KR102604590B1 - Bacteriophage having the ability to kill Acinetobacter baumannii and composition comprising the same - Google Patents
Bacteriophage having the ability to kill Acinetobacter baumannii and composition comprising the same Download PDFInfo
- Publication number
- KR102604590B1 KR102604590B1 KR1020200125818A KR20200125818A KR102604590B1 KR 102604590 B1 KR102604590 B1 KR 102604590B1 KR 1020200125818 A KR1020200125818 A KR 1020200125818A KR 20200125818 A KR20200125818 A KR 20200125818A KR 102604590 B1 KR102604590 B1 KR 102604590B1
- Authority
- KR
- South Korea
- Prior art keywords
- bacteriophage
- endolysin
- acinetobacter baumannii
- present
- baumannii
- Prior art date
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- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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Abstract
본 발명은 아시네토박터 바우마니에 대한 사멸능을 가지는 박테리오파지 및 이를 포함하는 조성물에 관한 것으로, 박테리오파지 Ab1656-2는 아시네토박터 바우마니에 대한 사멸능을 갖는 신규한 박테리오파지로, 이로부터 분리된 Ab endolysin 또한 아시네토박터 바우마니의 임상 분리 균주에 대하여 탁월한 사멸능을 나타내므로 아시네토박터 바우마니 감염에 의해 유발되는 감염성 질환을 예방 또는 치료할 수 있을 뿐만 아니라 항생제, 소독제 등 다양한 용도로 활용 가능하다.The present invention relates to a bacteriophage having a killing ability against Acinetobacter baumannii and a composition containing the same. Bacteriophage Ab1656-2 is a novel bacteriophage having a killing ability against Acinetobacter baumannii, and the Ab isolated therefrom Since endolysin also exhibits excellent killing ability against clinically isolated strains of Acinetobacter baumannii, it can not only prevent or treat infectious diseases caused by Acinetobacter baumannii infection, but can also be used for various purposes such as antibiotics and disinfectants.
Description
본 발명은 아시네토박터 바우마니에 대한 사멸능을 가지는 박테리오파지 및 이를 포함하는 조성물에 관한 것으로, 보다 구체적으로 아시네토박터 바우마니 임상균주로부터 분리된 신규 박테리오파지 Ab1656-2 및 이를 포함하는 아시네토박터 바우마니 감염증 예방 또는 치료용 약학 조성물, 항생제 및 소독제에 관한 것이다.The present invention relates to a bacteriophage having a killing ability against Acinetobacter baumannii and a composition containing the same, and more specifically to a novel bacteriophage Ab1656-2 isolated from a clinical strain of Acinetobacter baumannii and Acinetobacter baumannii containing the same. It relates to pharmaceutical compositions, antibiotics, and disinfectants for preventing or treating Mani infections.
아시네토박터 바우마니(Acinetobacter baumannii)는 감마프로테오박테리아(Gammaproteobacteria)에 속하는 그람음성균으로서 토양, 물 등의 자연 환경에 널리 분포하며, 면역력이 강한 건강한 사람에게는 약한 병원성을 보이나, 면역 시스템이 손상 또는 약화된 사람들에게서 높은 독성을 보이는 기회감염균이다. 특히, 카바페넴계(carbapenems), 아미노글리코사이드계(aminoglycosides), 플로로퀴놀론계(fluoroquinolones) 등의 항생제에 내성을 갖는 다제내성(multiple drug resistance, MDR) 특성으로 인해 중환자실 환자 감염과 같은 원내 감염(hospital-acquired infection)의 주요 병원균으로 주목 받고 있으며, 아시네토박터 바우마니 감염 시 폐렴, 심내막염, 혈류감염, 요로감염, 복막염 등을 포함한 다양한 감염증을 일으킨다. 아시네토박터 바우마니 감염증을 치료하기 위해서 콜리스틴(colistin), 티지사이클린(tigecycline), 이미페넴(imipenem), 메로페넴(meropenem)과 같은 항생제들이 주로 처방되지만, 이들에 대해서도 장기간 사용 시 저항성이 나타나므로 아시네토박터 바우마니에 대한 새로운 항생물질의 개발이 여전히 요구되고 있다. Acinetobacter baumannii is a Gram-negative bacterium belonging to the Gammaproteobacteria and is widely distributed in natural environments such as soil and water. It shows weak pathogenicity in healthy people with strong immune systems, but is not effective in people with a damaged or immune system. It is an opportunistic infection with high virulence in weakened people. In particular, due to the nature of multiple drug resistance (MDR), which is resistance to antibiotics such as carbapenems, aminoglycosides, and fluoroquinolones, it can cause in-hospital infections such as infections in intensive care unit patients. It is attracting attention as a major pathogen of hospital-acquired infection, and Acinetobacter baumannii infection causes various infections including pneumonia, endocarditis, bloodstream infection, urinary tract infection, and peritonitis. To treat Acinetobacter baumannii infection, antibiotics such as colistin, tigecycline, imipenem, and meropenem are mainly prescribed, but resistance to these also appears when used for a long time. The development of new antibiotics against Acinetobacter baumannii is still required.
최근 세균성 감염질환의 대처 방안으로 박테리오파지(bacteriophage)의 활용이 크게 주목을 받고 있다. 특히 항생제 내성균에 대한 우수한 항균력 때문에 더욱 큰 관심을 받고 있다. 박테리오파지는 세균에 감염하는 아주 작은 미생물로서 세균에 감염(infection)한 후에 세균의 세포 내부에서 증식을 하고, 증식 후 자손 박테리오파지들이 세균 밖으로 나올 때 숙주인 세균의 세포벽을 파괴하는 방식으로 세균을 사멸시키는 능력을 갖고 있다. 박테리오파지의 세균 감염 방식은 매우 특이성이 높아서 특정 세균에 감염할 수 있는 박테리오파지의 종류는 일부로 한정된다. 이러한 세균 특이성으로 인하여 박테리오파지는 대상으로 하는 세균에 대해서만 항균 효과를 제공하고 환경이나 동물 내의 상재균들에는 영향을 초래하지 않는다는 장점이 있어, 최근에는 기존 항생제의 대체 물질로의 개발 가능성이 부각되면서 박테리오파지를 이용한 항균제의 개발이 주목을 받고 있다.Recently, the use of bacteriophages has been receiving great attention as a way to deal with bacterial infectious diseases. In particular, it is receiving greater attention due to its excellent antibacterial activity against antibiotic-resistant bacteria. Bacteriophages are very small microorganisms that infect bacteria. After infection, they proliferate inside the bacterial cell, and when progeny bacteriophages come out of the bacteria after proliferation, they kill the bacteria by destroying the cell wall of the host bacteria. has the ability The bacterial infection method of bacteriophages is very specific, so the types of bacteriophages that can infect specific bacteria are limited. Due to this bacterial specificity, bacteriophages have the advantage of providing an antibacterial effect only against the target bacteria and do not affect the flora or fauna in the environment or animals. Recently, the possibility of development as an alternative to existing antibiotics has been highlighted, and the use of bacteriophages has been highlighted. The development of antibacterial agents using is attracting attention.
본 발명은 아시네토박터 바우마니에 대한 사멸능을 갖는 신규 박테리오파지를 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a novel bacteriophage with killing ability against Acinetobacter baumannii.
또한, 본 발명은 상기 박테리오파지를 포함하는 아시네토박터 바우마니 감염증 예방 또는 치료용 약학 조성물을 제공하는 것을 목적으로 한다.Additionally, the present invention aims to provide a pharmaceutical composition for preventing or treating Acinetobacter baumannii infection containing the bacteriophage.
또한, 본 발명은 상기 박테리오파지를 포함하는 항생제를 제공하는 것을 목적으로 한다.Additionally, the present invention aims to provide an antibiotic containing the bacteriophage.
또한, 본 발명은 상기 박테리오파지를 포함하는 소독제를 제공하는 것을 목적으로 한다.Additionally, the present invention aims to provide a disinfectant containing the bacteriophage.
본 발명의 일 양상은 아시네토박터 바우마니에 대한 사멸능을 가지며, 서열번호 1로 표시되는 염기서열로 이루어진 유전체를 가지는 박테리오파지(bacteriophage) Ab1656-2를 제공한다.One aspect of the present invention provides bacteriophage Ab1656-2, which has a killing ability against Acinetobacter baumannii and has a genome consisting of the base sequence represented by SEQ ID NO: 1.
본 발명에서 사용된 "박테리오파지"는 특정 세균에 감염하여 당해 세균의 성장을 억제하고 저해하는 세균 특이적 바이러스로, 단일(single) 혹은 이중(double) 사슬의 DNA 또는 RNA를 유전 물질로 포함하는 바이러스를 의미한다.“Bacteriophage” used in the present invention is a bacteria-specific virus that infects a specific bacterium and inhibits and inhibits the growth of that bacterium, a virus containing single or double stranded DNA or RNA as genetic material. means.
본 발명에서의 박테리오파지 Ab1656-2는 본 발명자들에 의해 처음으로 분리 동정된 것으로, 그 유전체의 서열 또한 본 발명자들에 의해 처음으로 밝혀졌다. Bacteriophage Ab1656-2 in the present invention was isolated and identified for the first time by the present inventors, and its genome sequence was also discovered for the first time by the present inventors.
본 발명의 일 실시예에 따르면, 국내 임상 분리 균주인 항생제 다제내성 아시네토박터 바우바니(Multidrug-resistant A. baumannii) 1656-2 균주로부터 박테리오파지 Ab1656-2를 분리하였다. 분리된 박테리오파지 Ab1656-2를 전자현미경으로 관찰한 결과 시포비리대(Siphoviridae)에 속하는 것을 확인하였고, 박테리오파지 Ab1656-2의 전장 유전체를 분리하고 시퀀싱(sequencing)하여 염기서열 (서열번호 1 참조)을 확인하였고, 약 51 kb의 크기인 이중 가닥 DNA로 구성됨을 확인하였다. 또한, 박테리오파지 Ab1656-2는 아시네토박터 바우마니 표준균주 (ATCC 17978)에 대해 사멸능을 가지는 것을 확인하였다.According to one embodiment of the present invention, bacteriophage Ab1656-2 was isolated from the antibiotic multidrug-resistant A. baumannii 1656-2 strain, which is a domestic clinical isolate. As a result of observing the isolated bacteriophage Ab1656-2 with an electron microscope, it was confirmed that it belongs to Siphoviridae. The full-length genome of bacteriophage Ab1656-2 was isolated and sequenced to confirm the base sequence (see SEQ ID NO. 1). It was confirmed that it was composed of double-stranded DNA with a size of approximately 51 kb. In addition, bacteriophage Ab1656-2 was confirmed to have a killing ability against the standard Acinetobacter baumannii strain (ATCC 17978).
본 발명의 일 구체예에 따르면, 상기 박테리오파지는 수탁번호 KCTC 14314BP인 것일 수 있다. According to one embodiment of the present invention, the bacteriophage may have accession number KCTC 14314BP.
본 발명자들은 항생제 다제내성 아시네토박터 바우바니의 임상 분리 균주 1656-2로부터 아시네토박터 바우바니에 대하여 사멸능을 가지고 있는 신규한 박테리오파지를 선별하였고, 분리된 박테리오파지 Ab1656-2 (ΦAb1656-2)를 한국생명공학연구원의 생물자원센터(Korean Collection for Type Cultures)에 2020년 9월 17일자로 기탁하였다.The present inventors selected a novel bacteriophage with killing ability against Acinetobacter vaubani from clinical isolate 1656-2 of antibiotic-resistant Acinetobacter vaubani, and isolated bacteriophage Ab1656-2 (ΦAb1656-2). It was deposited in the Korean Collection for Type Cultures of the Korea Research Institute of Bioscience and Biotechnology on September 17, 2020.
본 발명의 다른 양상은 상기 박테리오파지 Ab1656-2를 포함하는 아시네토박터 바우마니 감염증 예방 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating Acinetobacter baumannii infection comprising the bacteriophage Ab1656-2.
본 발명에서 사용된 "아시네토박터 바우마니 감염증"은 아시네토박터 바우마니의 감염에 의해 생기는 질환을 의미한다. 일반적으로 건강한 사람은 감염 위험이 매우 적으나 면역저하자, 만성 폐질환자, 당뇨병 환자 등 면역력이 약화된 사람에게는 감염이 취약하며, 입원환자, 특히 인공 호흡기구 착용자, 장기간 입원 환자는 감염 위험성이 매우 높게 나타난다. 아시네토박터 바우마니에 감염될 경우에는 폐렴, 혈류감염, 창상감염을 유발하여 감염 경로에 따라 다양한 증상을 나타낸다.“Acinetobacter baumannii infection” as used in the present invention refers to a disease caused by infection with Acinetobacter baumannii. In general, healthy people have a very low risk of infection, but people with weakened immune systems, such as immunocompromised patients, patients with chronic lung disease, and diabetes, are vulnerable to infection, and hospitalized patients, especially those wearing respirators and patients hospitalized for long periods of time, have a very high risk of infection. appears high. When infected with Acinetobacter baumannii, it causes pneumonia, bloodstream infection, and wound infection, causing various symptoms depending on the infection route.
본 발명에서 사용된 "예방" 또는 "치료"는 아시네토박터 바우마니에 의해 유발되는 감염증의 예방, 억제 및 경감을 의미한다.As used in the present invention, “prevention” or “treatment” means preventing, suppressing and alleviating infections caused by Acinetobacter baumannii.
본 발명에서의 박테리오파지 Ab1656-2는 아시네토박터 바우마니 균주에만 용균(lytic) 작용을 나타낼 뿐, 진핵세포에는 작용하지 않는 선택적 독성이 우수하므로 인체와 동물에 무해하기 때문에 항생물질로서 감염병 치료에 이용될 수 있다.The bacteriophage Ab1656-2 in the present invention only exhibits lytic action only on Acinetobacter baumannii strains and has excellent selective toxicity without acting on eukaryotic cells, so it is harmless to humans and animals and is therefore used as an antibiotic to treat infectious diseases. It can be.
본 발명의 일 구체예에 따르면, 상기 약학 조성물은 박테리오파지 Ab1656-2로부터 분리된 Ab endolysin 단백질을 유효성분으로 포함하는 것일 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may contain Ab endolysin protein isolated from bacteriophage Ab1656-2 as an active ingredient.
상기 Ab endolysin 단백질은 세균의 세포벽 성분인 펩티도글리칸(peptidoglycan)을 기질로 하여 세포벽을 분해하고 와해시켜 세균을 사멸시킨다. 상기 펩티도글리칸은 세균에만 존재하고 사람이나 동물에는 존재하지 않는 바, 본 발명의 단백질은 사람과 동물에 영향을 미치지 않아 안전하면서도 의약산업, 생명공학 등에 응용이 가능할 뿐 아니라 항생제 다제내성에 대한 문제점 없이 세균을 목표장소 또는 목표물질에서 효과적으로 사멸시킬 수 있는 이점이 있다.The Ab endolysin protein kills bacteria by decomposing and disintegrating the cell wall using peptidoglycan, a bacterial cell wall component, as a substrate. Since the peptidoglycan exists only in bacteria and does not exist in humans or animals, the protein of the present invention is safe as it does not affect humans and animals, and can be applied to the pharmaceutical industry, biotechnology, etc., as well as to prevent multi-drug resistance to antibiotics. It has the advantage of being able to effectively kill bacteria at the target location or target material without any problems.
본 발명의 일 구체예에 따르면, 상기 Ab endolysin 단백질은 서열번호 2로 표시되는 염기서열로 이루어진 것일 수 있다.According to one embodiment of the present invention, the Ab endolysin protein may consist of the base sequence represented by SEQ ID NO: 2.
본 발명의 일 구체예에 따르면, 상기 Ab endolysin 단백질은 서열번호 3으로 표시되는 아미노산 서열로 이루어진 것일 수 있다.According to one embodiment of the present invention, the Ab endolysin protein may be composed of the amino acid sequence represented by SEQ ID NO: 3.
본 발명의 일 실시예에 따르면, Ab endolysin 단백질을 생산하기 위하여 서열번호 2로 표시되는 염기서열을 포함하는 재조합 플라스미드를 제조하였고, 이를 숙주세포에 형질전환시켜 최종적으로 약 22 kD의 Ab endolysin 재조합 단백질을 생산하였다.According to one embodiment of the present invention, in order to produce an Ab endolysin protein, a recombinant plasmid containing the base sequence shown in SEQ ID NO: 2 was prepared, and this was transformed into a host cell to ultimately produce an Ab endolysin recombinant protein of about 22 kD. produced.
본 발명의 일 구체예에 따르면, 상기 약학 조성물은 보조인자(cofactor)로 Zn2+를 더 포함하는 것일 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may further include Zn 2+ as a cofactor.
상기 보조인자는 Ab endolysin 단백질의 효소 작용을 나타내기 위해 필요한 물질을 의미하며, 금속이온, 철-황 복합체와 같이 무기물이거나 비타민과 같이 유기물일 수 있다.The cofactor refers to a substance necessary for the enzymatic action of the Ab endolysin protein, and may be an inorganic substance such as a metal ion or an iron-sulfur complex, or an organic substance such as a vitamin.
본 발명의 일 실시예에 따르면, A. baumannii 표준균주 (ATCC 17978)에 재조합 단백질 Ab endolysin과 보조인자로서 Mg2+, Ca2+ 또는 Zn2+을 처리한 결과, Zn2+를 처리한 경우에서 A. baumannii의 생장이 억제된 것을 확인하였다.According to one embodiment of the present invention, as a result of treating the A. baumannii standard strain (ATCC 17978) with the recombinant protein Ab endolysin and Mg 2+ , Ca 2+ or Zn 2+ as a cofactor, when treated with Zn 2+ It was confirmed that the growth of A. baumannii was suppressed.
본 발명에 따른 약학 조성물은 투여를 위하여, 상기 기재한 유효성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등을 들 수 있으나, 이에 한정되는 것은 아니다.For administration, the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable carrier, excipient, or diluent in addition to the active ingredients described above. The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
또한, 본 발명에 따른 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용할 수 있다. 상세하게는 제형화할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하나, 이에 한정되는 것은 아니다. 이러한 고형 제제는 상기 유효성분 외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 첨가하여 조제될 수 있다. 비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 과제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로솔, 트윈 61, 카카오지, 라우린지, 글리세로 젤라틴 등이 사용될 수 있다.In addition, the pharmaceutical composition according to the present invention is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterilized injection solutions according to conventional methods. You can use it. In detail, it can be prepared using commonly used diluents or excipients such as fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc. Such solid preparations may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the above active ingredients. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. In addition to oral liquid and liquid paraffin, it can be prepared by adding various excipients, such as wetting agents, sweeteners, fragrances, and preservatives. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and preparations. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, Wethepsol, Macrosol, Tween 61, cacao, laurin, glycero gelatin, etc. can be used.
본 발명의 약학 조성물의 적합한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 시간에 따라 다르지만, 당 업자에 의해 적절하게 선택될 수 있는 바, 상기 조성물의 일일 투여량은 바람직하게는 0.001 mg/kg 내지 1,000 mg/kg이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.The appropriate dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, drug form, and time, but can be appropriately selected by a person skilled in the art. The daily dosage of the composition is preferably It ranges from 0.001 mg/kg to 1,000 mg/kg and can be administered once or several times a day as needed.
또한, 본 발명의 다른 양상은 상기 박테리오파지 Ab1656-2를 포함하는 항생제를 제공한다.Additionally, another aspect of the present invention provides an antibiotic comprising the bacteriophage Ab1656-2.
본 발명에서 사용된 "항생제"는 화장품용 또는 의약용 방부제, 살균제 및 항균제를 총칭한다. “Antibiotics” as used in the present invention refers collectively to cosmetic or pharmaceutical preservatives, disinfectants, and antibacterial agents.
본 발명의 박테리오파지 Ab1656-2는 기존 항생제에 비하여 탁월한 아시네토박터 바우마니의 사멸능을 나타내는 것으로, 이러한 박테리오파지 Ab1656-2를 항생제로 이용할 경우에는 기존의 항생제를 이용하는 것과는 달리 황색포도상구균의 내성 또는 저항성(resistance)을 유도하지 않는다는 중요한 장점을 갖기 때문에 기존의 항생물질에 비하여 제품 수명(life cycling)이 긴 신규 항생제로서 제공될 수 있다. 대부분의 항생 물질들은 내성 증가에 직면함에 따라 갈수록 사용범위가 줄어들 수밖에 없는데 반해, 본 발명의 박테리오파지를 유효성분으로 포함하는 항생제는 항생제 내성 문제를 근본적으로 해결할 수 있기에 그만큼 항생제로서의 제품 수명이 길어질 것으로 기대된다.The bacteriophage Ab1656-2 of the present invention exhibits an excellent ability to kill Acinetobacter baumannii compared to existing antibiotics. When using this bacteriophage Ab1656-2 as an antibiotic, unlike using existing antibiotics, the resistance or resistance of Staphylococcus aureus Because it has the important advantage of not inducing resistance, it can be provided as a new antibiotic with a longer product life cycle than existing antibiotics. While the scope of use of most antibiotics is inevitably reduced as resistance increases, antibiotics containing the bacteriophage of the present invention as an active ingredient can fundamentally solve the problem of antibiotic resistance, and the lifespan of antibiotic products is expected to be extended accordingly. do.
