aacggatctg tatttgatat 46740 taccatttta gaagcatggt ttgatgcggt aggtatccgc tgcccgtgga aattctggaa 46800 tgttcgcgat gtgcgcacgg cggtggattt gctgggtatc aatactaaac tgtttatccg 46860 tgatggtgtt tttcataacg cgctggatga ttgccttcat cagatcaaat atctcaccag 46920 cgggactaaa catttatgac accacttgaa caatgggcga aacgccacgg tgtcagccag 46980 atggcactat atgaactgta tggtctgttt cagccggacg ggaaaccgca tgaagatggt 47040 gttagcgagt cagcaacgtc taaagaatgc gaactgatcg cggcccgtgc gggtcagcgt 47100 ctctggcgaa acaacaatgg cgctttacag aatgaaaaag gtcagtgggt tcgctacggt 47160 ttgggtaaca ccagcaagaa gatcaacgat gttatgaaat ccagtgacta tatcgggatc 47220 aaaacgttga ttatcacccc tgctgatgtt ggtcgtaaaa ttggaatgtt tatcgcggct 47280 gaaatgaaag agccaaactg gcacatgacc cccagtgata aacgcgcaca ggcgcaggcc 47340 acttttggta cagttgtagt taacgcaggt ggtgaatttc gtttcatcac ccacccctca 47400 cagtttgaac aatggatgaa agaatgaata acgaacgcgt aaaccgtctg caaaaattga 47460 tcgatactca cgggattgaa aacgttgcta aacgtatgaa cgtaagtgag atccacatta 47520 aacgtaatct tctcacaggt cattcagcaa tcaacctggt aaaactcatg gctgctgaac 47580 gtcagttcgg agcgtagatc atgatggaga gaaaatcact tccatcacag gattacataa 47640 aaaaatgttt cgtatacaac gaagatactg gtgatcttgt ttggaaatac agaccgcaaa 47700 accattttaa aaattccgtt ggttttaaaa acttcaacaa tcagaacgtg ggtaaaatcg 47760 cgggttcaat agttacaacc aaagagggta atcgttacag aagtgttaag ataaatggtg 47820 ttttttattt tgcgcacaga ttggttttca agctcttata caatgaagaa cctgattaca 47880 tcgatcattt aaatgggaac ggcattgata accgtaaagt gaatttagaa aaatcaactg 47940 ctcataaaaa caataaaaat caaacactta ataaaagaaa taaagaaaat aaaatgggtg 48000 tttattggcg tgaggaccac ggtcgttttt gtgcgtcaat tggttataaa ggaaaacaaa 48060 ttcacatagg ttcttttatg agcaaaaaag aagccgtaaa ggcccgtgaa aaagctgaaa 48120 aagaactctt attttcttcg aatcacggga gacttagaac atgaaaggtc tgctgaaccg 48180 taaacagtgg atttgttgga ggctggaaca cgttgaaggt cgcccaaaac ctaccaaagt 48240 accttacagc ccaattcacg ggtataaggc cagtacaaca aaccctgctg actggtctga 48300 ctatcatact gcgctgggta tggcgcaaat gtatggtatg tcaggtgtcg gtttcgtgtt 48360 cactgaaaac gatccttatt ttttcattga cgtcgataac tgtctggtag accaggctac 48420 cgctacatgg tcgccactgg cgcatgaatt tgtaaaccgt ttccccggcg cttatacgga 48480 agtaagccag tcaggaacag gtttacatat catctgtgcc tacaccagtt taccggaagg 48540 tttcaacagc cttaacgatc agaaaaccgg acttgaaatg tactggcgcg atcgttttgt 48600 cgccatgacg ttaacaggga acggtgaagt tgacgttgat tatacacagg gcgttcatga 48660 ctcaatcgcc cggtatggtc gtattcgttc cgatcgttca gcacactgga ccagtgcacc 48720 ctgtgacgaa tggtccgggc cggaagatga tgaagaactg atcgcaatgg cgttaaagtc 48780 gtcaagtgcg gcttcagttt ttgggaataa agcatcgttt gcggatctgt ggactgcgaa 48840 tgttgaaaaa ctgtctgtca gttacgccag tgatcaggga aaagactaca acgcgtcagc 48900 cgctgatgct gctttgtgtt cacaccttgc tttctggacg ggtaaaaact gtgaacgaat 48960 ggagcggtta tttaataaat ccgcgctggt tcgtggtaaa tggaccgatc gccaggatta 49020 ccgggaaaca accatattag