본 발명의 일 구체예에 따르면, 상기 항생제는 유효성분으로서 박테리오파지 Ab1656-2로부터 분리된 Ab endolysin 단백질을 유효성분으로 포함하는 것일 수 있다.According to one embodiment of the present invention, the antibiotic may contain Ab endolysin protein isolated from bacteriophage Ab1656-2 as an effective ingredient.
또한, 본 발명의 다른 양상은 상기 박테리오파지 Ab1656-2를 포함하는 소독제를 제공한다.In addition, another aspect of the present invention provides a disinfectant containing the bacteriophage Ab1656-2.
본 발명에 따른 소독제는 아시네토박터 바우마니에 대해 효과적인 사멸능을 나타내는 본 발명의 박테리오파지 Ab1656-2를 포함함으로써 원내 감염(hospital acquired infections)을 막기 위한 병원 및 보건용의 소독제로 유용하게 사용될 수 있다.The disinfectant according to the present invention contains the bacteriophage Ab1656-2 of the present invention, which exhibits effective killing ability against Acinetobacter baumannii, and can be usefully used as a hospital and health disinfectant to prevent hospital acquired infections. .
특히, 본 발명의 소독제에 사용되는 박테리오파지는 자연 분해되므로 친환경적이고 액상으로 준비 가능하기 때문에 일반 환경 또는 의료 기구에 존재하는 아시네토박터 바우마니 균주를 제거하기 위한 소독제의 용도로서 매우 유용하다는 장점이 있으며, 박테리오파지를 생산하는 비용 또한 항균제 개발 및 생산에 비해 훨씬 경제적이기 때문에 보건산업에서의 박테리오파지의 효용성은 매우 크다고 할 수 있다.In particular, the bacteriophage used in the disinfectant of the present invention is naturally decomposed, so it is environmentally friendly and can be prepared in liquid form, so it has the advantage of being very useful as a disinfectant for removing Acinetobacter baumannii strains present in the general environment or medical equipment. , the cost of producing bacteriophages is also much more economical than developing and producing antibacterial agents, so the utility of bacteriophages in the health industry can be said to be very great.
본 발명의 일 구체예에 따르면, 상기 소독제는 유효성분으로서 박테리오파지 Ab1656-2로부터 분리된 Ab endolysin 단백질을 유효성분으로 포함하는 것일 수 있다.According to one embodiment of the present invention, the disinfectant may contain Ab endolysin protein isolated from bacteriophage Ab1656-2 as an active ingredient.
본 발명에 따른 박테리오파지 Ab1656-2는 아시네토박터 바우마니에 대한 사멸능을 갖는 신규한 박테리오파지로, 이로부터 분리된 Ab endolysin 또한 아시네토박터 바우마니의 임상 분리 균주에 대하여 탁월한 사멸능을 나타내므로 아시네토박터 바우마니 감염에 의해 유발되는 감염성 질환을 예방 또는 치료할 수 있을 뿐만 아니라 항생제, 소독제 등 다양한 용도로 활용 가능하다.The bacteriophage Ab1656-2 according to the present invention is a novel bacteriophage with a killing ability against Acinetobacter baumannii, and the Ab endolysin isolated therefrom also exhibits an excellent killing ability against clinically isolated strains of Acinetobacter baumannii. Not only can it prevent or treat infectious diseases caused by Tobacter baumannii infection, but it can also be used for various purposes such as antibiotics and disinfectants.
도 1은 본 발명의 일 실시예에 따른 아시네토박터 바우바니 표준균주 (ATCC 17978) 배지에서 발생한 파지 플라크(phage plaque)를 확인한 결과이다.
도 2는 본 발명의 일 실시예에 따른 박테리오파지 Ab1656-2의 형태를 전자현미경으로 확인한 결과이다.
도 3은 본 발명의 일 실시예에 따른 박테리오파지 Ab1656-2의 유전체 DNA를 1% 아가로스(agarose) 전기영동으로 확인한 결과이다.
도 4는 본 발명의 일 실시예에 따른 박테리오파지 Ab1656-2의 전장 유전체의 구조 모식도이다.
도 5는 본 발명의 일 실시예에 따른 재조합 플라스미드 pB4_Ab endolysin의 모식도이다.
도 6은 본 발명의 일 실시예에 따른 재조합 플라스미드 pB4_Ab endolysin로부터 생산 및 정제된 Ab endolysin에 관한 것으로, (a)는 정제되지 않은 MBP와 결합된 Ab endolysin을 전기영동으로 확인한 결과이고, (b)는 TEV protase를 이용한 MBP가 제거된 Ab endolysin의 정제 과정을 나타낸 모식도이며, (c)는 TEV protase로 정제된 Ab endolysin을 전기영동으로 확인한 결과이다.
도 7은 본 발명의 일 실시예에 따른 재조합 단백질 Ab endolysin의 활성에 관한 것으로, (a)는 Ab endolysin의 cofactor를 확인한 결과이며, (b)는 아시네토박터 바우바니 표준균주 (ATCC 17978) 및 임상 분리 균주 (643, 2496, 3097, 3680 및 4316)에 대한 Ab endolysin의 활성을 확인한 결과이다.Figure 1 shows the results of confirming phage plaques generated in a standard Acinetobacter baumannii (ATCC 17978) medium according to an embodiment of the present invention.
Figure 2 shows the results of confirming the form of bacteriophage Ab1656-2 according to an embodiment of the present invention using an electron microscope.
Figure 3 shows the results of confirming the genomic DNA of bacteriophage Ab1656-2 according to an embodiment of the present invention by 1% agarose electrophoresis.
Figure 4 is a structural schematic diagram of the full-length genome of bacteriophage Ab1656-2 according to an embodiment of the present invention.
Figure 5 is a schematic diagram of the recombinant plasmid pB4_Ab endolysin according to an embodiment of the present invention.
Figure 6 relates to Ab endolysin produced and purified from the recombinant plasmid pB4_Ab endolysin according to an embodiment of the present invention. (a) shows the result of electrophoresis confirming Ab endolysin bound to unpurified MBP, and (b) is a schematic diagram showing the purification process of Ab endolysin from which MBP has been removed using TEV protease, and (c) is the result of electrophoresis confirming Ab endolysin purified with TEV protease.
Figure 7 relates to the activity of the recombinant protein Ab endolysin according to an embodiment of the present invention. (a) is the result of confirming the cofactor of Ab endolysin, and (b) is the Acinetobacter vaubani standard strain (ATCC 17978) and This is the result of confirming the activity of Ab endolysin against clinical isolates (643, 2496, 3097, 3680, and 4316).
이하, 본 발명을 보다 상세하게 설명한다. 그러나, 이러한 설명은 본 발명의 이해를 돕기 위하여 예시적으로 제시된 것일 뿐, 본 발명의 범위가 이러한 예시적인 설명에 의하여 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail. However, this description is merely provided as an example to aid understanding of the present invention, and the scope of the present invention is not limited by this example description.
실시예 1. 박테리오파지 Ab1656-2의 생산 및 분리Example 1. Production and isolation of bacteriophage Ab1656-2
1-1. 박테리오파지 Ab1656-2의 생산1-1. Production of bacteriophage Ab1656-2
국내 임상 분리균주인 항생제 다제내성 아시네토박터 바우바니(Multidrug-resistant A. baumannii) 1656-2 균주를 LB(Luria Bertani) 액체 배지에 접종하여 37℃에서 배양한 후 지수성장기에서 미토마이신 C(Mitomycin C)를 1 μg/ml 농도로 처리하고 37℃에서 하룻밤 동안 진탕 배양하였다. 배양액을 5,000 rpm로 10분간 원심분리하여 상층액을 수집한 후 상층액 볼륨의 2% (v/v) 클로로포름을 첨가하고 5,000 rpm 10분간 원심분리 하였다. 이후 상층액을 0.45 μm의 필터를 사용하여 여과하고, 그 여과액을 4℃에 보관하였다.Multidrug-resistant A. baumannii 1656-2, a domestic clinical isolate, was inoculated into LB (Luria Bertani) liquid medium, cultured at 37°C, and then treated with mitomycin C (Mitomycin) in the exponential growth phase. C) was treated at a concentration of 1 μg/ml and incubated with shaking at 37°C overnight. The culture was centrifuged at 5,000 rpm for 10 minutes to collect the supernatant, then 2% (v/v) chloroform of the supernatant volume was added and centrifuged at 5,000 rpm for 10 minutes. Afterwards, the supernatant was filtered using a 0.45 μm filter, and the filtrate was stored at 4°C.
1-2. 박테리오파지 Ab1656-2의 분리1-2. Isolation of bacteriophage Ab1656-2
굳지 않은 액체 상태의 5 ml의 0.75% BHI 고체 배지에 상기 1-1에서 보관된 용액 500 μl와 LB 액체 배지에서 하룻밤 배양한 아시네토박터 바우마니 표준균주 (ATCC 17978) 균액 100 μl을 섞어준 후 1.5 % BHI 고체배지 위에 부어 37℃에서 하룻밤 배양하였다. 다음날 세균이 1.5 % BHI 고체배지에서 증식하면서 생긴 흔적인 용균들(이하, 플라크-plaque)을 확인하였다. 그 후 단일 플라크(Single plaque)를 추출해 100 μl의 SM buffer에 풀어준 후 13,500 rpm에서 5분 원심분리하여 상측액을 수득하고 해당 용액을 LB 액체 배지에서 지수생장기 단계의 아시네토박터 바우마니 표준균주 (ATCC 17978)에 추가 접종하여 37℃에서 하룻밤 배양하였다. 세균은 5,000 rpm로 10분간 원심분리하여 상층액을 수집하고 상층액 볼륨의 2% (v/v) 클로로포름을 첨가하고 5,000 rpm 10분간 원심분리 하였다. 이후 상층액을 0.45 μm의 필터를 사용하여 여과한 후 SM buffer와 1:1의 비율로 희석하여 4℃ 또는 -70℃에 보관하였다. 순수 분리된 박테리오파지의 플라크 형성 시험을 통해 박테리오파지가 제대로 수확되었는지 확인하였고, 그 결과를 도 1에 나타내었다.After mixing 500 μl of the solution stored in 1-1 above and 100 μl of Acinetobacter baumannii standard strain (ATCC 17978) cultured overnight in LB liquid medium with 5 ml of 0.75% BHI solid medium in an unhardened liquid state, It was poured onto 1.5% BHI solid medium and cultured overnight at 37°C. The next day, lysates (hereinafter referred to as plaques), which were traces of bacteria growing on 1.5% BHI solid medium, were confirmed. Afterwards, single plaques were extracted and dissolved in 100 μl of SM buffer, centrifuged at 13,500 rpm for 5 minutes to obtain the supernatant, and the solution was grown in LB liquid medium with the standard strain of Acinetobacter baumannii in the exponential growth phase. (ATCC 17978) was additionally inoculated and cultured overnight at 37°C. Bacteria were centrifuged at 5,000 rpm for 10 minutes to collect the supernatant, 2% (v/v) chloroform of the supernatant volume was added, and centrifuged at 5,000 rpm for 10 minutes. Afterwards, the supernatant was filtered using a 0.45 μm filter, diluted with SM buffer at a ratio of 1:1, and stored at 4°C or -70°C. It was confirmed whether the bacteriophages were properly harvested through a plaque formation test of pure isolated bacteriophages, and the results are shown in Figure 1.
1-3. 전자현미경을 이용한 박테리오파지 Ab1656-2의 형태 관찰1-3. Observation of the morphology of bacteriophage Ab1656-2 using an electron microscope
상기 수득한 박테리오파지 Ab1656-2의 형태를 관찰하기 위하여 바이오 투과전자현미경 (Bio-TEM, Bio Transmision Electron Microscope)를 통해 관찰하였다. 약 108 pfu의 순수분리된 박테리오파지를 탄소로 코팅된 구리판에 바른 후, 2% 우라닐 아세테이트(uranyl acetate)로 염색하고 바이오 투과전자현미경을 사용하여 관찰하였다. In order to observe the form of the obtained bacteriophage Ab1656-2, it was observed through a bio-transmission electron microscope (Bio-TEM, Bio Transmision Electron Microscope). About 10 8 pfu of pure isolated bacteriophage was applied to a carbon-coated copper plate, stained with 2% uranyl acetate, and observed using a bio-transmission electron microscope.
그 결과, 도 2에 나타낸 바와 같이, 박테리오파지 Ab1656-2는 시포비리대(Siphoviridae)에 속하는 박테리오파지인 것으로 확인되었다.As a result, as shown in Figure 2, bacteriophage Ab1656-2 was confirmed to be a bacteriophage belonging to Siphoviridae.
1-4. 박테리오파지 Ab1656-2의 유전체 서열 분석1-4. Genome sequence analysis of bacteriophage Ab1656-2
상기 수득한 박테리오파지 Ab1656-2의 유전체를 Phage DNA isolation kit (NORGEN)를 사용하여 제조사의 프로토콜에 따라 정제를 하였다. 해당 DNA를 1% 아가로스(agarose) 전기영동을 통해 확인하였고, 그 결과를 도 3에 나타내었다.The genome of the bacteriophage Ab1656-2 obtained above was purified using the Phage DNA isolation kit (NORGEN) according to the manufacturer's protocol. The DNA was confirmed through 1% agarose electrophoresis, and the results are shown in Figure 3.
해당 유전체를 마크로젠(Macrogen)에 의뢰하여 차세대 염기서열 분석(Next Generation Sequencing)을 통한 전체 서열 분석을 진행하였다. 해당 차세대 염기서열 분석은 일루미나 플랫폼(Illumina platform)의 시퀀서 유형과 De novo assembly의 분석 유형을 통해 진행되었다. The genome was commissioned to Macrogen and full sequence analysis was performed through Next Generation Sequencing. The next-generation sequencing was conducted using the sequencer type of the Illumina platform and the analysis type of de novo assembly.
그 결과, 도 4에 나타낸 바와 같이, 박테리오파지 Ab1656-2의 유전체는 이중가닥 DNA로 크기가 약 51 kb (서열번호 1)인 것으로 확인되었다.As a result, as shown in Figure 4, the genome of bacteriophage Ab1656-2 was confirmed to be a double-stranded DNA with a size of approximately 51 kb (SEQ ID NO: 1).
본 발명자들은 박테리오파지 Ab1656-2를 한국생명공학연구원의 생물자원센터(Korean Collection for Type Cultures)에 2020년 9월 17일자로 기탁하여 수탁번호 KCTC 14314BP를 부여받았다.The present inventors deposited bacteriophage Ab1656-2 at the Korean Collection for Type Cultures of the Korea Research Institute of Bioscience and Biotechnology on September 17, 2020, and received accession number KCTC 14314BP.
실시예 2. 박테리오파지 Ab1656-2 유래 재조합 단백질 Ab endolysin 생산 및 정제Example 2. Production and purification of recombinant protein Ab endolysin derived from bacteriophage Ab1656-2
2-1. 재조합 플라스미드 pB4_Ab endolysin 제조2-1. Preparation of recombinant plasmid pB4_Ab endolysin
아시네토박터 바우마니에 대해 사멸능을 가지는 신규 박테리오파지 Ab1656-2의 단백질 Ab endolysin을 생산하기 위해 재조합 플라스미드를 제조하였다. A recombinant plasmid was prepared to produce Ab endolysin, a protein of the novel bacteriophage Ab1656-2, which has the ability to kill Acinetobacter baumannii.
먼저, pB4 플라스미드에 클로닝 하기 위하여, 박테리오파지 1656-2의 엔도라이신(endolysin) 유전자를 PCR을 통하여 증폭시켜 주었다. 상기 유전자를 pB4 플라스미드에 LIC method를 통하여 클로닝 하였고, 이로부터 제조된 재조합 플라스미드의 구조는 도 5와 같다 (서열번호 4 참조). 새롭게 구축된 플라스미드는 마크로젠(Macrogen)에 의뢰하여 DNA 시퀀싱을 통해 확인하였다. PCR 증폭 및 DNA 시퀀싱에서는 하기 표 1의 프라이머를 사용하였다.First, in order to clone into pB4 plasmid, the endolysin gene of bacteriophage 1656-2 was amplified through PCR. The gene was cloned into the pB4 plasmid using the LIC method, and the structure of the recombinant plasmid prepared therefrom is shown in Figure 5 (see SEQ ID NO: 4). The newly constructed plasmid was commissioned by Macrogen and confirmed through DNA sequencing. For PCR amplification and DNA sequencing, the primers shown in Table 1 below were used.
(서열번호)primer
(SEQ ID NO)
(서열번호 5)Ab_endolysin_LIC_F
(SEQ ID NO: 5)
증폭Ab endolysin
amplification
(서열번호 6)Ab_endolysin_LIC_R
(SEQ ID NO: 6)
(서열번호 7)pB4_seq_F
(SEQ ID NO: 7)
시퀀싱pB4 vector
sequencing
(서열번호 8)pB4_seq_R
(SEQ ID NO: 8)
2-2. 재조합 플라스미드 pB4_Ab endolysin으로부터 Ab endolysin 발현2-2. Ab endolysin expression from recombinant plasmid pB4_Ab endolysin
Ab endolysin을 발현하기 위하여, 상기 2-1에서 제조된 pB4_Ab endolysin를 E. coli BL21 DE3 star 균주에 형질전환 시켰다. 형질 전환된 E. coli는 암피실린(ampicillin) (100 μg/ml) 항생제가 첨가된 LB 고체배지에서 선별하였다. 상기 선별 과정을 통해 구축된 단백질 발현 균주가 Ab endolysin을 발현하는지 확인하기 위해 IPTG(Isopropyl β-D-1-thiogalactopyranoside) (0.2 mM/ml)를 첨가한지 2시간 후 해당 균주를 수집하여 단백질 전기영동으로 확인하였다.To express Ab endolysin, pB4_Ab endolysin prepared in step 2-1 was transformed into E. coli BL21 DE3 star strain. Transformed E. coli were selected on LB solid medium supplemented with ampicillin (100 μg/ml) antibiotic. To confirm whether the protein expression strain constructed through the above selection process expresses Ab endolysin, the strain was collected 2 hours after adding IPTG (Isopropyl β-D-1-thiogalactopyranoside) (0.2 mM/ml) and subjected to protein electrophoresis. It was confirmed.
그 결과, 도 6a에 나타낸 바와 같이, IPTG 첨가하여 약 64kD의 단백질 밴드를 확인하였다. As a result, as shown in Figure 6a, a protein band of approximately 64 kD was confirmed by the addition of IPTG.
2-3. Ab endolysin 정제2-3. Ab endolysin tablets
상기 2-2에서 발현이 확인된 Ab endolysin를 대량 정제하기 위하여, 상기 형질전환된 단백질 정제 균주를 암피실린 (100 μg/ml) 항생제가 첨가된 LB 액체배지 1 L에 접종한 후 37℃ 진탕 배양기에서 OD600 = 0.7까지 키운 후 IPTG를 최종 농도 0.2 mM/ml가 되도록 첨가하고서 18℃에서 18시간 배양하였다. 이후 배양된 균주를 원심분리하여 수확하고 100 ml의 용해 버퍼(lysis buffer) (20 mM Tris pH 7.0 및 0.5 M NaCl 함유)에 풀어 주었다. 수확된 세균을 초음파 파쇄기로 파쇄하였다. 파쇄된 세균을 30분 동안 15,000 rpm으로 원심분리 하여 상등액을 취한 후 0.45 um의 필터를 사용하여 여과하고 FPLC(Fast-protein liquid chromatography)를 통해 Ni-NTA 컬럼에 주입하였으며, 용출 버퍼(elution buffer) (20 mM Tris pH 7.0, 0.5 M NaCl 및 0.5 M imidazole 함유)를 사용하여 N-말단에 존재하는 히스티딘 태그(His-tag)된 MBP-Ab endolysin을 수확하였다. 수확된 단백질에 TEV protease를 첨가하여 인공투석 및 TEV site 절단 (20 mM Tris pH 7.0, 0.5 M NaCl, 10 mM β-mercaptoethanol 및 1 mM EDTA 함유)을 진행하여 MBP(His-tag)와 Ab endolysin을 분리시켰다. 이후 해당 용액을 다시 2차 Ni-NTA 컬럼에 주입하여 히스티딘 태그가 존재하는 TEV protease 및 MBP를 걸러 내어 Ab endolysin을 분리하였다 (도 6b 참조). 정제된 Ab endolysin은 단백질 전기영동으로 확인하였다.In order to mass purify the Ab endolysin whose expression was confirmed in 2-2 above, the transformed protein-purified strain was inoculated into 1 L of LB liquid medium supplemented with ampicillin (100 μg/ml) antibiotic and incubated in a shaking incubator at 37°C. After growing to OD 600 = 0.7, IPTG was added to a final concentration of 0.2 mM/ml and cultured at 18°C for 18 hours. Afterwards, the cultured strain was harvested by centrifugation and dissolved in 100 ml of lysis buffer (containing 20 mM Tris pH 7.0 and 0.5 M NaCl). The harvested bacteria were disrupted with an ultrasonic disruptor. The crushed bacteria were centrifuged at 15,000 rpm for 30 minutes to obtain the supernatant, filtered using a 0.45 um filter, and injected into a Ni-NTA column through FPLC (Fast-protein liquid chromatography). Elution buffer Histidine-tagged MBP-Ab endolysin present at the N-terminus was harvested using (containing 20 mM Tris pH 7.0, 0.5 M NaCl, and 0.5 M imidazole). TEV protease was added to the harvested protein, followed by artificial dialysis and TEV site cleavage (containing 20mM Tris pH 7.0, 0.5M NaCl, 10mM β-mercaptoethanol, and 1mM EDTA) to produce MBP (His-tag) and Ab endolysin. separated. Afterwards, the solution was again injected into a second Ni-NTA column to filter out TEV protease and MBP with a histidine tag, thereby separating Ab endolysin (see Figure 6b). Purified Ab endolysin was confirmed by protein electrophoresis.
그 결과, 도 6c에 나타낸 바와 같이, MBP(His-tag)가 제거된 Ab endolysin은 약 22 kD의 단백질 밴드로 확인되었다.As a result, as shown in Figure 6c, Ab endolysin from which MBP (His-tag) was removed was confirmed to be a protein band of approximately 22 kD.
실시예 3. Ab endolysin 활성 분석Example 3. Ab endolysin activity analysis
3-1. Ab endolysin의 활성을 위한 보조인자(cofactor) 확인3-1. Identification of cofactors for Ab endolysin activity
정제된 Ab endolysin의 활성에 영향을 미치는 cofactor를 확인하기 위하여, A. baumannii 표준균주 1주 (ATCC 17978)를 대상으로 다음과 같이 진행하였다. To identify cofactors that affect the activity of purified Ab endolysin, the following procedure was performed on one standard strain of A. baumannii (ATCC 17978).
먼저, U-type 96-웰 플레이트(well plate)에 well 당 최종 볼륨(volume) 200 ul가 되도록 Ab endolysin 100, 50, 25, 12.5 ug/well을 넣어주었으며, Cofactor로서 2가 양이온인 Mg2+, Ca2+, Zn2+을 최종 농도 1 mM/ml가 되도록 넣어주었다. 또한 A. baumannii 표준균주 1주 (ATCC 17978)는 4Х105 CFU/well의 세균수가 되도록 넣어 주고 37℃에서 18시간 배양하여 Ab endolysin의 활성을 확인하였다.First, Ab endolysin 100, 50, 25, 12.5 ug/well was added to a U-type 96-well plate to a final volume of 200 ul per well, and Mg 2+ , a divalent cation, was added as a cofactor. , Ca 2+ , and Zn 2+ were added to a final concentration of 1 mM/ml. In addition, 1 strain of A. baumannii standard strain (ATCC 17978) was added to ensure a bacterial count of 4Х10 5 CFU/well and cultured at 37°C for 18 hours to confirm Ab endolysin activity.
그 결과, 도 7a에 나타낸 바와 같이, Mg2+ 또는 Ca2+를 처리한 경우에는 A. baumannii의 생장이 관찰된 반면, Zn2+를 처리한 경우에는 Ab endolysin의 농도 의존적으로 A. baumannii의 생장이 억제되어 투명하게 보이는 것으로 확인되었다. As a result, as shown in Figure 7a, when treated with Mg 2+ or Ca 2+ , the growth of A. baumannii was observed, whereas when treated with Zn 2+ , the growth of A. baumannii was observed in a concentration-dependent manner of Ab endolysin. It was confirmed that growth was suppressed and it appeared transparent.
3-2. 3-2. A. baumanniiA. baumannii 임상 분리 균주에 대한 활성 확인. Confirmation of activity against clinical isolates.
A. baumannii 임상 분리 균주의 성장 억제 실험을 진행하기 위하여, U-type 96-웰 플레이트에 well 당 최종 볼륨 200 ul가 되도록 Ab-edolysin 100, 50, 25, 12.5, 6.25, 3.12, 1.56 ug/well을 넣어주었다. 이후 Zn2+을 최종 농도 1 mM/ml가 되도록 넣어준 후 대조군인 A. baumannii 표준균주 (ATCC 17978) 및 A. baumannii 임상 분리 균주 (643, 2496, 3097, 3680, 4316)를 각 4Х105 CFU/well의 세균수가 되도록 넣어 주고 37℃에서 18시간 배양하여 Ab endolysin의 활성을 확인하였다. To conduct growth inhibition experiments on A. baumannii clinical isolates, Ab-edolysin 100, 50, 25, 12.5, 6.25, 3.12, 1.56 ug/well was added to a U-type 96-well plate to a final volume of 200 ul per well. I put it in. Afterwards, Zn 2+ was added to a final concentration of 1 mM/ml, and then the control A. baumannii standard strain (ATCC 17978) and A. baumannii clinical isolates (643, 2496, 3097, 3680, 4316) were added at 4Х10 5 CFU each. The number of bacteria was added to each well, and the activity of Ab endolysin was confirmed by culturing at 37°C for 18 hours.
그 결과, 도 7b에 나타낸 바와 같이, A. baumannii 표준균주 (ATCC 17978) 및 A. baumannii 임상 분리 균주 5종에서는 모두 Ab endolysin의 농도 의존적으로 균주의 생장이 억제된 것으로 확인되었다.As a result, as shown in Figure 7b, it was confirmed that the growth of the A. baumannii standard strain (ATCC 17978) and all five A. baumannii clinical isolates was suppressed in a concentration-dependent manner of Ab endolysin.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.
<110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Bacteriophage having the ability to kill Acinetobacter baumannii and composition comprising the same <130> PN200249 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 50929 <212> DNA <213> Artificial Sequence <220> <223> Bacteriophage Ab1656-2 <400> 1 tcgaaaggtg aaaatcctga ccttacatta cttggttcaa gcgctaactg gatcaaatat 60 gcaaccagca acaaaatgac agcaggtacc ttacttgatt tatcgggtac agcgacaact 120 ggttaaaacc taaaaattaa aacctaaggg ggctaataag ccctcttttt tattattaag 180 agaaaagcgc catgaagatt atctatacac gcattgcagc agcggctgca ttagagacag 240 gcattattgc taaccctgac tattatgaaa acccaaattt gaaagcaaaa gaggtaatta 300 tttacggtaa ttatccaaag attcaaaagg attatgaatc tttggaagtt ccagttgaag 360 ttcgtaagtt ggaagtgcca caaaaaacga ctttggccac agtaaatgtc gcagtgggaa 420 ttacccctga acttcaagct gtgatggatg atgcaaaagc tgaatgtgaa aaggtagttg 480 aagaaaacac tcagcttaag cagaaaattg ccatcttaga gcaggccggt ggtaaccagt 540 cagagttgtt atctgaaaat tcacgattaa aagatgcagc agtcttagca gataaagctc 600 tcaaagatgc tgaagctcaa gtggtcggta taaaaactga atttgaagct tttaaaaatg 660 atattcctgc aatgcaggca cgtattgctg aattggaagc tggaaaagcg gcagaaaacc 720 cagctacaga aacggcagct aatgattttg aaaactggtc aaatgatcaa ttaaaagagt 780 atttggctag taaaaacatt ggttacaagc cgtctgcaac aaaagcagaa cttcttaaat 840 taatcccgaa ggaataatgc aatgagcttt attactgtag atgacgcaaa ttcaattttg 900 ggcagcgatt ttgcaccaga cagtgataag gctcgtctgg tgaagctggc aaatgtgtgg 960 atgaaaaaca gaattggttt tgtaccagat ccaattgatc cacttcttaa ggacgcggct 1020 tgtgaaatta tcaaaggaat tctggccaaa gtaatttata acggcaaaga gcagcagttg 1080 aagcgtaaga aagttaaggc tgattctgtt gagtcagaaa aagaatttca agacggatct 1140 gaagcaatct ctagctttga acagatagca attgatttta ttgattcact tgatttgaaa 1200 gatccaaatg caagttttaa tggctttggc ataccacttt acagggcatg atatgggctt 1260 acgtgacgaa attcaggcag acattgctga agcatttaat gatgatttag cagatgccat 1320 tcataccttt acatgtgagc ggatctctaa aacgaattgg gatcctaaaa ctgaaactta 1380 tgttgaagtt aaagaaaact attctggccg tggcgttctg tttggctcat acagtcaata 1440 tgagatccaa acacttggag tactggccac ggataaaaag gcaaccgtgc ttcaaaatga 1500 agtaactatg actccaaaaa ttgaagatga atggttaact gccttaggct cattccgggt 1560 aattaatatt caacaggatc cagctaatac tatttggaaa tgtcagcttc gaaaagtgta 1620 ggggctaaaa tggttaatcc tgattatgtt cctgaatggt atatctcgcc ttttcaacat 1680 gtgcagtaca cgcttgctcg aaatcaacta cacatggatt tgttatttga agatatggat 1740 aaggccgatc aatttttgga tatgggagcg gatgcgcaag ttagtacttt ttctgatggt 1800 gcatatgcaa tcgtccaaat tggtgatacg gcggataaag accgaattca agtttatgga 1860 ttgcttttac atgaagctgt tcatgtctgg caaaagatta aaaagctcat gggtgaacga 1920 gaaccgagct ctgagtttga agcttattca attcaggcga tcgctcaaga cctttttaaa 1980 atgtatgaag aaagcgaggt gaatgatggg atggaagggg aaaaagccaa ctgaatttag 2040 ttttgatgtg tctaaagcag cagaagacca ggtgaagcat attgttatgg atactgtgca 2100 atccttagtt aatttaagtc ctgttgatac tggagcatac cgtgcttcac atattgtttc 2160 ggttggatct gctgatttcg gcgtgcgtga acctgaaaca aaccctatta acgacgcagc 2220 gattcaggca atgaagatta agttaggtaa tttggtttat atccagaaca ataaagctta 2280 tggaccgcgc ttagaaaacg gctggtctga tcaagcacca caaggtattt atggcctcac 2340 gtttaacttt atttctcaaa agtacggtgg ctaaaatggc aatgacttta gagcagacaa 2400 ggcaagctat tattgatcgc atgcaaagct ttacgggtat tgctcaagaa cggattcagt 2460 atccaaatgc acctgacttt actgttccaa caaaaggtgt atggtgccgt ttaacgattg 2520 caggtggccc gagttttacc tcaggcattg cagataagcc atgtacacgc cgtaccggta 2580 atatcatgat ccaatgcttt gaccgattac atactggaga gaaggccgta acggttctaa 2640 gcgatgcatt gctggctcat tttgaatatt tcacaatcga acacttagaa tgtttgaatg 2700 gccaatctat ttatgcgggt aaagatgctg atttcattca gtataatgtg agcattgggt 2760 acaaggtgaa ttgatatgtc atgtatgctg actttagaag aaatcgaaat taaacggcaa 2820 gaactggaac ggcatcttga agatgttatg tctgttgagt tgagcaaatg gcaatctgaa 2880 aacaagctat gtgtttctga tgtgaatata cgcttggcta atgttgttag tctcggaggg 2940 cctaaacata acgttgttac tggagtaagt gtcgatttag ataatgagct ttgagttcaa 3000 gaaaaagcta ctgcaaggcg attattttta atgacctcag catattatca tttgtgatta 3060 cattctgtta cagtaatgga aatttataac aaatggtaaa acatgaaaaa atcaacttta 3120 ggctggggtg ccgcaggatt agtagcttta gggatttttg gttcaggcaa tgataactct 3180 ccaaaacaaa cttcagactc agaaaatgcg cagagtgcag tagaggaagt tatcgaatca 3240 aaatatatca acactaattc tttaaatatt agagataaac caaacggtca agtagtagga 3300 aagttaggac gtggggaaaa agttgatatt tatgagatga aaggaaactg ggcacgtatt 3360 tccttaaatt cctcatcacc tcagtggtta tcaacaaagc tattatgtga aacggatggc 3420 tgttttaaac aaaagtctcg atcaaccacg tcaaataatt atcaggcctt aaaatctcat 3480 cctcatcatt ctgaaagaaa acagaaaaaa acctactacg atagtgattg ttcatgtgct 3540 gtggtggatt attgcgtggg tcctagaggt gggcactact gtattacgag tggaggaaac 3600 aagagatata aacctagata ttaattaatt tgaattatga gacctccatt ttgagaggta 3660 ctttatgtct taatcactac cacctcatcg gtggtttttt tatgtctata ggaatcactt 3720 atgagcaatt ttgtatttaa gcgtggtgac actttcaact taaatcttca gctagttgat 3780 atggatgaag ccctgcaata tccaccagat gatgtgcgcc gtgcaattga tcttacaggt 3840 tataccttca cttcacaggt taaagctctg gctgatggtg ctactgtggc cacattaact 3900 tgtactgcat taagccaaag cacacagaaa gggtggctga acattaaatc tagtgcaagc 3960 actgcaactt ggcctttagg gctgtgtcag atggatatta aagctgtagt tagtggcact 4020 acacagcaca ctgaaacttt gactttccaa gtgattgacg gagtaacagc ataatggcaa 4080 atcttgtttt taaatttagt tgggatcatc ggccattccc atataacgcc tcacagggca 4140 agcggcagtt tatgttgcca tttgcgtcag gtattcccaa tctggcaccc aacttttctc 4200 aagtagttgg tactgcagct atctctcaag gtggaacggg ggcaactaca gcggctggtg 4260 cacgagctaa cctaggcgca gctgcaagtg gggtaaatag tgatattagt gagcttaagg 4320 gacttacaac ccctttatca atttctcagg gaggattagg agctgataat gcacagacag 4380 ctagaatgaa tttggggtta ggaactgctg ctgtactagc gtcaacaaca agtcaatatg 4440 atcctacgcc gggacgagca ctaagagtcg gtgattgggg gataggggct gaaggttctc 4500 gtgtatctga tatggttgct cctcttaata atggtttttt tcgaacagat gacactttaa 4560 caaatgatac tggtaatagt attggtcctt atggtttctt tttacactgt acccgacgct 4620 caatgggttt atatacaaat ggaagtcatt catttcagct tgggaaagct gcctcatatt 4680 ctgccctgaa gtatcgattt aataatagtg gtacttggtc taattggttt aatttattga 4740 ctgcacaaaa tactacaact gatggaaatg gttttattaa agccgcttca ccagtcgtta 4800 agcttttcca aagtcatatt gagctaaata acgatgctgc caagcaaccg atcacttttg 4860 acaaattagg cactggtgac tatctgatta agggctcttt aggctttgca caggaaggtt 4920 ggtatatcga agtacctaag gatgccaacg gtaatacggt agtagcagtt gaatattcaa 4980 ccttagaaaa tggtgatctt tctattaaaa cttataaacg taagtttgat gtggaaaagg 5040 cagccattgt agctgatctc gaaaatccac ttgatattcc agaaggccgc tggattgata 5100 tccgtctgca tgaagaacct gaaccagagc ctgaagagcc gttgagtgaa acaccagtgg 5160 atttccagcc gactaactta tctcaggcag ttgctgcagc catgaatggc gtggaaccgc 5220 cagaaatctc agaaacagac gaaacacttt aataacccgc ttaaacagcg ggttttttat 5280 tgcctaaatt ttggagaacc ataaatgagt tcaggcgcaa aaattcgatt atatgcttgt 5340 gaggaagcag ttttaggaac aactcctgca aatccagtct ggtacaccgt tcgccgtgtt 5400 actgatagtt tgactgaaaa tgttactact gaagatagca gtgaagtagt tgattcacgt 5460 tttcgccaag gcgctgttgt aacggaagcc gaagtaactg gtcaactaga gtttgaatta 5520 tcactaggta cctttgactt attcttaaat gttctcgctt tcaataactg ggctgcaaat 5580 gctttaagtt ttggtggtgg agtacgtaag tctcttacct tggtaaaagt ctttgaagat 5640 attggtcaag tctttattta tcgtggtatt caagtgaata caggtgaaat gacgatccag 5700 accacaggca aaatcactgg taactttggt ttagtaggta gctcatttac gcgacagcag 5760 gttaatcctg ttacaaatcc tattccagca tcgactcgcc ctctggtgag tatgccaaat 5820 gttgaaaagc tacttattaa tggtcaatca attcagggta aagcttgtct gcagacactt 5880 accatcaact ttagtaataa tctggaagcg atccgttgta tcggttctgg taagtacacg 5940 cctgagtttt acttagagaa aatgatggat attggcgtaa atgctaattt catgttttca 6000 gcaacatctg cttcttggat tgatgctatt aaaacccgtg atgtatttac attgaccttc 6060 gatattacag ataccaaagg cagtaagtac tcgtttaact tcccgcaact tgaagttaag 6120 gaagcaaatc accctgatgg tggtggcgat gacattatta caatagatat caattttgcc 6180 caagtgcgta ccagtccaac gattgtacgt gctcttgtgt aatcaactta ttcagtaaca 6240 aagcctatgg aaacccatgg gcttttttat ttctaaaaat tagaggttgt tatggcttta 6300 aaagtcggaa ttattaaaag ctcagacgta tcaaaatggt gtgaatacaa gggtgctgat 6360 ggcgatgtac aggctgagtt caaagtccgt ggtatcgctt ataagccttt tcaggtagct 6420 attgaacggg caggaaacca gatctcgtct aaaggctatg atgtgatggt caaagatgaa 6480 gatgccaagc tttaccacga gcttttaatg gatgcatgcg cggcccactt aatcgaagac 6540 tggaaaggtg tggtatttgc cgaaatcgta gacggtaaaa ctgttgagtc cgaaaagcca 6600 tatacacctg agaatgcctc aaagcttctt aatcttggtg atattggtat ttcaatctgg 6660 ctattcatta aagaacaggc ccagaagatt caggaagacg cagacaagga caaggcttta 6720 attctgggaa agtcatggag ctctacaaat accaaaaaac gtatgcgtcg aaaacgccgc 6780 acgaaatcga gcaaatcaag ttcttaggcg gccgtattcc ggatccgcca gaatattcgt 6840 atgcggctga ttcaattctt tcggcattta gcactatatg tcgatccaga cgttatgagc 6900 aaagcatacc gttatcttta gatcagcagg ctatcaatgt ctatgctgag cataatgatt 6960 tgccagtggc tgctcatatt tttaatgact gtatttttgc gttggataat ttgtttttgg 7020 aggagtgcca taagaagata tcaaccaaaa gcaaaggtaa gtgaccaaat taggtattgc 7080 cagggactga