gcgcggttga acgttgcgat accgtttatc gtgcgcaacc 49080 agcactgaca caggaactga ttaatgctgt tacgccagcg cctacagtag ctgttactgg 49140 tggtgttccg gcatatatga ctatcagacc tggtgaaggt gcatatggtg ctaaccatac 49200 cgttaacgcg tcaacgttcg ttaataacta ttatccgaac aacacgctta tttttgtaca 49260 gcagcaaccg taccgcttta acggtcgcgt ctgggagcgg gtgacagaag atgaattaaa 49320 acatcagtta tctatggcaa tgctggcgag cgaaccaaaa gctgatgtga ttaatggcac 49380 atataaagtt ttaagctatc tgtttacccg tgccgatcgt gagttaggca cctggccggg 49440 cgttgatgtt tcacactata tcgtgtgtca aaacgggatc cttgacgttc acacgagaaa 49500 atgtgaaccg cacaatcctg atttcttcac taccagtatt ttaccataca gttacgatcc 49560 gtttgcacag gcacccgttt ttcaggaatt tctgaatacg acactggaag gcgatcagga 49620 acgtattgca ctgttgcagg agtggttggg ttatatgctt gttaactcct atgactatca 49680 gaaagcaatg ctgatgatcg gtgcaccacg ttccggtaaa ggtacaatcg gccagattat 49740 acaggcgctg gtaggtgaag aagcgtatgc agggatcacg ctcgaaggtc tggcgaatga 49800 tgcaatactt gaaactgttc tggataaatc agtgttgttt atcggtgatg ctcacagtgt 49860 ttccgggcct gaccgtaaca ggatccttga ccgctttaag tcaataactg gtgctgatgc 49920 gatacctgtt aaccgtaaat ataaaggtgc gtggaacggt cgtttaccag gtcgtatgac 49980 acttgccgcg aacaatattc cggcttttgc ggatgattcc ggggcaatgg ctaaccgtct 50040 gctgatcctg ccgtttaacg tgtcgttcct caatcgtgaa gatatcacct taaaatcacg 50100 actgatgaag gaattaccgg ggatctgcaa ctgggctatc gaaggtctgg aacgtttacg 50160 taaaaataac cgcttcacag aacctgcagc gagtatcgca gaacgtcagg aaatcatgga 50220 ccagcaggca ccgttaatgg cttttgtgcg tgactgctgc gaactgctgc ctgatagcgc 50280 tactcacact gaagaacttt tctgtagata taaaatgtgg aagatgcagg agggaggcgc 50340 aaccatgact aaaaccgcat ttagtcgggc gtttaagtca atgcttcgtg ggcgagtggt 50400 taaagatgtg gtatcagtca atggtcagcg tgctaacggc ttcaggggtg tccgtttact 50460 ctctttccag tcagcggcta atgtgctgcc gttcccgcct gtcagtaata gttaaaataa 50520 ttcttgacgg attacaagga agtgatccat actctgtaca tcaactgaac aggggttaag 50580 aaaatggtta acgttaagtg catcaaagat aacgaaggtt actggaccga aggtgaaatt 50640 tatcaggctg aaacagaacc gggtggtttt ttaagaattg gtgacgataa cgacaaaaat 50700 gctgattggt gtttagtgcc attatcatat gatgaaaatg aaaaagccac ttatttatta 50760 gctggcttag atgctgaatt tattgatcta tgaaacgtcg ccgtaagcag tatacatgcc 50820 gatgcagcgc ctatggtttc ccacaccgtt ttagtggtgg gcgctgtcag gggttatggt 50880 tggtcgaacc taataattat tgccccgcgt gtaatttgct tactggttct ggttgccagg 50940 ttattaacgg tgttgaacac ccgcgcgaat gtccgttagt tcaggatttt tgcacttatc 51000 acgaggttaa attatgaagc cgcgttatcg attaatgaaa ttatcagaat gtgcgaacgg 51060 gacgcgattt tatttctatc gttctaaatt gatgtggcct tatacgctaa ttgctatcaa 51120 tcgtaagaaa tacgaaggtg tttatcacat agggcatggt tttaatatta acgttcggat 51180 gtttagaaca tcgttgaata cacaagtttg ggctaaggtg gattaaatgg aatggaaacg 51240 tattaaacga agttacggat cgaacccatt atatctgtat ttgaataaac ttcatgttgc 51300 tacagtttca tgggattttg ggcattctaa aaataacccc aatactcatc gtgctaatgt 51360 gcatttaccg