aaagcctaat ttggtcaaaa cgtcaaacaa ttaagcagtt gctcttaaac 7140 gcgactcaaa ataacgcagt cgatgttaca aaatacttga tctggattga cagaaaatta 7200 cctttaaggt gttgcgcgtg attatcaaat gatgaataat caccttaccg tcaatatttg 7260 acggttcagc attcttttac tctttccaag aaccttggtg tttgcttgta tgtgtttaac 7320 attaactgaa gctaaacaaa aacttagagc atttgctaga gatactagca aaatcaagtt 7380 aactgcacat gcaaaagaaa gaatgaaaga acgctgtatc tctatgaagc aaattatttg 7440 ctgttttgag catggagata ttactgaggg gccgtaccca aatactcgtg gtgattgcca 7500 gttaaatgtt tctgttcgca ctgcaggcga atacataaca acagctgttg caatcaagca 7560 gagcgagaac ggtgaattct cagtagtagt cactacattt agagagtagg ctaaattatg 7620 tatcactatg aagaatgcgg tctgagcaat atttggctgc gcaatggatt tacaattgaa 7680 aatgatgaag actatggtga actcgtatct attgaatctg ttcatgagct tcataatgcc 7740 attgggttgt tcttaattac gcaaaagcct gacttgaatg gtgaggaaat tcgtttttta 7800 cgtaaagaac taaacttgtc acagaagaat cttgctgggc ttttaggagt cagtgagact 7860 agtattagac attgggaagc tgatcgcggt ttaattggta aacctactga gctattactt 7920 cgtgcattat ataaagagca tgttcaaggt gatggcaaac taagaagtat gattgagtca 7980 ttaaatcatc aggaacgaac tttagtacca agtgaaatta gtttttcata tggaaataac 8040 cattcatggc atcaaaccaa ttgtgaaata gcttagttag ttttatttga tagaaaccac 8100 cttcgggtgg ttttccttta tgtgacattt agtaaccagt ttgttaaagt tagtacactt 8160 tataacaaac ggtgaaattc atgaaaaaaa tattggctgc gggtttaatt ggtcttgggt 8220 tggtggggtg cgctactcca gcctataatt atcaagctat acctaaaaat ataagcaaac 8280 cgccaattgg atcagttaat aaagcatttg taggggatca aatgcttgaa cagggaatgg 8340 tggttgatcg tgaagttcta aacgtccctg aaaatattaa aattagtttt gcttattcac 8400 ttacttcagg catttactta aaaacaggca aaaatgaaaa agggcaatat tttcagccat 8460 tcaacactgt cagtggtggg gggatggttc agaaaaaccc tttagctgac ccatttaaag 8520 tagttatgtt agatactgaa ggtaagctct gtgtagtaac agtatttaat gcaaaaaact 8580 gtactgataa acatcaagct actatgaaga cagtagcaat tgcatcagat aattccttcc 8640 aacaaacatt aatttatagt ggaaaatttg gaaataaaat taatgtcggg taccgtgaat 8700 tctcaagtaa tcaagcacgt cctgcattca ataatgatgt tgaatatgat ttaagccaat 8760 ctaagcaaat aggttataaa ggtgctttat tggaagtaat tgatgccact aatcaagata 8820 ttacttacaa agttttgaag aactttaaca aggtagatta agatgagtgc accacaatat 8880 aaaccaatga gagaaagtga agtttgtaat gctatcgggt gggtgttaat agctcttggc 8940 tttatcgcag gttttttatt tattcttgca tttggtcgaa ttgaagtagc ttcttactat 9000 ggtaaagaaa cggtttggtc tggagttatg atagcaacag gaatcggaat tatatttaat 9060 ggattccttg caggctactt atttcaaaaa gtagctagta ttcttcgtta ccatgagaat 9120 aaataatatc ttgcataagc accctaggat gctttttaaa attggtttaa ctaccctgct 9180 tggtaattat atttaactta aaaagaacta cccactcatt gagtgggttt tttattgcct 9240 agaggaaagt aaaatggcac aagaatcccg tttggtcatt gttattgatt cgcaaaatgc 9300 tgaacgtaat gcgcgtaatc taggcaatga acttgttagc attgaacgta aaggtgaatt 9360 tgcatctaag tctatggaca gcttgtctgt agccaccaga gctttagctg gacacatggc 9420 tggtttatta acagtaggtt cagccatttc aaagatggat acatatactg gattacaaaa 9480 tcgccttaag ttagtcacta acaatcaagt tgaactaaat aaagcaacgg aagacacttt 9540 ccgaattgct caaaaaacct attcagcttg ggattctgtg ttacaggttt accagcgttt 9600 tagtgataat gccaaaactt taaacctcac aatggatgac acagcacgtt taactgaaac 9660 agtttctaaa gctgtagcaa ttagtggtgc aagcgcagaa gctgctgatg cagctttagt 9720 tcagttcggg caggccttgg ctagtggaac gttgcgtgga gaagaactta attctgtaat 9780 ggagcaaacc ccagcactag caaaggctat tgctaaaggt atgggtatta ctgtaggtga 9840 attacgttca gtagcagctg aaggaaaaat tacttcacaa gaaattgtaa aagcgcttag 9900 aaatgtagaa tctgatgttg atgctctttt tgctaaaaca gatatcacaa tcgggcagtc 9960 tctcacactc ctaaacaacg agatcacaaa atttgttggc gaagcaggta agggaagtgg 10020 tgcggcacag gtattagctg gatcagttca aactcttgca agtaatttag atttaattgc 10080 tgatggggct ttagtagttg gtattggata tatcactcgt gcaattttga tgaagagcgc 10140 tgctattaaa gagggaatgg cttcaacttt agcgagccgc caagcatctg tattaaatgc 10200 tcaagcagaa tatgcagaag ctaccgctgc tttgaatgca gcaaaagctc atctcgcgaa 10260 tgtgcgagca acaaatgcag aaacccaagc taaatttggc gcaacagcgg cagcaactcg 10320 atacgcacaa gcacaggcag cagtaactgc tgctacaaat gcacaaacag cagctcaaat 10380 taagctaaat actgcaactt caattgcagg gagactagct aaaggggcgt ttggattaat 10440 tggtgggtgg gctggagttg caacattagg agtaatggga ttagcggcag cctattctta 10500 ttttaataat aaggcagagg aggcaaagca aaagcttgct gaacaagcta aagttgctga 10560 gaaagctgat gaggagttaa aaaaattaac tggcaatgat aaggctaaag cagttaatga 10620 tttaactact gcttttaatg cacaaaataa agcattagag aaatcatcgc gtgctgtagg 10680 gtctgcatta attgatatcg agaactatgc acgaggaaat agggaggttg aaaaaatttc 10740 ccaagaagcg agaactggaa ctatcagcta tacagaagcc attgaacgtc taaataaaat 10800 taagttgcct acagatctat atgaaaatct gaaaaaacag gctgcgcagt atgatgacaa 10860 tgcatctaaa gcaagtttat cagctgagaa acttaaatta ttaagagttg aagtgaaact 10920 tggaggtaat gaagcacaaa atgcggcaat tcagcatcaa aaacaagcgg atgctttagg 10980 aaatactgct actgaagcag aaaaggcaac taaggctttg caagattatc aagccaagca 11040 aaaagatagc gttattgatt caatctataa atcaggttgg cttgataaag gttacactgt 11100 tgctcaagct aatgccattt tagaactgca aaaagctaaa ggaatgagtg caattttgtc 11160 taaagatgaa attgatagcg cacttagaaa tctcaagatc atcgaagaac aacaggagcg 11220 agaagataaa ttaactgaag ctaaaagaaa gcagacgcag gaaattgaaa aacaagcaaa 11280 acttactaaa cgcttggtcg gtatttccgg tcaatccggt attggtactg gtccacatct 11340 tgacgtccga tatggtggct cattgtcagg tcagaaagtt tctaatgaac atctggctcg 11400 attacaggcg ggaggaaaac ctttaacttc ctacaagatc agttctaatt atggtccacg 11460 aaaagcccca actaaagggg cttcttcatt tcataaaggt attgattttt caatgcctga 11520 aggaacacca atcacgacca atgttgctgt gaaagatatc aagacatggt atgacagcaa 11580 gggaggtggt tatgtcagtg aagtgatctt tgaggatgga gtgtctctta agcttctaca 11640 tcaatctccc aagatgcaga gcaaggtgaa aggtggtgca agtaaaggaa gtgataaagc 11700 agctggtgat attcaatctc aacttgaacg tcaacaggat ttgcaacggt cacttgaaaa 11760 tgaggtggct agtgaagtcg gacggattaa caataataga aaggcaagac tggaggatgt 11820 tgataaagca aactttagcc cggaacgtac tgcagaaata aaggcggaaa taaatcgtcg 11880 tgcagataat gatattgcta tagccaaaca agcccttaga acgaaattgg aagactataa 11940 ggagttccag aaaaccgagg aacagttact agaagagtcc tttaaccgta aaaagttcaa 12000 tgcagctcat gaccttgaat taagtaagtt tgagcagaag caagctgttg aattgctgga 12060 acagcaaaaa cagcaagagt tagggttatt aaaactagct caggaacagc ggttgtttca 12120 agcccgttta tctctgcttt ctgaaacgca agccatgcag gaacgttaca gactcgaacg 12180 ggaggaaatt cttaagaata ccaagctttc tatagaagag cggcaaaagc taatcgcatt 12240 atctaaagcc aatcaggata aagagacacg cgataaagtg aataatgctg ttcaaaactg 12300 gggtggtatc caagcggata tgaatggtac cggagaattt ttcagacagg atcaggaacg 12360 atttagccgt ttaaatgctg caaatgattt agcagatagt caatttgctg ctactgatct 12420 tgatgaaaaa aatggtttag atgttctaaa tgcacacatg gaagcaggac tcatcaagca 12480 acaggacttc gaaaaccgga aaacagctat cattcaagct gctcaggacc aacgcaatca 12540 gatcgctgcc gaatatgctc agaatgctca ggatattgaa gataagtatc accaagatcg 12600 attgaatgct caaattgctc ttggtggcca aatgatgggt tcactcacat cgatgtttgg 12660 ttcaatgttt ggcgagcaat caaaagcata caagatcatg tttgctgctg ataaagctta 12720 tgccattgca gctgcaggta tttctattca gcaaagtatt gcaaaggcgg ctagtgttgg 12780 ttttccagca aatatcccat taattgcaag tgctattgca caaggtgcaa gcatcattgc 12840 aaacatccgg gcaattaaag atcaaggctt tgctgacggt ggttacactg gatcaggtgg 12900 gaaatatcag cctgctggta ttgtccataa aggagaggtg gtctggtccc aagaagatat 12960 taaacgctgg ggcggtgttg gcttagtcga gaaaatgcgt aagagtgcaa accctgaagc 13020 ttttctcaat aacaatgcct tggcagatag tgtcatgcgc cgtgcaatga tgagctctag 13080 tgcctttata gaaagccaaa agcaggctga catctttaat caaccggttc aagatactca 13140 gattatctat aagggtaata gagacacacc taaattagct tcttctggaa atttagactt 13200 attccatgat ggcaaggtct acttctcatc caatggttta gttcaggatc gttcaaatct 13260 ggatgatgtt caggacttta ctttaggaag tacttcacgc cctcaagctg agatgatgcc 13320 ttcaattgag ccagcttcac cgacaatcaa tttcaaaatt gaagtgatta atcaggtgag 13380 tggggcgaca gttgaagccg aacaactgga cgagcaaaca gtccggatca ttgttaaaga 13440 tgaactggat aagcagcttc caagaacggt acctaagctt gtaagtgatc aaatcgcaaa 13500 tccaaactca accattagtc ggtctttgac tgagaatacg acagcgagaa gaaatcgtac 13560 ttaataattt gaaccctttt cggagggttc attttcataa tatttaaatt tcaaggtgat 13620 agagtctgtt ggcattaaaa ttgatggtta agacatgaaa aaaataattg taatttctac 13680 aacactttta ggccttacgg gatgtgccat tcctgcggta aataatctcg taagatccac 13740 aaatatgtat caggatgatg tttcgggaaa tactgcaaat ttaagggttt atagaagtaa 13800 tattcccatg gtgcagttct atattactta tcaaaataat gagggtgaaa aaatttcaaa 13860 aaacctaata actaagcaga tttcaaataa tttaacaaag tatggctcta tgcatgagcc 13920 caaaaaatta aatatgccta aacccacaat cagtttaaat aatggtgaag agttttttga 13980 gtttaaagta cccgcaaata agaagttaac tttcaggctt acttctgtta ttgggtcaac 14040 tactatgtat agttgtgatg taaaaatgga ctatcagttg gaaagaaatg gaaattatga 14100 attgatccgt ttaaaacaga tcaaagattt tgtgaatcca gctttactga ctgaaccatc 14160 tcaagatgaa gcctactgca agtttgtagt aaaagagatt tttgaagatg gtaaagaaac 14220 tattattaaa tcgatttctt aatgttaaat cgtttttgta attaatttaa atatctaaac 14280 cttatttcat caaaccacct ttcggggtgg ttttttatta cctgaaggaa agttatgtac 14340 aagttaaagc taaatcctca gaccagcggc tatggcgtaa caccgggtga tgatgtgaaa 14400 cgtcagcaga tggatggcgg tcgtggtcgc tattacatcg atgtgaaacg taacagccac 14460 attgttgatg tgaactggaa cttaagtaaa accgatttca ataaaatgat ggctttctgg 14520 cgggtctacc agaacaaacc agcctcattt tatgcggatt tggtgattga tcagggaaca 14580 cgtcagcaat atctatgcaa tttcattcca aactcgttca agaccaatga agtcaacggc 14640 aacttatatc gtgtgaacgc gcagctcgaa gttgttcaaa accagcctaa cctgaatgcc 14700 gatatagcat taattaaaga ttgggaggtc taatggataa cgaatatgcc aagttctttt 14760 tcaatcggaa agttgatgtc tatcaactgg agtgtattga gctatcacat ccttctttta 14820 tgaatactta tcgggtagtc cgtaatgatg accgaggtgt ctatgtacaa cataaggaag 14880 gatccggtca ggtctattat gagttcttgc cagtctctat acaaagatcc ggaatgcttg 14940 gtgatctgga ccagacatta accgtttcta tctctggtct aggtgatgtg atgcctgatg 15000 agtttgaacg ggtaatcgaa gggcaatatc cagatgtaaa gccaaccgta aattaccgga 15060 tttacagttc agacaatctg aactctccaa tgttttattt acttggactg caactctcaa 15120 gtgtcgccat gaaccataaa gctgtgacat tcaaggctga atcaccacga ttaaatacca 15180 ctaaaactgg ggacattttt gcactggatc gctttagtgg tttgaagggg gctatatgaa 15240 aagtcatgat catttgctcg ataggcaata tgacgaggat cactacaact gtgttcactt 15300 tgttcatgaa gctgcaatgg acctatatgg catagatcgg gctgaagcgc ttgaactctt 15360 tatgcagcct aagggcaaaa ttactttttt atcttcacgg ttaaaacttt taaatccgct 15420 acccatgccc aaggaaggct gcatagtcgc cttccatccg agacaaagaa ataagccccc 15480 gcatgtgggg ctttttcgtg ggcaaaagat tcttcacctc atggaaagcg gagtcactta 15540 tttgcctgaa gaggttgtga tggaaatggg gtttaatcgg gtcagttatt atgattaaag 15600 ttatttataa aaaagacgct ttgtctgaag aaaagacaat tgagcaggct caaaccattg 15660 ggcaatggct cacttcaaaa tatgaacata tgcctgagca tgtccgtatc tttcatacta 15720 caagcaatat ggatcatgcc gaaatttcat ttgcgaatga agtcacacca aagaatgcat 15780 atgacttaaa gcagcttgat ttcttaccgg gcacttttat cgtagttgag aaccctaaat 15840 gggtcgcggc tattgtttcg attgtgatta gtattgcgat cgcattttta atgccaacgc 15900 catcaatagc acaaacgact caaaatacta accagtcttc ttcagcaaac aatgaacttt 15960 ctaaccggga aaacaagatc cgggtgaatg gtcgtattgc tgataactat ggagctgggt 16020 ggaatactcc cgacctaatc gcagtacctt acaaggtata tgaaaacaac gttgaagttg 16080 agcatgtagt gggctgtatt gggcgtggac actataaaat caatggagct tatgacggtg 16140 aaaccaatat tgtcgatatt gctggcgcat cggtagaagt ctttcgacca ggtgtagata 16200 ttgtttcagg tgagccatat ttctcgcttg gtaccgaaat taccacgccg ccactaacgg 16260 ttcagcatca aacttctgtt aatggccaag ttttacgtcc tgctgataca caatctttag 16320 aaggtacgaa ctaccttcat tttgcatatc caaacgagat tcttcgggca acggcaaaca 16380 acacagattt aaccactaag tttgtaagta atgaccgcgt agaaatcacc aatgcctcat 16440 tcacgtttaa tggccagact tttgatttaa atggtactta tagcgttcta tcggtagctg 16500 atgaccgtat gacgttatca aatccggcgg ccgttaatgc taactggtta aagcttaaag 16560 agttaaataa ccaacaaact gcagctttgt caccaaagat cagttcaata ggtgaaaaat 16620 ggattggtcc attcattctg gacaatgttg aacgtagccg ggtgctgtgt aattttgtgg 16680 ccaccaatgg actttatacc gtttcttcag gtgggtatca ggccgctgtt aatgtcacga 16740 ttgaagttga agtaacaccg gtaaatgaat ctggtgcagc gattggtaat ccgatgctga 16800 agcagatcat tttgaaaggt tcggcaaagt cacgtcagac cgttggtgca acacttgata 16860 tggtcacgtt tcaggggcgt tgtagtgtcc gtgcacgccg tttaactccg actccgacag 16920 tcacaacagt tgttgatgaa gtaaagtggc aggcgcttta cggtgcttat cctttacaaa 16980 gcacagtgta tgaacatgaa acggtttttc gtgcgcgtac ttatgcaacc actggagctt 17040 tatctgttaa gtcccgcaag atcaattttg atcttcagcg aatgttgccg acttataaaa 17100 acggggcaat gacaacagag ctatatccaa cgtctagctt tgctgatgct ttggtatcta 17160 tggcactcga tgacaagatt ggccgccgtt cgatcgatga gattgatctt gaaaacatct 17220 atcggaccta taatgatgta gttgattatt ttggtacgcc gctagcggct gagttctgta 17280 ctaccattga tgatacgaat ctatcttttg aagagctggt taccaatctt tgtgatgcgg 17340 tgttttgtac tgcatatcgg caaaacaata agctcaagct ttattttgaa cggccaactg 17400 ataactcggt aatgctgttt aacttcagga atatcattcc ggatagttac aagcatgacc 17460 tgacctttgg cgtgatggat gactacgacg gactgatcta tgaatacacg gatccgaccg 17520 acgatagccg tatcaatatc tatttaccgg ataaaggagc caaaaaccca aaagaggtga 17580 aatctgttgg tgtacgaaac aagtggcaag cgcatttcaa tgcataccgg atttggaaca 17640 agatgcgctt ccagcgcaaa tccattacct ttgatgcggc accagaatca gaattactgg 17700 ttttacgtga ccggattgct gtagcggatt atcgcaatgg tattcatcaa agcggtgagg 17760 tggtacagca agaaggttta gtcctcacct taagccatga tgtagatttc attgcaggca 17820 agagctatgt gatttatctg caaatggcgg atggcacagt ggacctgatt cctgttacac 17880 cgggttcagc caaaaataag gtggttttag ggcggttgcc gaacggggcc ttaaagctaa 17940 gtcctgatga ttttgtaaat accatctata cagtagttaa tgatgatact aaaggttcat 18000 tgccttatct ggttgcaaaa agagaaccgg ttgaccagtt ctctaatact attacagcaa 18060 ttaattacga tgagcgctat tacctcaacg ataaagactt tattgacgtg ccggttgatg 18120 attctccaat ttacattcga tatgaccagc tggatattaa tctggcgcgt ttatatcaga 18180 tgcaaagagg ggatttgcca acgactggcg aaatcagttt tgtagttgaa tctggtgcac 18240 tagtttctag ttcgagttct tatcgaccgg aaaccagatt tgtctataaa ttcgactaca 18300 actccagtcc gccgaaacag gaatttattg cccctgcagc gactgaacta cccgccattg 18360 atactggtga gttcccacct gatctggtgg taaatctgac tattaaaggt gctgttgttg 18420 ggcgtggtgg tgatggcggt ttacctcatt tggcatttgg cgcatgggag tccgatccgg 18480 attacaactt tactaaaacc cgacgtgatg ggtttcaggg agcacccggt ttattgaacc 18540 ggcacagcaa actaaacctg attattgatg gcggcactct agctcgaggt ggatctggtg 18600 gtggagcaac accaagcggt atttacactg ggttgtctta tggtgttcaa ggtattccgg 18660 gtggagctgg tgcaccattt ggacgggtca tgacaggcca gccaatttca agcgactcac 18720 aagattggcg ctggtatttt ggaagttact tcaatgtctt aaaaattact gatgccgaag 18780 cttcggtacc cggaaaaggc taccgaaccc aaaatgaccg ttatggatcc ccattatcag 18840 gtgatggcgg aaactggggc gaacgtggta ccaagtctac taatgatgga acatggaact 18900 ggaaatacca tggcacaact gaaggtcagc cggggccagg tggacctgca attgtgggag 18960 ttgcaccact gacaactcaa ttgattaatg gagggaaaat cttacaaacc ctttaaacct 19020 tataagaact ttgagcaccc aattcgggtg cttttttatt acctaaattt tctggagaaa 19080 ttaatggaac cagtttccac