ggtatgaaac aagaattttc tacttctaca caccccagtg aacaaatagc 51420 aaaagacgct gttgaaacta ttgttaaacg ctgggtagat gctgccggac tggagtttaa 51480 ataatgagtg gtcgtcgaac tcgttcgtta cgctgtagca agtgttatga acaatacggt 51540 tataacggtc tggtcgaagt tactggtgag aacggaaacg cttttacctg ccgttgtaaa 51600 acctgtggtc acacttatca aacaacatca gcggctgcac gccgtgcctg gagatatcgt 51660 gaaaagagaa tttgatcgtt atgtggtaat caagaatagt catgcagaac aagcactaac 51720 cgatgatgaa cgtaaagaac tttatcggtt aggtgtgaag tgcgcaaaat ggcgtcggga 51780 taacggcaaa aaacctttcg agtgtgttgt agttgaacac gactggcctg aatatgaacc 51840 tgtctggaaa gcgattgaac aacgtgttga tggtccacac cctttaccag taatgaataa 51900 agatgttcgg tgtttagttg acgctattag tcaggcagcg ttagctgatg atatttctgc 51960 tggtatattt ggtcctgttt ttagtcagct tattttccag ttagcagaaa taaagcgcaa 52020 atcacaatta ctcgatcagt tacgcgatct gatgggttac gttcaaaacg gaacagatgg 52080 aattatcact ttgttccagg atgatgctac tttaacttat tgggttactc atcgaacagc 52140 aggtaaaaaa gaacatgact ggcaagaaca tgctgcatca ctagaacaag ctattcgtaa 52200 tgcgtatgat aaacatgggg ataactaaga tgcttgaacg tatcgttatt tcgattattt 52260 ttctgatctc cgtggcgctg gtttcatcga atctggcgtt tattactcaa cagttcgtac 52320 tggctttaac gggcgtaatt gcagcgttag ccagtatcgc cgcgtgcatg tggggcgcta 52380 aacatgaata aggtagtctg gtcacttttc gacggttccg ggatcatggg tttgccgtgg 52440 gctgaggctg gttatcaggt gtactgtttc aatgcggata agggtaatca cggtgaatat 52500 aaaattaaaa tgtatcaccc taacctgcat tatgttgatc agtggattga tccagatttt 52560 gctattaaac gtgaaatcct cggaacgccg ttaccgtcta ttatttttgg tttccctgat 52620 tgcacgctat ttgctcaaag tggatcacaa catgaacgat cgcagggagc gctacaatac 52680 gcgctaatgc tggcaaaact gatccgtgaa ttgggtgaaa gatataacgt accgtggatg 52740 attgaaaacc cggtgggtgc tttgtcacga ccagaaatga tgggtaaagc aaatgcttat 52800 tttcatccgt gggaatatgg cggtcatatg agtattgacg atcgaccata tcacccaaaa 52860 atgccgatgt ttgatgggta tacgaaaaaa acatgtttgt ggttcggcaa tggttttaaa 52920 atgcctgaaa agtgtccggg gccgattaac attggtttct tctggggctg gaaattcctc 52980 ggtggtaact ctacacggac taagcaatta cgatcactta ccccacgggg ctttgctcgt 53040 gctgtgttca aggctaacca tcatgacgca tcttgaaaaa ttacgatcgc tgatggggta 53100 ttaccagtcc ggtagcgatc agataatcag tcttgcccag gatcctcata cggggcttta 53160 ctgggttagt tgtaaacgtg cctggtatga atgcggcgca acactggaag ccgcgattga 53220 taccgcttat gaaaaacatg gggtgccttc ttatgagtga acaatacgtt tatcgataca 53280 atgatgttaa ccgggttggt gatggtaatc cgacaccata tggtaaatgg cataacgtat 53340 ttgctcgcca gtatttacag ttaggtaagt ttaaaacaaa cagtcagggt aatctgcaac 53400 atattgaaac aggtgataca gattatcaaa actatcttgt accaccatct gaggtgagca 53460 aaccatgaaa cgactgatat tactgacgac tcttacgctc gccgctgcag tgaacggtgc 53520 ggagttaaaa cgctgtgacc tgacgatcac ccggctgaac tcgacagaca gcattacgcg 53580 gcccggtggc gcaactgttg ttgatgatgt agatcggttc gtggtgatga ccagcgattt 53640 tacaagctgg agcctgaaac tgaaccgtta cgggttcggg aagtcgaaag acggtaaacg 