tagcggtttt acagcacttt taaaattata tgggattgca 19140 atcatggtga ctttagcagt cggtttggtt gcagcagttg tattaatgac tcgtatgcca 19200 cgctcaccac aagagtgggc agttggtttg atctgtacgg ttgtatcaag tttggctggc 19260 ggctcattca ttattgtgaa gtggggactt catgaatggg ttactgatgt atgggggatg 19320 attgctctag gtgggttctt ctttgtttgt ggtttacccg gttgggcttt agtccgttgg 19380 atttttaatt ttatagataa acaggaaggt aaaacgatcg ttgaagtgat caaagagttt 19440 aagaaagcca gaaaagacat tgaaaacagc taatgccgcc ttcgggcggt tttttacatc 19500 tgaaggaaac cgaaatgaac attgaacaat atctggacga gttaattaag cgtgagggcg 19560 ggtacgtaaa caacccagca gatcgaggcg gtgaaacaaa gtacggtatt actgaagcag 19620 tagcacgtac taacggcttt aagggcaaca tgaaagattt accgcttgat gtggccaaag 19680 ccatttataa aaagcagtat tggacagatc cgcgatttga tcaagtgaat gtaattagct 19740 cgttagttgc tgaagagctt ttagatactg gggtaaattg cggtaccgga tttgcaaaac 19800 cactcttaca gcgtgcttta aatttgctga ataaccaagg taaagcaggt tggccagatt 19860 taacagttga cggaatttat ggtccagcaa ctcttaatgc actcaaaact tatctggcca 19920 agcgtggaaa agacggcgaa aaagtcctgg tgcgtgttct taatatcatg caagggcaac 19980 gttacattga aatctgtgaa cgcaatccta gccaggaaca gtttttctat ggttggatcg 20040 ccaatcgagt tgttatatga aagtctttca ttgcagacga tcaaagatag ctttaacaat 20100 tacattgctg tgcattctat tttcaggatg cacagctcat acgatcaata gcaatgtcaa 20160 tgtctcaatt tgcgctagag cattataaaa aaaagccctg aatgatcagg gctatttaat 20220 aaacttcaat tcacatactt ctacaaagct cgagtagtct tatgtttgtt attgtatagc 20280 ttgataatcc tctatctttc atcctagggt tgtgcacata cttctatcct taaattgtgt 20340 aatgaaattt cttctgttgt agttgagaag cttttcaatc tgttaaaaga atccaaaaag 20400 catcaaatga ataaagaaac tacttattta acttgaatca tcattttctg tttactaata 20460 aatgaaagtg cttggatgta tagggattgt ttttttaatg ttatgttata atataacctt 20520 ttcttaaaaa agggggggat tatgaaacct ttggcagctt taccgttaat ttttatagca 20580 attcagcaag tgcaagctga ggagagaatt gcaattttaa agcctcttgt ttttaaggca 20640 aatgcattaa aggaaaaaaa ttatgtggtg gacaaagaaa aagtagaaag ttccaataca 20700 ataggtgatg ctcttaaaaa tataacaggt atacaaagta cttcatttgg acccaatgca 20760 ggtgcaccag ttatacgtag tttgagtgga aatcgggttg gagtaattga aaatggagaa 20820 tttattaatg gaatgaatgc atttagtgga aatattaata taccattcga tccaattttt 20880 atagaaaaag tgatagtgaa caaaaataca gataatattc gttatggcgg aaatgcaata 20940 ggcgggagtg ttcaaataga atcgggttta attcctaaaa aaattgaaga aaagccaaac 21000 aaattagata ttgtctttcg gaaaggattt aatgattttg atgtaaaggg gttcaatttt 21060 aacatcaatg atcaaaaaaa ctggtctaca aatataagat attcagaata tgaaatttct 21120 tcttataaaa ttccaggaaa tagtaaagcc aaattatgtg aagaccagat tttttcaaat 21180 tcaggtggga tcaatagtgc attagcagct tcctgtcaaa aagatagtag agtccaacat 21240 atttataaca agtcgtcaca accatacata gataaattta tgactgagaa tcctgattgg 21300 gcagatggcg atttttcttt ttatacagat aagcccacat ctatatgggg aggaaaaaca 21360 tatataaatc caaaaaatcc agagtacata cctaatactc cgcaaaatac aataaaaaag 21420 atcaatacgg atgttacacc aaattatttt aaaaaattag gtaacagtta tgctcagaat 21480 gagaatattg ggtttggaac aacatacttt tttgataaag gtttcattgg attgagtgca 21540 gataagaaaa aaagtgaata tggtgtacca ggattttcat tacaaaatca atcttttgct 21600 gattcttatg aaacattacc ggttggtgtg aaaatagatc aaaatcgttt tgtattaaat 21660 tccaatttta tccaaccaat ttcctctgca gaagagataa gtttgaattt tcaacagctt 21720 tctaataaat ctggagaata tgttggtact gcaaaagcta atgagtataa aattgataat 21780 caattaattg aattaataat gaaacagtca tcctttaagg gattagatgg gatacttggt 21840 tttagcctta aaaataggaa tatcgaagga agtggtactc agcgctattt acctaatgta 21900 agtactatta gtaaagctat attcttacaa gaagaattaa atatcaaaca atttacttta 21960 aatacgggct atcgttttga aagaattgaa catgagcttc aagataatga ttttaaacta 22020 gcaagaaatg ctagtaattc aagaatagaa aatagaaaat ataatttaaa ccaatatttt 22080 atcggaggag aatataaggt taataatttt ataaatttaa aagttgatta tggtatttca 22140 gaaagagcac ctgaagtgaa tgagctctat tcaagtaatg ttcactattc tgttatggca 22200 caagaagaag gcgaccagaa tctcaaacca gaaaaatcta aaagtttaga gttaggtatg 22260 tttttgaatt ggaataattg ggtcatgcaa cttgttgggt atcaaatgga ttttgaaaat 22320 tatatgtatt tatctcattc aggtgttgct gtgcaaaatc gattaccttt aaaatactgg 22380 aaacagacag acactgacgt caaagggttt gaaattgatt taatttatga ttttaatcta 22440 gctcatattg ggaatattaa actaggtggt ttagctgatt ttgttaaaaa taaggctgtt 22500 aatcctacag atataaggtt agctaatgat ggagtttacc taccaaatat gcctactaat 22560 cgttatggca tgtttcttga gtggagaaat gattcttgga aaggtaaaat ttcaagtatt 22620 tactacgatg agccaagata tctaggtaag aatgtaatac aggaagttcc tttatctggt 22680 tacaacttac ttgaatttaa gatagataaa aaattaaaga ttaaaaatgc ttcatttgat 22740 atatttttaa atggtacaaa tctgctgaac gaagaggcta gaccacaaaa ctctcctcta 22800 aaatatattg cccctctacc agggcgagca tttcaactgg ggataactat gcatatttag 22860 gttgctaaag atataaagtt agttcttatc tcctgtcttc aaatttagta ataaaaatat 22920 agtcttaaag ccgaataatt aatcggtttt aagattttaa aataatcaat tataaagttt 22980 aaaatttttt atttataaaa tgtgttcaaa taatgaactg attttttagc tcaaggagcc 23040 atcgtcatat aaataaagaa tattacaaag gttctttttt aatttttctt taaggtatgg 23100 tatctaatct tagcattttt tatatttaat ggtttttaaa aatggcactt aatgttttta 23160 aattcaaaaa aatatgcaag gatgttacac tattaaattt taatttgctt ttatctatct 23220 ggctaggttt atttctgaat ataggttttt ttaaaaaaat ccatcaactt acaccttata 23280 atggtattaa gtcagttctt ttcttagggg cgacattagt tattttaata gcggcatata 23340 atttaatttt tcaattaata aattggaaat ggactgccaa aatctttgca attttattga 23400 tatttattgg tggctttagc tcttattttg taaacacatt gggtgtcatt atttcacccg 23460 accaaattca aaatatggtg cagaccgatg tttcggaatt taccgatcta atctctttac 23520 gctttgtttt atggacagtt ttttttgtta ttttgcccat ttttttaatt actcaagtta 23580 aatttaaaca agaaaaagca tcacggttgt tattgaagaa agtattctca ctggtagctt 23640 catttgcagt ggtcggtgtt ttacttttta cttactatgt cgatttcgct gcaatatttc 23700 gtgagcatcg tgatttaaaa gggatgattt caccgcaaaa tagtatttca tcgcttatgt 23760 cttactatca taagaaggct ccgaagaaaa atctgcctct tgtgatatat ggacaagatg 23820 ctcatcaagt tcagcaagta caaaagaacc tccctaagtt aatgatactt gttgtaggtg 23880 aaacggcacg tgccgaaagt ttctctctaa atgggtatgc aaaaaatacg aatccggagc 23940 tttctaaaca agatattttc aacttttcgc aagtgagctc atgcggtacg gcgacagctg 24000 tttctgtgcc atgtatgttc tcgggtatgc cacgtgtaga ttatgatgag caattagcta 24060 gtcaccgcga aggtttatta gatattgcaa aacgtgcggg ttaccaagtg acttggattg 24120 ataataactc gggttgtaaa ggtgcatgtg atcgcgttga acaataccag attccagaaa 24180 acttaaagaa aaaatggtgt aaagatggcg aatgttatga tgacattctc attgacagct 24240 taaagcagta tttggctact attgccaaag atgatgatcg tccgcgtttg attgttctgc 24300 atcaagtggg tagtcatgga cctgcatatt acaagcgtgc acctgaggca tatcaacctt 24360 ttaaaccgac ttgtgatact aatgcgatac agggctgttc gcaaactgaa ttgctaaata 24420 gttatgataa tacaattgta tatacagacc atgtattaag ccaaatgatt ctctgtacac 24480 gacaaatttc acagaaccct tatcctatca gggttctgcc ttcttaaaat tgccaaaatt 24540 tccttaaact cttctttttt cccaaaacca attaaacgct gaatcgccat ttgaacatag 24600 tctaaaccat agcgaaataa actcattgag agtcgtccat gcttctttat ttttatcgct 24660 tttttttgat catgttgcca ttcacccgtt aagtaacacc aacagaagct tatagctaac 24720 accgcaatca attttttcac tcgtctaggg tctgtcaagc gcgtattttc aagattaaac 24780 ccgcgtcctt tgagacaact gaataaggtt tcaatttccc agcgtaatgc ataatcctga 24840 atagcattgg cattaaactg aggagaaacg acgagtaaaa gctctccatt ttctaactgt 24900 agtgcactta tatatagttt cacccgacca accaaaatcc gtcgtttacg acattcaatt 24960 tgaccaactt taagatggcg aaataaatca ctaattttat gattctttcc taaatgattg 25020 gtgacaatga agttttttta acacgaatgc agaagttgat gtcttgttca attaaccatg 25080 taaaccactg ctcaccgata aactctctgt ctgcgaacac attcacaata cggtctttac 25140 caaaaatggc tataaagcgt tgaatcaaag caatacgctc tttcgtatct gaatttccac 25200 gtttattaag caatgtccaa aggataggta tcgctattcc acgataaacg attgcgagca 25260 tcaggatatt aatatttcgt tttccccatt tccaattggt tctatctaaa gtcagttgca 25320 cttggtcgaa tgaaaacata ttgaaaatca actgagaaat ttgacgataa tcaaaatact 25380 gacctgcaaa gaagcgctgc atacgtcgat aaaatgattg tggtaagcac ttgatgggca 25440 aggctttaga tgcagaagaa agattacatg tttgctttaa aataatcaca agcatgatga 25500 gcgcaaagca ctttaaatgt gacttgttcc attttagata tttgtttaag ataagatata 25560 actcattgag atgtgtcata gtattcgtcg ttagaaaaca attattatga cattatttca 25620 atgagttatc tatttttatc gtgtacagag caaatgatta atactctaaa agaaatatca 25680 aagtatcaga caggtttatg gtatttatct gatcatggcg aatcaaccgg agaacatggt 25740 ttatatttac atggttcacc ttatgcaatc gcaccgagcc aacaaacaca tgtaccaatg 25800 attatgtggt tctctgaaag ttggaaacaa cataatcttg ctcaagtgaa ttgtttaagc 25860 caacaaacta aacaaaagtt aagtcaggat aatttattcc caagtttgtt aagtttgctg 25920 gatgtaaaaa ctcaggtagt aaataacaaa cttgatatgt tgagccaatg taaataaata 25980 tatttttaat ttatataaaa cgaagcaaaa tagacttgct tcgttttata aaatgtattg 26040 gttcttttat atttaaaaaa taagagggca gtcgtaaccc ggataaacac cattcttata 26100 gtcgaatgtc ggttcgaata gatctagtag gtgaactcga tctttattta taggttcata 26160 gttcgcgcac atacaaagta acctctttat gattttcgaa attacttttc catcataact 26220 aatataaata aaaagagggt aaataataga ctgtagacgc tattattcac cctcatggta 26280 tatatcttta acgccagcta ttcggaactt tgaatttacc tgtaggcatt ggagaaccca 26340 gaacatactt aacgttgtaa attaaaccag gcaaaacagt gtttggcttt tcattaaagc 26400 aaacataggt attgtttctg gatggtttaa ttaacttata ttgtgtacca gcacttgaga 26460 cataatagac accatttggg gtagtcttaa ggccagcatc aactttagaa atattttgat 26520 tgtaactctg gcttgtattg ttaatagctg agaaataact acaccctagc gatttagata 26580 cttcagcagc tttacgtaat gcgtactggt ttgctatcga tttatgggta tatccgttta 26640 cagatgcgcg tacttgaaag acattatcat caataatagt ggcttcaacg ccaccagaag 26700 cccccatttc ttgataaggt gtagtacagg cttgtaaacc aattgttgct aaagcagcta 26760 aaaatatctt tttcataatt tatataaagt gataaatgcg tcacattaat tttaactatt 26820 tagaagaatt tttcaattac ttaaggattt cttaaaactt gagttctaaa aatctagaat 26880 ttggcctgcc attttaaagt tatctaacac ttgaatgtgg tggttaatta attcttgagc 26940 ctgatttctc gattcatttt tctcgaaata taagcgactt ttgattaatg cttttactgg 27000 ttcagaaata atcacgtctt caatcatatt catagctttc tttaaatcat cgaaagaaac 27060 ttgaatatat ccatcagtca catcgttatc atcatcgtca gtggtatggt taattagcct 27120 tttaatcgta tagcttccta tggccaagct gttcgcgata gtgccaaagg tgcggcgtaa 27180 atcatggaac gtaaattcga taccagaatt ctcagttact ttgtcacgtg ctgctcggcg 27240 gtctgaaata tgggaaacac catttctatc ggtaaagaca tatttgttat caccggcacg 27300 tttttttcgt tcacgcataa tgtgccaaag ggtatcaccc ataggtagca aaagatcctc 27360 atggtttttc gtattaataa ttttgatggt accaaattga agatctacat ttttccattc 27420 aacagattct gcttcactac gtctaaaacc agttagagca agtaagaata aaaagtcttg 27480 gtttgtgtac gctctaaaat cgttattttg ttcacccatc caataagtag tggccacagc 27540 caatgcccat gcttcgcgct gatctgcacg aacatggcct tttctacgtt taattttatt 27600 gaaagctttt tcttctttaa cgataacaac cgggtttttt atatttagaa ttttattccc 27660 ggactcatcc ttatacctgc taatcgtatg gttaaagaga gcatgtaaaa attttgatgc 27720 aagattagct cgggaagggc ttgctttcga aagcttcaga tgacgatcaa taatcattgc 27780 actggtgatt tggtcaagtt ttaaatcttt ccaatcacta aagtagtttt ctatgcatcc 27840 gtcataggca attaaagatg tttccgccag ctttttacgc aatttatagt attggtaagc 27900 ttcactaagg gtagggacta gcttttgtaa ggcatcattt tgaattgctg aagctcgtaa 27960 atcacgcttt tgcttaactg gatctacacc ttcatccatc aagataagaa gccgtttagc 28020 ttcagttctg gcttgttcta atgtatagac gccatgtttt ccaataactt tacgtttaga 28080 cttgccatta ggcattttct tttcagcaaa atagctttta gttttgccca cacataagcc 28140 aaatcctata gttactgtat ctctgtaaaa gatttgtttc tcttcagaca aaggaataga 28200 gtctattacc gatttagtaa atttaatgtg ttgagccatc tttaaattaa gcaatacaaa 28260 gcaataccta acgatacaat acaataattg tgaagtctat taagagtcta ttttgaaggt 28320 ttggtctatt aaaaaagaga gttttaagta ggggattttg ttttaagtta ttgttatcta 28380 ttaaaaataa atgctccgaa gatgccgctg catgtcgtta cccttgaacc ctaaagttca 28440 gcgggtcttt ctcaattcta gcaatacatt gcaatattaa gcaataccta gcgatattaa 28500 aaaatcaata tttttaataa tttatattaa agcaatacaa tgcaatatta cacaatcttt 28560 agcaatacaa aaatagtcta ttaatggtct attttgataa atacggtcta tttttcaagt 28620 ttaagtctat taaaggtcta tttttggtga ttaaaaaagc ggcacttagc cgcttatgct 28680 gtatgtgcca ttttgttttg ttcaatataa gccaaaacat cagacttcat ataatttact 28740 tgtcgtttat gaggtttaga gaatggaatg ccgccacctt cacatctttt cttctgcaac 28800 cacggtaagg atacgtgcat aacaatagct actgtttcag gtggaaaagt ttgattatca 28860 gcagcttccc aaaattcctt cttagcagcc tctttttctg catgagtcat acgatctaat 28920 ttagttaaac gtgacattta tttctcctta ctttccgctt taggatttgc ccaccaaagt 28980 acagggccat cttctgaatc aaatgctgca attaaaaaga gtccttgttc tggcggttct 29040 ggcttccagt ttggccaaac tactgcatct tccggtatat ttggtatttc atcgtaatct 29100 aatagttgag tttcaatttc aactctaaga ttcatttgaa gttgtgccca ctgttctctt 29160 gtataggctt cagctccttc ttcaatggtg tcaaacaatt caatatctgg atgaaaccaa 29220 ttgaaaaggt tttcaggtgg ttctattggc tggatctgat atttaaaacc cgtctcacta 29280 gatccataaa atagttttgc ttcatcaaag cttttggtta caagaggggc agagcctttc 29340 ttgtagcaaa ttactatttc atcaaattta aaaacacgtt cagctgtctt caaatcaaag 29400 cattggtaca taggttcact aaaccaactc tcaacataaa atagattttt aatatgatct 29460 ttgcgggaac cgtgccattt ctgaactttg ataacatcat caaaaatttc taagaaaaag 29520 ttgttgcctt ccttttcatg catttttcta taacgctcaa cagctcgctc agctatctct 29580 tttgaagctg ctggcgtttg cttaaaaggg ctgtaacctt caggtcgcat tgcaaccgcc 29640 cataaagttg attcactcat ccttcagctc ccgattcgct aacacccaac ttaatgcaac 29700 cttcctcagg taaatcagca taccaacagt agtatccttc accgtcataa ccatcttgga 29760 gccatttgat ggtcatttca gtttccatct ggaattgatc tttttcccca tctggcgcac 29820 caaaatcaaa ggcttctttt agttcagcgc aagttagagt gacactaggg gtgggagtat 29880 ctggcaccgt ctcggctttg gctttattcc ataactgcca agcatcatta gttacaatat 29940 tgaaatagcc attcattgtt tcactgaatg ctaggatgtc atttttacga atagcacttt 30000 cacgtttaaa aatttctgta gttttgaatt gtgattcaaa agggatacgt tcattacctg 30060 tcatttaagc caccatctct gcatattctt ctttagtcca ttcaacaaac tctttataaa 30120 gctgctgcgc gggtttattt aaccggttgt gatagtcgat cgttatgcgg cgccaagcga 30180 ctggtaccgc ataatgcttg gttagaaaca tcgcttgatc catgccttgc cggactatta 30240 cgtagcccag caattgcaag tagtacataa aaccaagcat gtgtttttgg ctcactttct 30300 tgtactgatc tttcatatta gaaaccgtct cctaataaat aatcaggctc agcctcttga 30360 agtggcgtag atgtagggtt ctctaattca aagcggcgtt tcttaacaaa gtccatgagt 30420 cgtgattgaa tctgtggatc tcgtgcggcc acatctattt ccaaagcatc taatgttgtg 30480 agatcgggcg cgttttggat ctggaccatt agtgaaggtg gttcagttgc ttgcgcctta 30540 gatttttcga gctcttcaag acgtttgtga gttgcaagta gcaaaggctc catttgttta 30600 tcagaccaag tgcgtgtata tcgataaact gcatttactt cgtctggtgt ttttgagtcc 30660 ttaactcgtt gcagcagggt atcaagtttc ttctgatatt ctgaatcagc ggtttctgat 30720 tcaatagccg gctcagctgt ttgtgctttt tctacaacct ctggttttga atttttaact 30780 tttagagatt ccgcatgact ttctgaaggc ttttcttctt cgacttcttc agtaggctta 30840 tttagaagtt ttagaatgtc ttccgcaaac tcaccaccgc tgattttaat aatcgcgcag 30900 caatgagcaa atgcattatc aaaacttgag tgaacttggc catgctggag catgcgcaat 30960 tgtcctttag atccattcca cttaaactgc tgcacaccta attcaacagt tgggctaggg 31020 taagagcaag tagaaccttt ttctggcgca actcttaatg gttctggtac