53700 gatgttcgta aaagacaacg gcaactacac cgcgaaagaa acgctgatca ccttatctgc 53760 aacaaactgt catcccttct gaactgctgg cggggcgctc aaccccgctg catatctgta 53820 tagaattgca taatcacatc gtctggtaca gcatcaaaat cacactcaga gttcatcatc 53880 atggcgaacg gtcgaacgta ttcgcggatc tcctgtgtta cacccatcgc attaaacggc 53940 gtgcctgtac cttcataatg ctctgtcagt gtcaccattg tttccagcac atcagaaggc 54000 cattcccgat cgatatggtt gtgtagccag ttttccgtga tgttgtaccc ggtaacgttc 54060 cggcgcaggg tgtacagcgc gttgttgaag ttcccgcaca tggtttcaaa ccgtttccag 54 120 acgtcataac cataacggat cactgcatcc ttatgactca ttacccgtgg tgatccgtcg 54180 ccctgggaca ctggtaaacc gttctggatc acgtcatcca taaagttcag aacatccggg 54240 taccagccgt tatcgatccg gttcagtacc catgattcag tgacccggcg attcagtgac 54300 ccggcgttac gcagcacatc aactgcctta aacgtcccgc cgcagatatc cctgaaacgt 54360 tcccagacgt catagccgta gatcacccgt tcaacttctt tatccatcat ccgcaactgc 54420 tgaaaataat tatcgctgaa ccgacgatga ggaagcgccg cacgcagcat atcaacactg 54480 accgttttgt tcagtacgat ttctgctttc ggtgtttgcg ccgggatgac cacggggacc 54540 agatccagtt ccccgcccgt taccgtagta aggattaaat ttaaagtttc tgcccgtggt 54600 aaccgtttcc cggtcatcca ttctgtgaac cgacccctgt ttacgctgca acccatcatt 54660 tttagataac ttactgcgtt gtctgccgat ccaaaatgac tggcgaattt ttcaaacaag 54720 ttcatgttgt ttcaccttac cagatatata acgagaactt tacgccttat atgaaacaag 54780 gtcaactctt atatgcaaca gtttcaaagt tggccttgtt tacgctggta aggtgaaaca 54840 gaaaagttgt tacatctggt aagctgaaac aaagatctat 54880 <210> 2 <211> 107 <212> PRT <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF57 <400> 2 Met Ser Asp Asn Pro Val Leu Lys Tyr Trp Pro Ile Ile Thr Phe Ile 1 5 10 15 Val Thr Gly Ala Val Gly Phe Gly Val Leu Gln Gln Gln Val Asn Ala 20 25 30 Thr Ala Lys Asp Val Ala Asp Ala Lys Val Asn Ala Ser Asn Ala Tyr 35 40 45 Asn Leu Ala Lys Arg Ile Glu Ser Arg Val Asp Val His Asp Val Lys 50 55 60 Leu Glu Tyr Gln Ala Val Gln Asn Thr Gln Ile Leu Ser Ser Val Lys 65 70 75 80 Glu Leu Thr Gln Ser Thr Asn Asp Leu Lys Val Val Ile Glu Gly Leu 85 90 95 Lys Asn Gln Arg Arg Thr Glu Gly Asp Arg Arg 100 105 <210> 3 <211> 80 <212> PRT <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF59 <400> 3 Met Asp Met Leu Ser Met Phe Arg Asn Ala Ala Gly Gly Ile Ser Leu 1 5 10 15 Ser Arg Ala Gln Ala Ala Leu Gly Phe Leu Val Val Thr Gly Ile Leu 20 25 30 Ile Tyr Gln Ala Val Asp Gln Thr Leu Asp Asn Thr Val Leu Leu Met 35 40 45 Tyr Phe Gly Phe Cys Ile Gly Gln Tyr Val Gly Ala Lys Lys Ile Ala 50 55 60 Val Asp Lys Asp Ile Lys Glu Gln Lys Ile Asp Ala Gly Leu Asn Pro 65 70 75 80 <210> 4 <211> 324 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF57 <400> 4 atgtccgata atccggtatt gaaatattgg cctatcataa catttattgt aactggtgcg 60 gtaggtttcg gcgtactcca gcagcaggtt aacgcaacgg ctaaagatgt agctgacgca 120 aaggtaaacg ccagcaacgc atacaacctc gcaaaacgta ttgaatcccg tgttgatgtt 180 cacgatgtaa aattagagta