ctcaaattca 31080 ccaataaaaa tagttctagg ctttaattga aattcgaatt tatcaaaaac atcaaagcca 31140 aagtcataag ggttaaatgg ttcccagcca ttacgctcag tattatttac taaaagtaat 31200 tcaccgttgg cccaagcaag tttggcttca actttattta gaattttcat gctgtcatcc 31260 ccgttttcgc taaggtttca atttcttgtt taactgcagt tagttttgcc gcttcaattt 31320 ggatcagggc atctatgccg aagtgctcac aaactgtttt tacatcgagg ccacgttcag 31380 caataaagtt ttgaagttca tctctttgtt gatctgagat accgttaaat tctggtggac 31440 taatccaagt gccacgttgt ttatcaaacg tgcaattcaa tgctttagct ctcattaaca 31500 ttgcttggcg catgttctgg taatacatgt gttctttatc aagcgactca gttaattgat 31560 taaggtcacc tgcatgctca gcttcttcac agctttgttt ccagttttct agctcttctt 31620 gggctttagc tgctgcaagt tgtgcaggcg ttaaggtgtt aatgtgatct ttagcttgag 31680 taatcaggtc agccaagaaa gtaggatgtg ctttaagatc tggtacccat acttcaccag 31740 tttcaccacc taaagcacct gagtttttcg catgatgtgt aggcgagggt ttaaaattaa 31800 taacgcgggc atttttacct tcacctgtag taacagttgt tagataaccc atcaaatctg 31860 cgatacggta aagctcgtta cggtttttac cacctagatc tgggcggtaa ataatttgat 31920 caccgttttg atcttctgat gcgtgtgcaa tgaaaacaac atctttacct aaactgatca 31980 aagtattgat gtattgcttg aacgtttggt tcgctaaacc ttgagccttt aactttaaag 32040 agccatcttt ttgacggtta ttagcagtta gcaatagatg ggttttaatg cattcaagca 32100 ttgcacccac ggtatcaatg actacggttt tatatggtgc taagtcctgc ggagtaaggt 32160 ttgcaacatc actccattgt tgaacctgta caaccgcacc acgacgtaat tcaccagtac 32220 ggtgagcacc acggtcaaag tcaaaagaaa ttgctttttc cgcagtaaag cccatcgatg 32280 atttacctaa acccggatca gcgtataggt acacaataat tgcttgaacc aataaagttt 32340 ggtcagcagt aataatcggt aacgccattt ttcttatcct catctagagc cggtgaagcc 32400 gcgtttttgc ttatatgctt tgcggtcata agtagggatg tttgtttcac gcagttttat 32460 tgcgagctgc tttctgcgtt ggaaatcgat ttcttgggtg agttcattcc aaacttttgg 32520 ataagaagtt tggaacctga acacatttaa aggcgtctta actccgtctt taactttgta 32580 aagaactgag ccattagcat tagatgcgta cacttgccag ccaatgcgga cagagtagag 32640 gcccttatca tcacggccta aaaatgacat gtagccgtca gggtgttttt tgaaattaga 32700 catgttcagc ctccttacat tcgcatgtac caacaaaggc atacgtaagc gggctaggag 32760 catctacagg tgagacgtcc ctaatattta aaggaataat ttctttgcga tatttaacta 32820 aaaccacatc accttcacgg caattgacaa ttccttctct agaagaaaaa cgtgcagatt 32880 tagaagattg ggttactctg caaaatgaaa cctcatcacc agctttgatt tttgaacggt 32940 caacaggaat catcttcttg caagtagggc agttataatc tttcattagg ctgcctccaa 33000 ccagttatta cggtcgatat agccagccaa taaaatattt atatttttat ggtcatcatg 33060 attggtaaag tcattgaaag acttcccgct tagatccgtt actgaatcaa tagccaaatt 33120 tgtaatttca gcagttgtaa agtcagatcc agctacgccg tagctatcag ctacaccgtc 33180 aaaatcgaag ctcacgttta atttgaagcc gtcaatgcgg ataactgctt caccagattt 33240 ttctccagtt ttcttaacag ccagaagttc atattcagaa gcaacgactt gctcgctttc 33300 atatgagtaa ttagaaggga cgctagaatt agcagttcga tattcacaag aactcaaggc 33360 tacaagtaca gcaattgctg taactccagt taccttatgc ttgtttgaaa aggtttttac 33420 gttcataatt gatctcgcag ttttgcaaaa gcacatcgga cctggggagg ggcggtgtgc 33480 ttttttgttg tctgtgagat aaatattagg taaacctaat tattaagtca ataggtattc 33540 ctaacaaaat tagaaatacc taatttttgt gttttaatag acaaaagaaa acccacacgt 33600 ggtggtgggt agattagatg aattggatcg ctttttactt attgctcaat acttttgctt 33660 ttgcctctct tgattctttg cgatctttta atgttttttc aagcaaagag atttctctta 33720 agtcagacca agctaagaag aagctaaaaa ttgaggtgag tccaacagaa agtattagag 33780 ctaaaagatg cttagctgaa agtaagccta ataaattaag tatatacata ctaaaaacaa 33840 gaataataaa aagcatagcc acatataaag atgacttact tcttatgtcc acagttgaag 33900 tcaacctatc tcgttctgac tgatttaaac catcaagctt taatgcatcg agcatacctt 33960 tataagccaa ataaatttga cttaaaggga gaagcagtac aaatgaaaat tgaaccagat 34020 ttattgtaat atttaactct aaatatttaa aaattattga aaatatagca aacagaccga 34080 ctaacactag tgcgataaat ctagcattat tgtagaaggg taagtagcgt ttagccatat 34140 tagtcaccaa aatttatatt ggtagtcatc caattataca attgaacttt taggccgtcg 34200 ttataaactt tattattgat tgtttcaact gaaatcttgc cgctcatttt tagattatca 34260 gccgtaacct tggtcccatc ctcaagagta ataacataat catcattatg tcgcatggat 34320 gaagctacag tatcaataac tttttgccca ctttttgagg ttttgcggtt gtatgtaagt 34380 gttaatttta actttaggtt tgcgtcatca agcccatcct ctagttttaa attttctaaa 34440 tcaactccaa aagctgactt aagcacatca accacattat cttcaatttt atagtcaatt 34500 ttcgcaggta tgcttgattc gacagtatga acaggttgaa gttctgttga cccaatgcca 34560 gatgagattg aaatagtttt agctggagtt gattcaagct tttgcttaac agtgggattt 34620 ggagcatctt ttaatattaa tgcactattc tctggcaatg ctttggctgc ttcacccaaa 34680 agccagccca aatatgactc caaggttcta gcggtaagtg atcttgattg aatgattgcg 34740 acatggttat caataacacc aaagtaaaga acactatcaa taaactcttt tcttacaacc 34800 tctgtagcgt caacgccatc ttcatcatct ggcagatcat ctgttaaata ggttttaatg 34860 ggaaattcag tagcatcatc actgtctatc tttaatacag cctgagcttt gcctgactca 34920 acaataatca actcgccaaa gaacatgctt tggtgtgaac tagcatgatt aattagaata 34980 aaatcatctt ttgttgcgga gacaaattgt tgacgattta tggctttata gtaaaaagaa 35040 tccttatcca gcaattgtgc ttttagtaat tgacctagat tggcgccttt tagaaaatct 35100 acttttttgt agtgtactgt tttgtctttt actactgttt tactcattat ttcctcctcc 35160 cgaatcgctc taaagtactg tgtagggttc acaacttatt aatctttggt gttgttaatt 35220 ttatgcccaa gctttccttc ttttaccaac tgcactactt gttcatttgt aaggactgga 35280 ataaagactt tatcaccaat gtcctttgag aggatcttca cttcttcggc tgttagcacc 35340 aaagcttcac catgtttcgc agcatcattg atgcgagcaa taatctggtt gattggtcgt 35400 tttgaattgt ccataagtct tcctgtgatt aatgcgaata aggatgttct tgtctatgct 35460 gacttggcgg cacgatatct gtaatagcgg taatactttc aacctcgtcc atttcaaaga 35520 aaaatcgctc accaccattc acagaaagca aacttaaaac cccaccattg atgccgacaa 35580 attctttaat tgtgcatctt ccatccttca agcacacctg aacaaactca ttcggcacaa 35640 gatctgcatc agggtcgcac acaacgtacc aaccattacg aattgctgga aacattgagt 35700 cgccagtgcc tttaatgcca taggctcttg gtcctgctga gtgggttgga acatatccat 35760 caccagcatt tccttcataa cccatgtcag taaaataacc atccattccc atcttggagt 35820 acgcctttac aggaacccaa cgtttagatg atggggtaaa aggtttttcg ataattgttg 35880 aaaataaaag agcttcatca ctatcactaa tgttgtattt ctttttgaat gcttcaatat 35940 ccagttgttt aaatttatct ctcgtgcttg attgaatctc tcctgtgcca gatgcaagcc 36000 aagaaggatt aacattcaaa aattttgaag cacgtaataa attttcacct tccattgttt 36060 tggattttcc agacagccaa tcactcacag aaggaggttt gactcctact gcacgagcaa 36120 gctcaacacc tttaatcttt ttaggtggca aaacttccat agcataccta agtcgttcag 36180 caagagtatt catacaacta tcctcacaat gttaggaaat cctaacataa ataaaattag 36240 gtattcctat tgatttatca taaggaatgc ctaataatta aagaaaaatt aggagcacgt 36300 tatgaatgac gcacaactta tagacaagct aggtggtgtc acagcggtag caagacttct 36360 agggattact ccgccatcag ttagtggatg gaaagctatt ccccttgata aaaaaatcag 36420 gttagcagtt attgctgaag atcttggttt aacaacacga aaagagcttt tccctgataa 36480 ctatcaagat atttggattg aactacgtcc ccagacgaca aaaagtagaa accttggatc 36540 attaaccgct taggacctta accatgagca aagtatcaaa tgaattgcct gcaagcgcta 36600 gcaataacga atcgctcata ttgcaagcgc taaatactag caaccaaaga caagtagccg 36660 agaaggtggg aatagatgca agcaccttgt cgagaatgaa aaatgacaag aaaaacaatg 36720 gattgacaga gattgaattt attagctctt tgttgacagc cattggattg aaggtggtgc 36780 cagaaagtga tgtgtattgc tcacctgaaa ttgcagaagc aacgcgagtt tatttagcac 36840 atgcattcac ttcacctgaa tacatgcgga ttttattcaa ataaaaaacc actacctgcg 36900 ggaacaggag tggttaggca ttcaaatgag gtggatcaaa tgaacacaaa caatttatca 36960 gaacaaccaa tcgaactcaa ctcaccagat tttttaatag gtgacgttgt agtacttact 37020 aaagagtgtc gaagttttaa atcaaacgat ttatttgagg ttaaaaataa aactttgact 37080 aggttgtgga ctatcaaatc ggagaatcat ttgattctgg tttcatcaaa agaaatccgt 37140 acagcaacag tagcagagct caacgctaaa cgccgcctaa caaaagctga gcaagcatta 37200 gcggaggtgt catgaatagt caatttaagt ataaacctga gtacaaacag actcaggaaa 37260 ttcagtcctt ctttgatcca gcgttagtga ttctcaatga gctacatgat cgtaaccgta 37320 aaaatctaag agccaaaggt tatgacgaaa ataatgctgc aataacgcgt gaagaatttt 37380 cacaaactat ggcacagcgt tttcgcatta atcagtggtt agcagggcag atcgttaata 37440 gtttggctaa tgctgacttg gttcaaaaat ttggtgggta tgtaaagcct aaggtcggtg 37500 tacatgagta attttgtgcc taattccttt caagtgccta atgcatttgt tgacgaggtt 37560 ttaaataaaa tctctgatgc tgcatgcaaa atttatttag ttatttgccg taaaactcgt 37620 ggctggaata aggagatgga ttccatctct ttaactcaat ttgaagagat tacagggaag 37680 agtagaccga cagttgttaa atgccttaat gaattaatta aagttggttt agtcgtggaa 37740 caaccaagca caattcatgg aaatacattc aaattaggta acgatactag cgttggttta 37800 gtgcttaaat tccctagtaa aaatttttta ctacctgaaa tttatggcca aactagtaaa 37860 aattctttac cactgctagt taaaaatttt aactacacta gtaaaaattt tttaccgcta 37920 ctagtaaaaa tttttaacac acaaagtatc actatcaaaa acaactctca aagtaataaa 37980 aaaataaata aaaaaagaga gcctgtttct gaaaaaccta aatcagaaaa accaactgaa 38040 tttaatccac gtttagttga actaccagca tgtgtagatc cagagctgtg gaacaatttt 38100 gttgatatgc gtatcagcat caaaaaacca ctttctgaaa atgcagtaaa gctaatcctt 38160 aaaaaactta tctcgtttgg ccctttggct aaccaatcac tggaaaactc aattatcgga 38220 aattatcagg gtgtatttga gcctcgccaa aatcaaattc aggaaaaccc acaatctcat 38280 aacgttcctg aagaaccggg ttatttcact caaatgtacg ctgagagcaa ccgttcaaac 38340 gtgattgacg ttacgccagt gtcacaagat tttggaggct attaatcatg aatgaattag 38400 caccatttga aagtttttta aaagaactaa ttgcggctta cagaactaaa tacgctgttc 38460 agttcaataa gaattttcca gtagagggga aaaatgccgt tccaatgcaa atcgttgaac 38520 agcagcttgc taaagcattg gttggggtta cacctaacca acttcaaaga ggcttagcgc 38580 tattttacgc aagtacaaat acatacatgc ctaacttcgc tgaattccgt gctatgtgca 38640 tgggtgatga ttggtggagc gctgagaagg cttgggttaa ggcttgtgaa tacactcaga 38700 tctctcaaca caaaaaagtg acattgccag acggaagaga gcagaaccaa gaaattacaa 38760 ccttgaccaa atttgtttta gaccaagttt attcactaat ccaagatggt gaaatgtaca 38820 aagccaaaat ggaatttatc aaaatctatg atgaatacaa ggctgaagca caactgaagg 38880 gtaaaaccca agcttggtac caagaaccaa ttttattagc tcagaaaaat gagcaaaagg 38940 tgcataagcc tgtttcaaat gacgaagcgc aaaagcatct ccaatcattg atggaacgtt 39000 taaaaatcaa tggtcgtaaa cctgtaccag tacaaaagct taaggctaag gaaaaagagc 39060 cagaactcaa acaagagcta ggtccagatc cttttgacaa tccgcacgaa tacgcagaga 39120 tgtgccgccg tgaaggtatg ccaattccta gaaatattct taagttaatt gatggggcga 39180 atatatgaat aaattcgaga ttttagcgtg gggtttactc atttcatttt ttacagcagc 39240 tattagcggt gcggtggttt ggtggtggtt ggcgcgtaaa gagcttgatg agaaaggagc 39300 cagccatgaa agcaactaaa ttgattagag ataaaggact gcaatacgcg aaggaaatcg 39360 tagattcagc acccgataac gcaactgaat ggaacgaggg ttatgagttc caatgtggtc 39420 aaagtgtaga aatcagccca gcagatcgtg agaagtattt tgtagatttg gttgagctta 39480 aacgtctggt ggagtctttg aaaatcatca acgatttagg tggagttgag aagctaacgc 39540 ctgcattcat tacgacagat aagcatgttg gttacacgca tgttcgcatg gtgggaaatg 39600 ggagattgag ctttcttgat gatttttgcg acttcattcc agatggttcc atttcaatta 39660 agcgtgtgat gactgctatc cgcgaccacg aatcaatata cggaggcggt gaatctcatg 39720 ccaactagat ataacacagg cgagtatagc tacgatcttg aatatcacta tggagatatg 39780 tcagcaagca tggagatgct tagagcacgt ttaattgaat tgttgactcc tcatctgtct 39840 ggccgttatg tgaaatggag agaagcatat ttcacatggt ttacaaagtg cggcggggat 39900 tcggggtgga tgttttgtgt aggtccacac gaatttcata ttgatggggc gttaaggcgc 39960 tattactcag gttctattga tattacctac aaccagaaag atcgatattt cttggtgggt 40020 gagaaaaaga aagtcaaatg taaggcttgt aaggggtttg gcttcattcg agatgatggg 40080 tgggggcata tagataaatg tgaaatgtgt gatgcagaaa aaggagccag ccatgagtga 40140 gtttgagggt aaatctggaa agtgggcttg ggagattcaa aaagaacaac aagcgaaagt 40200 ggaggagctg caaaagcgtt tagatggggc attaaaagag actcaatatg ctttgcagta 40260 tgttgaagaa gacatgcgcg gcaatcatga atttctacaa atggcaatga ttcgaaccct 40320 taaagctata gagcaagtgc tcaaaggtgg tgcttgatgt catcagtcag cattgctgaa 40380 taccgcaagt tatttcccat aaagaaaaat aaaaagcgcc gttcagcaaa gcaagttgcc 40440 agacaaccaa gtgtgggtga agtggttctg gcaacgcatt taagagcatg caagattgga 40500 tttgaacagg aatataagtt ccatcctgaa cgcaaatgga gagcagattt tttaataaag 40560 ggttcaaaga ttttgattga ggtagaaggc gggatctgga gcggaggccg tcacacaaga 40620 ggtaagggct atttagggga tatggagaaa tacaactccg cagcaatgat gggttttaca 40680 gttttacggt tcagcacaga gcaagtgaaa tccggtatgg cattaaagca aattgaatta 40740 ttaattaagg gtaaatagga aggcgattat gttggttgaa aagtttgatt ttattgagtt 40800 acttcgcctt gctattgctc aaggcaaagc tgaaggtaag aaaatttcta aagatgtagt 40860 tttaggtgaa ttagcgctgt tatcgccagc tgcaaagctt tgggccactg tcttgattga 40920 aaaggttgat tttgagcgaa tcgcaataat taccccagca caaaaacaga ctgaaacttt 40980 ttacagtaag tatgacttta attttcaaac tgaacgccgt attgaagata ttccgggcaa 41040 ggttgagttt gttcgtggtg agattaaatc aggtaatttt ttcagagcgc gaaataaatt 41100 agcggtagag attcataaag aaatggtaaa gaaaaaattt acccctacta atgcccaagg 41160 tgatcttact aatctggcaa aaggtatggc tgagattatt ttgcgtggcc atgtttttgt 41220 taaggctatg tgtggagtct gccaagggtt gggtaaaatt gagacatttg gtttaaatgg 41280 ctttccaaat ggggcaaggt tttgtgaaaa atgtaatggt actggaaaac gaccatatac 41340 gttgaaagag aaaatgaata ttgctggcat tgatgcaacc aaaacagctt atataaagag 41400 ttatcagaaa tttgagctgt ttggagaatc aatcgttgct gaatgggaaa atgaaattag 41460 aacgcgtatt tctcgatcat tccgttttga acttcctgat agtcaagaaa cttacgcttg 41520 acagttgggt atacacttga gtataaagat ttctaaaatg ggcgaaatgt aaagtaatcg 41580 ccagaatgaa tttaagagct cgccaatcgg tgggcttttt tatttttaaa tatttcagta 41640 ttatcagtgt gttgctttaa gtaacactaa accttattga tcagcgcaaa tatcaaaaaa 41700 aagggggagc ttgcctacta ggcaagcttt ttaaattgat gatttaaaca caataatcca 41760 ttttaaagct caatagaaag atcaaacttc catagctttt atttgtacta atttattgaa 41820 tataatcgtt tttataattt ttaaaatttt cttaaactaa aaatggaaaa tttcttgttg 41880 caacattgtt ataataggac taccttaaga aaaatacttt ataaaaatga ggagctgctg 41940 aaatgacaca gtatctcatg tttgcggaaa atatttataa caaaattaaa gatgaggaat 42000 tgttttcaca tgactgtatt gaaaatatga acttacttat gacatgtata cgcagagaaa 42060 ttaagggaac agaatttaaa ttaaaatata attttattga ttttgttgaa ttgtttagta 42120 gaccattaga tgaatgtaaa gtaaaaatag atgttagttt gattcctcct cataattcag 42180 aaggtgagta tattttatgg ttagctggat taatcgaaaa aattacagaa ggtggaccta 42240 aaccacctcc gcctataaag aagtttattc cagagtatat gagcttgaaa tttgaattag 42300 attttttacc cttaaatgag gaaaaaattc aaaacgaagg taaagaaatt acggattact 42360 ttaattcaaa gctttataag gcaactttta agaagtaata ctatattgcc tgtgagttta 42420 gccaccgcct aagggcggtt ttttttatgg gtaagaataa tggattctac agaatacttt 42480 tggcttactc ggaaaaaaga acctaaaact aaacctaaaa gccggccatt gcctaaggcg 42540 aagcaaaaat atctcgaggc tgaggcaaca cttaaggaag agcttgagga tttggcgatt 42600 ggatttgaaa gtaagtttca gccgatccat accaaacact ggcgctttga ttttcatata 42660 gtgaaattgc gtttgctcat tgaaattgag ggtggtccct ggtctggtgg gcgtggtgga 42720 aagctgtcaa ataaagcatg gagtcttaat cgatatgatc atgctgaaga gatgggttac 42780 aaaatagagc gctttcatcc agattctatt ttgtcgggat atgtcatcaa ctggataaaa 42840 agtgaattag cgagaattga agatggagca gatcagacca tttccaccga ctgattttat 42900 tgatcaagct gaagaagagg aagcaattag actaacacca gcaccggact taaaaaaatg 42960 ggttgtggct aattacttaa ctattggggg tcctatttat aatccagatc atgatcatat 43020 tgctgagctg cttcatgata