tcaggctgtt cagaatactc aaatcctttc cagcgtcaaa 240 gaacttaccc agtctactaa cgatctaaaa gtcgttatcg aaggtcttaa aaatcaacgc 300 cgtacagaag gtgacagaag atga 324 <210> 5 <211> 243 <212> DNA <213> Unknown <220> <223> Bacteriophage YMC17/01/P6_KPN_BP ORF59 <400> 5 atggatatgt taagcatgtt tcgtaatgca gcgggtggta tctcgttaag ccgtgcgcag 60 gctgcgctgg gtttcctcgt ggtaaccggg atcctgattt accaggcggt tgatcagacg 120 ttagataaca ccgtgctgtt aatgtacttc ggtttctgca tcggccagta tgttggcgct 180 aagaagatcg ccgttgataa ggatatcaaa gaacagaaaa ttgatgcggg gttgaaccca 240 tga 243

Claims (13)

클렙시엘라 뉴모니아(Klebsiella pneumoniae)에 대하여 특이적인 세포 사멸능을 가지며 기탁번호가 [KFCC11804P]인 박테리오파지.A bacteriophage having a specific cell killing ability against Klebsiella pneumoniae and having a deposit number [KFCC11804P]. 제 1항에 있어서,
상기 박테리오파지는 서열번호 1로 표시되는 염기 서열로 이루어지는 것인, 박테리오파지.According to claim 1,
The bacteriophage is made of a nucleotide sequence represented by SEQ ID NO: 1, bacteriophage. 삭제delete 삭제delete 제1항에 있어서,
상기 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 항생제 내성 세균인, 박테리오파지.According to claim 1,
The Klebsiella pneumoniae is an antibiotic resistant bacterium, bacteriophage. 제5항에 있어서,
상기 항생제는 카바페넴(Carbapenem)계 항생제인, 박테리오파지. The method of claim 5,
The antibiotic is bacteriophage, a carbapenem antibiotic. 제1항, 제2항, 제5항 및 제6항 중에서 선택된 어느 한 항의 박테리오파지를 유효성분으로 포함하는, 항생용 조성물.Claim 1, claim 2, claim 5 and claim 6, wherein the bacteriophage of any one selected from the active ingredient, antibiotic composition. 제1항, 제2항, 제5항 및 제6항 중에서 선택된 어느 한 항의 박테리오파지를 유효성분으로 포함하는, 사료 첨가용 조성물.Claim 1, claim 2, claim 5 and claim 6 comprising any one of the bacteriophage selected from the active ingredient, feed composition. 제1항, 제2항, 제5항 및 제6항 중에서 선택된 어느 한 항의 박테리오파지를 유효성분으로 포함하는, 음용수 첨가제.Claim 1, claim 2, claim 5 and claim 6 containing any one of the bacteriophage selected from the active ingredient, drinking water additive. 제1항, 제2항, 제5항 및 제6항 중에서 선택된 어느 한 항의 박테리오파지를 유효성분으로 포함하는, 소독제.A disinfectant comprising the bacteriophage of any one of claims 1, 2, 5 and 6 as an active ingredient. 제1항, 제2항, 제5항 및 제6항 중에서 선택된 어느 한 항의 박테리오파지를 유효성분으로 포함하는, 세척제.A cleaning agent comprising the bacteriophage of any one of claims 1, 2, 5 and 6 as an active ingredient. 삭제delete 삭제delete
KR1020180164212A 2018-12-18 2018-12-18 Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics KR102142018B1 (en)

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PCT/KR2019/018053 WO2020130652A2 (en) 2018-12-18 2019-12-18 Novel bacteriophage for lysing bacteria

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KR102142018B1 true KR102142018B1 (en) 2020-08-07

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Genome Announc 2 (4) (2014)
Salmonella phage 9NA phage(KJ802832.1, 2014.09.25.)

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