atgacgagtt tttagcattc gcgtgggcct cttctgcata 43080 taaaagcaag caagctatgg tgttaggcca gtgcgaaaaa gtcatgttca atgttggtgg 43140 ctggcgtaaa gctcgacaag agcaacagat gcgtgattgg tttggttttg tacctactta 43200 tttaataact gtcgacgctt ctttctgtga gcgtgcaaac gatacagagt tctgttactt 43260 acttgaacat gagctttacc acattggagt gatgagagac gaggacggag aaattgttta 43320 tagcgatagt tctggtcttc ctaagcacta tcttgctggt catgacgttg aagagtttat 43380 tggcgtagtt aaacgttatg gaccaagcaa aaatgttaag cgacttattg aagtcgcaaa 43440 aaatccgccg tttgtttcga atcttgatat ttcaaaatgc tgcggcaact gtgtaatcaa 43500 ttgagcctaa tggctctttt ttttgcccat tttgttatac gtagttatac gatgaggaag 43560 ttatggcgac actaaaagag cctgtgaaaa tctttatagt tcagtctctt gcttgtcgtg 43620 atacacctca agaagtggct gaactcgtaa aacaagagtt tggcgttgat atagatcgtg 43680 ttcaagttgc aacttatgac cctacaaagg ttgctggtaa gaacttaagc aaaaagtatg 43740 tcgaactatt tgaaaaaacc agagatgagt ttgataaagg cttaattgat attccaattg 43800 ctaataagta ctaccgattg aagcaatacc aaagacaact tgagaagact agaaacgtca 43860 aaacagcctt aaaaattctt gagcaagccg ctaaagacat tggtggtcaa tttactaatc 43920 gccaagaaat tacaggcaaa gacggcggac cagtccaaac agttaattca gaaattccag 43980 ttccaatgga agattactta aaagcgcgga gggaagtctt agatgagtac tgatgcggct 44040 cgggataaag ccatccggat cgaggcgcaa gaagatttat atttcttcac aaggtacatg 44100 tttaaggagc gccgtggtta taaatggatg caaaattggc accacttaga aatctgcgaa 44160 gctttaatga aagtttatcg cggagagata aagcggttaa ttattaacgt tccaccacga 44220 tattctaaaa ctgaaattgc tgtaattaat ttcatggctt ggtgttttgg taagaatcca 44280 gactgtgagt ttattcatat cagttactcg gcaatgcttg ccgcaaataa tgccttccaa 44340 atacgaactc ttgtacaaga agaggcgtat agaaaagtct ttcctgagct tacattgcgt 44400 gatgatagta aggctaaaga cttctggaga acttctcaag gcggtgtctg ctatgcgaca 44460 ggtacaggcg gtacgattac tggttttggt gcaggaaaac ttcgtaaagg ctttggtggc 44520 tgcattatta ttgatgaccc acataaagca catgaagctt catcaaaaac tattcgagaa 44580 ggggtaattg attggtttca gaacacactc gaatcgcgta ctaactcgcc agatacgccg 44640 atcattgtga ttatgcagcg acttcatgaa gatgatttag ctggatggtt gctaggtgat 44700 agaaaagacg gcgttcctgt agctggtggt aacggtgaag tgtgggagca tctatgtctt 44760 tcagctattc aggaagacgg atccgcactg tggccagcaa aacacaatat ccaaaaattg 44820 aggctaatgg agcaagcagc accatatgta tttgccgggc agtaccgaca aatgccatca 44880 ccgccagcag gcggtttttt taagcccgac aatattcaaa ttgttgatgc tttgcctgcg 44940 gatgtagtga aacaagttag ggcttgggat tttggggcta ccgaaaatga gggcgacttt 45000 acagtaggtg tgcgagaagc tctaggcgca gatggtttta cttacattgt cgatgtaact 45060 agaggacagc ttggacctga caatgtgaat aagcgcttag aacaaacagc aaaaatagat 45120 gggaaaaaag tttctgtgcg tctaccacaa gatcccggtc aagctggtaa atcacaagct 45180 agttcatttg tgaagcttct tgcgggttat agcgtgatag ctaagccaat ttcaggtgac 45240 aagcttacac gtgcacaacc atttgcggcc caagttaacg taggaaatgt acgaatgctc 45300 aaaggtgaat ggaataagga ttttattgat gagcttcgtc attttcctaa tggcacacat 45360 gacgaccaag tggatgcagc ttcagatgcg tttaatgaat tacatgaagg ttttgaagcc 45420 ttctttgctg atatgggatt tgctcgatga gtgatgtaac ttttcaacat gctgaatatg 45480 ttaagaactt gccatactgg caaaaacttg atgatgtttg tgaaggtgaa gatgcagtta 45540 aggctaaagg tgaaaaatat ttgccgatgc caaatgcaca tgataaatca cctgcaaata 45600 aaagcgctta tgaggcttat cttacccgtg cagtctttta tgaagtaaca gggactacat 45660 taaatagttt agttggtgca gcttttgcaa ccgatccaag ttttaaattt cctccggaac 45720 ttgctcattt agaacgtaat gcaaatggtg ctggtttaag tacttatcaa ttggctcaaa 45780 atggaattcg ccatttattg aagcattatc gttgtgcttt atatgtagat tatcctgatg 45840 tgccgccagc tcgtaatcta gcggaattta aagcacaaaa agcctatccg atgattcatt 45900 tactaaatgc ccttgatgta gtgaattggg attcagtaat gatcgataac cagaaaaagc 45960 tttgcttagt ggttatacgt gaatttaagt ctgagcgcgg tgctgatgga tttagtaaaa 46020 ccgaacaaga gcaatatcgt gtacttcgtt tagagcaaga gggaaatggg gaatatattt 46080 attccgttca ggtgtacaca aagggtgaaa agggtaactg ggttggcgga gagaagaagt 46140 ttccaacaga ttacaacggg aatttctgga cctatatacc ttttacattt gtaggtgcaa 46200 ttgataattc agaagagatt aaaaagccac cattacttcc tttggctaat ctcaatttag 46260 cccattacag agacagtgcg gactttcaag agtccgtttt ttatatgggg caacctcaat 46320 attatgcgaa gggtgttaat tgggagtggt atgaccaagc caagaaacgt ggcatctaca 46380 ttggagcgaa agtacttttg cctttacctg aaaatggtgg tttaggaatt gtacaagccg 46440 accctaatac tcttgcccgg gaagcgatga aagataagtg ggaaaaaatg aaggagatgg 46500 gggcgcgttt aattgagaag ggctcgggaa gtaaaaagac cgctaccgaa gcgaatagtg 46560 atgacgccgt tcagcattca gttctttcgc tctgtgtcgt taatatgaat gaagccttgt 46620 cagcagcatt acgatgggct gctaagtttg taacgcctaa tgtggatgtt ctaactaaag 46680 atgatttgat gttcgaaatc agtcaagaat ttaacaaaca gggttattta gctgagttag 46740 ctcgacagtt atttgaagca gctctacaag gccgatcttc atttaaatca tggtgggaat 46800 acaaccaaac aggtatgttc cctaaacaaa aatatgaaga agagcttcag aatgttgaag 46860 cagagcaaga tgggacttta aatcaaaagg tagagtgaga tggcaacaga tatcaaaaaa 46920 ctatttgaag tactcactca gcaccaggcc tatctttatc gtgcttcatc aaaaacggta 46980 aatgagttat tggctttatt caatgatgat acgagcaaga tgctatctaa gcttcgggat 47040 ttattggatg agcttaatga gtcggagaaa gttgctttag ctggtggtaa atatacaact 47100 tcaaatttaa gggaaattag ggatttgatt gcccaatggt ttgccagtgt taatttagca 47160 ttacctgaag cttttgccgt ttctgctacg gcgctggctg tttatgaggc caattacgta 47220 gctaagctct atggagcaaa aattaataag cctgatgggg aaaaactatt cttatccgct 47280 aaaaaagttc cgttggcagg tggcgctctt gtcgatgatc tgctttcaag aattgctgaa 47340 agtgcccgtc aaaaggttga gtatgcaatt cgagatggta ttaattcagg caaaactaac 47400 caagaaattg ttcagcgtat tcgtggtacc aaacggctta actatgaaga tgggatctta 47460 aatggtacca aaactgatat tgagcgaacg gtaagaactg tgcgaagtca tgtagctaat 47520 caagcctatc taaatagctt caaccaaatt ggctttgaat atgtccgatt tgttagcgtt 47580 ttagatggac gaacttctaa gctttgcgct tcattagatg gttcagtgtg ggaaataaat 47640 gatccggcaa agcgagtgcc gccgttacat cctaactgtc gcagtatctt ggttccggtc 47700 gagaaggacg gtcaacttgt tggcgaacgg ccatttgtaa tggacgaacg tagagttaaa 47760 gacatcccca aagaagagcg aagccagtta ataggacagt tagatgcaaa caccacattc 47820 aaagagttct ttaagaaaac agatgatttc tttcaaaggg agtggctagg gccaaagcgc 47880 tttaagctct ataaagatgg gaaatttgat tttgataagt tctttgatcc tgaaggccgt 47940 ttctatagct tagatgattt gagaaagttg gatgaaaaag cttttaaaaa gttgggtctg 48000 taatttttct tatgttatat tttttaaaac atcagaattt atacaatatg aaaacaatag 48060 cttttgtatg tctaacccta atttccatca cttgtttagc tgaaccaagt caaaaatatc 48120 ttaaagaata tgatcgattg tctgaagctt tggagtcagc aatggcaaat gcatattctt 48180 ttgatcctgc aactggtcaa gtaaaacagg ctactcaagg tttagaagct aaaaataatt 48240 tatgtagagc tgcccaggcg aaactaaacc tcaccacgtt tttaaaagac aatttagagg 48300 aatctaaaga gctttataaa tctattgatg gtgcagagac tctagataaa aattatctta 48360 gtggacaaca gcaggaacaa caaaatctcg tttcaaattt gaaaaaagac cttgttggaa 48420 ctggatttaa ctgtgagtaa ttattgccga ttacaggtaa ttctaaactc acttaagaca 48480 caattttcac ctatataagc gcccaaatgg cgcttttgtc atttatggag tttggcttat 48540 gagtgaatca aaagttagac atttggtact taaaagagtt tcagataaat cttctcatct 48600 tgctctttgt gacgaggaaa caggtattcc attagctgga ttaaccgctg taaaaatgaa 48660 ttgtagtgtt tttgagggtc cagcgactat cacggcaaca tttgatgtag gtggtcctca 48720 aggcatccgc ttagttggtg atgaacctag acaaaaggtt tggagtgcaa aggaaacgta 48780 gcgaaaggca ctacaaatgc ctgaaaagca aatcaatatg tcagatgctc aatatattct 48840 gagcacaaaa tgaattctgg tgccatttct tcaaattaag gtttcaagcc atggcaattt 48900 atggttttac ttttgaaaga ttaaaagcaa ttgcactcat caaatagaac ttaattttta 48960 accatagcac cttcgggtgc tttttttgcg agaagaaaat gccaagccct attatccaat 49020 atttccaata tgaacattta cctgaacatt tgcagcaagt tagtaagcca attggtgatt 49080 tagctcggca aatggatgag caacttcctg acgggcctga aaaatccaca ggattaagaa 49140 agctacttga agcaaaagat gcatttgtac gccaagcttt aagtaaataa tcatttatag 49200 aaatgaagcg tcctaaaggg cgctttttta ttgcctgccg aaagcggatg ctaacggcga 49260 atccgggcgg atgcccattt tgtatatata ggttggatga ccaatgaaac ttaaaacagt 49320 aacaatcgac ggtaaagttt atgcggaagt agacggtgat aagccgatct atattcatga 49380 tgacggcaaa gaaatgccac atgatgcacc acactcggta gcaacaattg cacgcttaaa 49440 caatgaagct aaaacacatc gtgaagccaa agaagcagcc gaaaaagcat taaaagcttt 49500 tgaaggaatt gaagacccag cggcagctaa aaaggcatta caaacaatcc aaaatctcga 49560 tgataaaaag ctggtggatg ccggtgaagt tgagaaagtt aaagctgaag ctatcaaagc 49620 agttgaggaa aaatatgccc cgattgttgc gcaacgtgat gctctagaag cctctttaca 49680 taaagaactt atcggcggtg gttttgctcg ttctaagtac attcaagaca acattgcagt 49740 acctgtggac atggttcagg caacctttgg tcatcacttc aaaatcgaag aaggcaaggt 49800 ggttgcatat gatccgaacg gcgaaaagat ttattcacgt gtccgcccgg gtgaacttgc 49860 aaatgttgat gaagctttag agtcattggt tggtggatac cagcataaag acttaattct 49920 taaaggtggt aaaggaactg gtggcggttt tcaaggtggg ggcaaaggtg gagcacctac 49980 tggaatgaaa cgcagtgaaa tgtctgtttc tcagaaagca gattacatca aagaacatgg 50040 caatgatgcc ttcctaaaac taccgaacta atcattaaat atttggagat aagtagttat 50100 gactacgaca gttaattcag acatgatcat ctataatcaa ttggctcaaa ctgcttattt 50160 agagcgtttg caagataatt tgaatgtatt taaccaagcc tctaatggtg caattgttta 50220 tcgcaatgag atcattgaag gtgatttcaa taaagaagca ttctacaaag tgggcggtag 50280 catcaaacat cgtgatgtga attcaaccgc caaagtagtt ccagagaaaa ttggttctgg 50340 tgagtctgta ggcgtaaaag tcccatataa atatggtcct tatgcatcaa ctgaagaggc 50400 atttaagcgc cgtgctcgta caccagaaga atttgctatg gttgttggtt acgatcttgc 50460 agatgcattg gttgcaggcc gattagagta cagtttagct tctttaaaag ctgctatttc 50520 tagcaatcca gacatggttg caaaaggtag tatcgttgtt gatggccgca aagcattgac 50580 tcgtggtatg cgaaagtttg gtgataagtt tggccgcatt ggcttatggg tgatgaactc 50640 agatacatat ttcgatattg tcgatgatgc aatcactaag caaatttatg gtgaatctga 50700 aatcgttatc tacggtggtt taccgggaac cttaggaaag ccggtcttgg tgacggacgc 50760 tgtaggtgat aacgatgctt ttggtttgca gtatggcgct gtcactgtaa ctgaatcaca 50820 agtaccgggc ttccgagctt atgacatcaa tgatgaagaa aacttagcaa tcggtatgcg 50880 tgctgaaggt gcatttaact tagatattct tggttatagt tgggataca 50929 <210> 2 <211> 588 <212> DNA <213> Artificial Sequence <220> <223> Ab endolysin <400> 2 atgccgcctt cgggcggttt tttacatctg aaggaaaccg aaatgaacat tgaacaatat 60 ctggacgagt taattaagcg tgagggcggg tacgtaaaca acccagcaga tcgaggcggt 120 gaaacaaagt acggtattac tgaagcagta gcacgtacta acggctttaa gggcaacatg 180 aaagatttac cgcttgatgt ggccaaagcc atttataaaa agcagtattg gacagatccg 240 cgatttgatc aagtgaatgt aattagctcg ttagttgctg aagagctttt agatactggg 300 gtaaattgcg gtaccggatt tgcaaaacca ctcttacagc gtgctttaaa tttgctgaat 360 aaccaaggta aagcaggttg gccagattta acagttgacg gaatttatgg tccagcaact 420 cttaatgcac tcaaaactta tctggccaag cgtggaaaag acggcgaaaa agtcctggtg 480 cgtgttctta atatcatgca agggcaacgt tacattgaaa tctgtgaacg caatcctagc 540 caggaacagt ttttctatgg ttggatcgcc aatcgagttg ttatatga 588 <210> 3 <211> 195 <212> PRT <213> Artificial Sequence <220> <223> Ab endolysin <400> 3 Met Pro Pro Ser Gly Gly Phe Leu His Leu Lys Glu Thr Glu Met Asn 1 5 10 15 Ile Glu Gln Tyr Leu Asp Glu Leu Ile Lys Arg Glu Gly Gly Tyr Val 20 25 30 Asn Asn Pro Ala Asp Arg Gly Gly Glu Thr Lys Tyr Gly Ile Thr Glu 35 40 45 Ala Val Ala Arg Thr Asn Gly Phe Lys Gly Asn Met Lys Asp Leu Pro 50 55 60 Leu Asp Val Ala Lys Ala Ile Tyr Lys Lys Gln Tyr Trp Thr Asp Pro 65 70 75 80 Arg Phe Asp Gln Val Asn Val Ile Ser Ser Leu Val Ala Glu Glu Leu 85 90 95 Leu Asp Thr Gly Val Asn Cys Gly Thr Gly Phe Ala Lys Pro Leu Leu 100 105 110 Gln Arg Ala Leu Asn Leu Leu Asn Asn Gln Gly Lys Ala Gly Trp Pro 115 120 125 Asp Leu Thr Val Asp Gly Ile Tyr Gly Pro Ala Thr Leu Asn Ala Leu 130 135 140 Lys Thr Tyr Leu Ala Lys Arg Gly Lys Asp Gly Glu Lys Val Leu Val 145 150 155 160 Arg Val Leu Asn Ile Met Gln Gly Gln Arg Tyr Ile Glu Ile Cys Glu 165 170 175 Arg Asn Pro Ser Gln Glu Gln Phe Phe Tyr Gly Trp Ile Ala Asn Arg 180 185 190 Val Val Ile 195 <210> 4 <211> 7882 <212> DNA <213> Artificial Sequence <220> <223> pB4_Ab endolysin <400> 4 taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60 tgtttaactt taagaaggag atatacatat gggcagcagc aatcatcatc atcatcacgg 120 taccaaaact gaagaaggta aactggtaat ctggattaac ggcgataaag gctataacgg 180 tctcgctgaa gtcggtaaga aattcgagaa agataccgga attaaagtca ccgttgagca 240 tccggataaa ctggaagaga aattcccaca ggttgcggca actggcgatg gccctgacat 300 tatcttctgg gcacacgacc gctttggtgg ctacgctcaa tctggcctgt tggctgaaat 360 caccccggac aaagcgttcc aggacaagct gtatccgttt acctgggatg ccgtacgtta 420 caacggcaag ctgattgctt acccgatcgc tgttgaagcg ttatcgctga tttataacaa 480 agatctgctg ccgaacccgc caaaaacctg ggaagagatc ccggcgctgg ataaagaact 540 gaaagcgaaa ggtaagagcg cgctgatgtt caacctgcaa gaaccgtact tcacctggcc 600 gctgattgct gctgacgggg gttatgcgtt caagtatgaa aacggcaagt acgacattaa 660 agacgtgggc gtggataacg ctggcgcgaa agcgggtctg accttcctgg ttgacctgat 720 taaaaacaaa cacatgaatg cagacaccga ttactccatc gcagaagctg cctttaataa 780 aggcgaaaca gcgatgacca tcaacggccc gtgggcatgg tccaacatcg acaccagcaa 840 agtgaattat ggtgtaacgg tactgccgac cttcaagggt caaccatcca aaccgttcgt 900 tggcgtgctg agcgcaggta ttaacgccgc cagtccgaac aaagagctgg caaaagagtt 960 cctcgaaaac tatctgctga ctgatgaagg tctggaagcg gttaataaag acaaaccgct 1020 gggtgccgta gcgctgaagt cttacgagga agagttggcg aaagatccac gtattgccgc 1080 caccatggaa aacgcccaga aaggtgaaat catgccgaac atcccgcaga tgtccgcttt 1140 ctggtatgcc gtgcgtactg cggtgatcaa cgccgccagc ggtcgtcaga ctgtcgatga 1200 agccctgaaa gacgcgcaga ctggtaccga ttacgatatc ccaacgaccg aaaaccttta 1260 cttccagggc ggcggtggtg gcggcccatg ccgccttcgg gcggtttttt acatctgaag 1320 gaaaccgaaa tgaacattga acaatatctg gacgagttaa ttaagcgtga gggcgggtac 1380 gtaaacaacc cagcagatcg aggcggtgaa acaaagtacg gtattactga agcagtagca 1440 cgtactaacg gctttaaggg caacatgaaa gatttaccgc ttgatgtggc caaagccatt 1500 tataaaaagc agtattggac agatccgcga tttgatcaag tgaatgtaat tagctcgtta 1560 gttgctgaag agcttttaga tactggggta aattgcggta ccggatttgc aaaaccactc 1620 ttacagcgtg ctttaaattt gctgaataac caaggtaaag caggttggcc agatttaaca 1680 gttgacggaa tttatggtcc agcaactctt aatgcactca aaacttatct ggccaagcgt 1740 ggaaaagacg gcgaaaaagt cctggtgcgt gttcttaata tcatgcaagg gcaacgttac 1800 attgaaatct gtgaacgcaa tcctagccag gaacagtttt tctatggttg gatcgccaat 1860 cgagttgtta tatgaggcgc aaaggagaag aactgttcac tggtgttgtc ccaattcttg 1920 ttgaattaga tggtgatgtt aatgggcaca aattttctgt cagtggagag ggtgaaggtg 1980 atgcaacata cggaaaactt acccttaaat ttatttgcac tactggaaaa ctacctgttc 2040 catggccaac acttgtcact actttctctt atggtgttca atgcttttcc cgttatccgg 2100 atcacatgaa acggcatgac tttttcaaga gtgccatgcc cgaaggttat gtacaggaac 2160 gcactatatc tttcaaagat gacgggaact acaagacgcg tgctgaagtc aagtttgaag 2220 gtgataccct tgttaatcgt atcgagttaa aaggtattga ttttaaagaa gatggaaaca 2280 ttctcggaca caaactcgag tacaactata actcacacaa tgtatacatc acggcagaca 2340 aacaaaagaa tggaatcaaa gctaacttca aaattcgcca caacattgaa gatggctccg 2400 ttcaactagc agaccattat caacaaaata ctccaattgg cgatggccct gtccttttac 2460 cagacaacca ttacctgtcg acacaatctg ccctttcgaa agatcccaac gaaaagcgtg 2520 accacatggt ccttcttgag tttgtaactg ctgctgggat tacacatggc atggatgagc 2580 tctacaaata agcttgcggc cgcactcgag caccaccacc accaccactg agatccggct 2640 gctaacaaag cccgaaagga agctgagttg gctgctgcca ccgctgagca ataactagca 2700 taaccccttg gggcctctaa acgggtcttg agggggtttt ttgctgaaaa ggaggaacta 2760 tatcccggat tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 2820 tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 2880 tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc 2940 tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 3000 gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 3060 agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct 3120 cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 3180 agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 3240 tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 3300 aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 3360 gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 3420 ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 3480 gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 3540 tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 3600 attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 3660 tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 3720 agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 3780 aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 3840 tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 3900 cacgatgcct gcagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 3960 tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 4020 tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 4080 tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 4140 tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 4200 aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 4260 gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 4320 tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 4380 aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 4440 aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 4500 tccgaaggta actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc 4560 gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 4620 cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 4680 acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 4740 cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 4800 cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 4860 aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 4920 gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 4980 atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 5040 tcacatgttc tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga 5100 gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 5160 agcggaagag cgcctgatgc ggtattttct ccttacgcat ctgtgcggta tttcacaccg 5220 caatggtgca ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc 5280 cgctatcgct acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg 5340 cgccctgacg ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg 5400 ggagctgcat gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt 5460 aaagctcatc agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca 5520 gctcgttgag tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa 5580 gggcggtttt ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg 5640 gggtaatgat accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac 5700 atgcccggtt actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc 5760 agagaaaaat cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac 5820 agggtagcca gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact 5880 tccgcgtttc cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg 5940 tcgcagacgt tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct 6000 gctaaccagt aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca 6060 tgcgcacccg tggggccgcc atgccggcga taatggcctg cttctcgccg aaacgtttgg 6120 tggcgggacc agtgacgaag gcttgagcga gggcgtgcaa gattccgaat accgcaagcg 6180 acaggccgat catcgtcgcg ctccagcgaa agcggtcctc gccgaaaatg acccagagcg 6240 ctgccggcac ctgtcctacg agttgcatga taaagaagac agtcataagt gcggcgacga 6300 tagtcatgcc ccgcgcccac cggaaggagc tgactgggtt gaaggctctc aagggcatcg 6360 gtcgagatcc cggtgcctaa tgagtgagct aacttacatt aattgcgttg cgctcactgc 6420 ccgctttcca gtcgggaaac ctgtcgtgcc agctgcatta atgaatcggc caacgcgcgg 6480 ggagaggcgg tttgcgtatt gggcgccagg gtggtttttc ttttcaccag tgagacgggc 6540 aacagctgat tgcccttcac cgcctggccc tgagagagtt gcagcaagcg gtccacgctg 6600 gtttgcccca gcaggcgaaa atcctgtttg atggtggtta acggcgggat ataacatgag 6660 ctgtcttcgg tatcgtcgta tcccactacc gagatatccg caccaacgcg cagcccggac 6720 tcggtaatgg cgcgcattgc gcccagcgcc atctgatcgt tggcaaccag catcgcagtg 6780 ggaacgatgc cctcattcag catttgcatg gtttgttgaa aaccggacat ggcactccag 6840 tcgccttccc gttccgctat cggctgaatt tgattgcgag tgagatattt atgccagcca 6900 gccagacgca gacgcgccga gacagaactt aatgggcccg ctaacagcgc gatttgctgg 6960 tgacccaatg cgaccagatg ctccacgccc agtcgcgtac cgtcttcatg ggagaaaata 7020 atactgttga tgggtgtctg gtcagagaca tcaagaaata acgccggaac attagtgcag 7080 gcagcttcca cagcaatggc atcctggtca tccagcggat agttaatgat cagcccactg 7140 acgcgttgcg cgagaagatt gtgcaccgcc gctttacagg cttcgacgcc gcttcgttct 7200 accatcgaca ccaccacgct ggcacccagt tgatcggcgc gagatttaat cgccgcgaca 7260 atttgcgacg gcgcgtgcag ggccagactg gaggtggcaa cgccaatcag caacgactgt 7320 ttgcccgcca gttgttgtgc cacgcggttg ggaatgtaat tcagctccgc catcgccgct 7380 tccacttttt cccgcgtttt cgcagaaacg tggctggcct ggttcaccac gcgggaaacg 7440 gtctgataag agacaccggc atactctgcg acatcgtata acgttactgg tttcacattc 7500 accaccctga attgactctc ttccgggcgc tatcatgcca taccgcgaaa ggttttgcgc 7560 cattcgatgg tgtccgggat ctcgacgctc tcccttatgc gactcctgca ttaggaagca 7620 gcccagtagt aggttgaggc cgttgagcac cgccgccgca aggaatggtg catgcaagga 7680 gatggcgccc aacagtcccc cggccacggg gcctgccacc atacccacgc cgaaacaagc 7740 gctcatgagc ccgaagtggc gagcccgatc ttccccatcg gtgatgtcgg cgatataggc 7800 gccagcaacc gcacctgtgg cgccggtgat gccggccacg atgcgtccgg cgtagaggat 7860 cgagatctcg atcccgcgaa at 7882 <210> 5 <211> 35 <212> DNA <213> Artificial Sequence <220> <223> Ab_endolysin_LIC_F <400> 5 gggcggcggt ggtggcggca tgccgccttc gggcg 35 <210> 6 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> Ab_endolysin_LIC_R <400> 6 gttcttctcc tttgcgccct atataacaac tcgattggcg atc 43 <210> 7 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> pB4_seq_F <400> 7 gtcagactgt cgatgaag 18 <210> 8 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> pB4_seq_R <400> 8 catcaccatc taattcaac 19 <110> Kyungpook National University Industry-Academic Cooperation Foundation <120> Bacteriophage having the ability to kill Acinetobacter baumannii and composition comprising the same <130> PN200249 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 50929 <212 > DNA <213> Artificial Sequence <220> <223> Bacteriophage Ab1656-2 <400> 1 tcgaaaggtg aaaatcctga ccttacatta cttggttcaa gcgctaactg gatcaaatat 60 gcaaccagca acaaaatgac agcaggtacc ttacttgatt tatcgggtac agcgacaact 1 20 ggttaaaacc taaaaattaa aacctaaggg ggctaataag ccctcttttt tattattaag 180 agaaaagcgc catgaagatt atctatacac gcattgcagc agcggctgca ttagagacag 240 gcattattgc taaccctgac tattatgaaa acccaaattt gaaagcaaaa gaggtaatta 300 tttacggtaa ttatccaaag attcaaaagg attatgaatc tttggaagtt ccagttgaag 360 ttcgtaagtt ggaagtgcca caaaaaacga ctttggccac agtaaatgtc gcagtgggaa 420 ttacccctga acttcaagct gtgatggatg atgcaaaagc tgaatgtgaa aaggtagttg 480 aagaaaacac tcagcttaag cagaaaattg ccatcttaga gcaggccggt ggtaaccagt 540 cagagttgtt atctgaaaat tcacgattaa aagatgcagc agtcttagca gataaagctc 600 tcaa agatgc tgaagctcaa gtggtcggta taaaaactga atttgaagct tttaaaaatg 660 atattcctgc aatgcaggca cgtattgctg aattggaagc tggaaaaagcg gcagaaaacc 720 cagctacaga aacggcagct aatgattttg aaaactggtc aaatgatcaa ttaaaagagt 780 atttggctag taaaaacatt ggttacaagc cgtctgcaac aaaagcagaa cttcttaaat 840 taatcccgaa ggaataat gc aatgagcttt attactgtag atgacgcaaa ttcaattttg 900 ggcagcgatt ttgcaccaga cagtgataag gctcgtctgg tgaagctggc aaatgtgtgg 960 atgaaaaaca gaattggttt tgtaccagat ccaattgatc cacttcttaa ggacgcggct 1020 tgtgaaatta tcaaaggaat tctggccaaa gtaatttata acggcaaaga gcagcagttg 1080 aagcgtaaga aagttaaggc tgattctgtt gagtcagaaa aagaatttca agacggatct 1140 gaagcaatct ctagctttga acagatagca attgatttta ttgattcact tgatttgaaa 1200 gatccaaatg caagttttaa tggctttggc ataccacttt acagggcatg atatgggctt 1260 acgtgacgaa attcaggcag acattgctga a gcatttaat gatgatttag cagatgccat 1320 tcataccttt acatgtgagc ggatctctaa aacgaattgg gatcctaaaa ctgaaactta 1380 tgttgaagtt aaagaaaact attctggccg tggcgttctg tttggctcat acagtcaata 1440 tgagatccaa acacttggag tactggccac ggataaaaag gcaaccgtgc ttcaaaatga 1500 agtaactatg actccaaaaa ttgaagatga atggttaact gccttaggct cattccgggt 1560 aattaatatt caacaggatc cagctaatac tatttggaaa tgtcagcttc gaaaagtgta 1620 ggggctaaaa tggttaatcc tgattatgtt cctgaatggt atatctcgcc ttttcaacat 1680 gtgcagtaca cgcttgctcg aaatcaacta ca catggatt tgttattga agatatggat 1740 aaggccgatc aatttttgga tatgggagcg gatgcgcaag ttagtacttt ttctgatggt 1800 gcatatgcaa tcgtccaaat tggtgatacg gcggataaag accgaattca agtttatgga 1860 ttgcttttac atgaagctgt tcatgtctgg caaaagatta aaaagctcat gggtgaacga 1920 gaaccgagct ctgagtttga agcttattca attcaggcga tcgctcaaga cctttttaaa 1980 atgtatgaag aaagcgaggt gaatgatggg atggaagggg aaaaagccaa ctgaatttag 2040 ttttgatgtg tctaaagcag cagaagacca ggtgaagcat attgttatgg atactgtgca 2100 atccttagtt aatttaagtc ctgttgatac tggagcatac cgt gcttcac atattgtttc 2160 ggttggatct gctgatttcg gcgtgcgtga acctgaaaca aaccctatta acgacgcagc 2220 gattcaggca atgaagatta agttaggtaa tttggtttat atccagaaca ataaagctta 2280 tggaccgcgc ttagaaaacg gctggtctga tca agcacca caaggtattt atggcctcac 2340 gtttaacttt atttctcaaa agtacggtgg ctaaaatggc aatgacttta gagcagacaa 2400 ggcaagctat tattgatcgc atgcaaagct ttacgggtat tgctcaagaa cggattcagt 2460 atccaaatgc acctgacttt actgttccaa caaaaggtgt atggtgccgt ttaacgattg 2520 caggtggccc gagttttacc tcaggcattg cagataagcc atgtacacgc c gtaccggta 2580 atatcatgat ccaatgcttt gaccgattac atactggaga gaaggccgta acggttctaa 2640 gcgatgcatt gctggctcat tttgaatatt tcacaatcga acacttagaa tgtttgaatg 2700 gccaatctat ttatgcgggt aaagatgctg atttcattca gtata atgtg agcattgggt 2760 acaaggtgaa ttgatatgtc atgtatgctg actttagaag aaatcgaaat taaacggcaa 2820 gaactggaac ggcatcttga agatgttatg tctgttgagt tgagcaaatg gcaatctgaa 2880 aacaagctat gtgtttctga tgtgaatata cgcttggcta atgttgttag tctcggaggg 2940 cctaaacata acgttgttac tggagtaagt gtcgatttag ataatgagct t tgagttcaa 3000 gaaaaaagcta ctgcaaggcg attattttta atgacctcag catattatca tttgtgatta 3060 cattctgtta cagtaatgga aatttataac aaatggtaaa acatgaaaaa atcaacttta 3120 ggctggggtg ccgcaggatt agtagcttta gggatttttg gttcaggcaa t gataactct 3180 ccaaaacaaa cttcagactc agaaaatgcg cagagtgcag tagaggaagt tatcgaatca 3240 aaatatatca acactaattc tttaaatatt agagataaac caaacggtca agtagtagga 3300 aagttaggac gtggggaaaa agttgatatt tatgagatga aaggaaactg ggcacgtatt 3360 tccttaaatt cctcatcacc tcagtggtta tcaacaaagc tattatgtga aacggatggc 3420 tgttttaaac a aaagtctcg atcaaccacg tcaaataatt atcaggcctt aaaatctcat 3480 cctcatcatt ctgaaagaaa acagaaaaaa acctactacg atagtgattg ttcatgtgct 3540 gtggtggatt attgcgtggg tcctagaggt gggcactact gtattacgag tggaggaaac 3600 aagagatata aacc tagata ttaattaatt tgaattatga gacctccatt ttgagaggta 3660 ctttatgtct taatcactac cacctcatcg gtggtttttt tatgtctata ggaatcactt 3720 atgagcaatt ttgtatttaa gcgtggtgac actttcaact taaatcttca gctagttgat 3780 atggatgaag ccctgcaata tccaccagat gatgtgcgcc gtgcaattga tcttacaggt 3840 tataccttca cttcacaggt taaagctctg gctgatggtg ctactgtggc cacattaact 3900 tgtactgcat taagccaaag cacacagaaa gggtggctga acattaaatc tagtgcaagc 3960 actgcaactt ggcctttagg gctgtgtcag atggatatta aagctgtagt tagtggcact 4020 acacagcaca ctga aacttt gactttccaa gtgattgacg gagtaacagc ataatggcaa 4080 atcttgtttt taaatttagt tgggatcatc ggccattccc atataacgcc tcacagggca 4140 agcggcagtt tatgttgcca tttgcgtcag gtattcccaa tctggcaccc aacttttctc 4200 aagtagttgg tactgcagct atctctcaag gtggaacggg ggcaactaca gcggctggtg 4260 cacgagctaa ccta ggcgca gctgcaagtg gggtaaatag tgatattagt gagcttaagg 4320 gacttacaac ccctttatca atttctcagg gaggattagg agctgataat gcacagacag 4380 ctagaatgaa tttggggtta ggaactgctg ctgtactagc gtcaacaaca agtcaatatg 4440 atcctacgcc gggacga gca ctaagagtcg gtgattgggg gataggggct gaaggttctc 4500 gtgtatctga tatggttgct cctcttaata atggtttttt tcgaacagat gacactttaa 4560 caaatgatac tggtaatagt attggtcctt atggtttctt tttacactgt acccgacgct 4620 caatgggttt atatacaaat ggaagtcatt catttcagct tgggaaagct gcctcatatt 4680 ctgccctgaa gtatcgattt aataatagtg gt acttggtc taattggttt aatttattga 4740 ctgcacaaaa tactacaact gatggaaatg gttttattaa agccgcttca ccagtcgtta 4800 agcttttcca aagtcatatt gagctaaata acgatgctgc caagcaaccg atcacttttg 4860 acaaattagg cactggtgac tatctgatta agggctcttt aggctttgca caggaaggtt 4920 ggtatatcga agtacctaag gatgccaacg gtaatacggt agtagcagtt gaatattcaa 4980 ccttagaaaa tggtgatctt tctattaaaa cttataaacg taagtttgat gtggaaaagg 5040 cagccattgt agctgatctc gaaaatccac ttgatattcc agaaggccgc tggattgata 5100 tccgtctgca tgaagaacct gaaccagagc ctgaagagcc gtt gagtgaa acaccagtgg 5160 atttccagcc gactaactta tctcaggcag ttgctgcagc catgaatggc gtggaaccgc 5220 cagaaatctc agaaacagac gaaacacttt aataacccgc ttaaacagcg ggttttttat 5280 tgcctaaatt ttggagaacc ataaatgagt tca ggcgcaa aaattcgatt atatgcttgt 5340 gaggaagcag ttttaggaac aactcctgca aatccagtct ggtacaccgt tcgccgtgtt 5400 actgatagtt tgactgaaaa tgttactact gaagatagca gtgaagtagt tgattcacgt 5460 tttcgccaag gcgctgttgt aacggaagcc gaagtaactg gtcaactaga gtttgaatta 5520 tcactaggta cctttgactt attcttaaat gttctcgctt tcaataactg ggctgcaaat 5580 gctttaagtt ttggtggtgg agtacgtaag tctcttacct tggtaaaagt ctttgaagat 5640 attggtcaag tctttattta tcgtggtatt caagtgaata caggtgaaat gacgatccag 5700 accacaggca aaatcactgg taactttggt ttagtaggta gctcatttac g cgacagcag 5760 gttaatcctg ttacaaatcc tattccagca tcgactcgcc ctctggtgag tatgccaaat 5820 gttgaaaagc tacttattaa tggtcaatca attcagggta aagcttgtct gcagacactt 5880 accatcaact ttagtaataa tctggaagcg atccgttgta tcggttctgg taagtacacg 5940 cctgagtttt acttagagaa aatgatggat attggcgtaa atgctaattt catgttttca 6000 gcaacatctg cttcttggat tgatgctatt aaaacccgtg atgtatttac attgaccttc 6060 gatattacag ataccaaagg cagtaagtac tcgtttaact tcccgcaact tgaagttaag 6120 gaagcaaatc accctgatgg tggtggcgat gacattatta caatagatat caattttgcc 6 180 caagtgcgta ccagtccaac gattgtacgt gctcttgtgt aatcaactta ttcagtaaca 6240 aagcctatgg aaacccatgg gcttttttat ttctaaaaat tagaggttgt tatggcttta 6300 aaagtcggaa ttattaaaag ctcagacgta tcaaaatggt gtgaatacaa gggtgctgat 6360 ggcgatgtac aggctgagtt caaagtccgt ggtatcgctt ataagccttt tcaggtagct 6 420 attgaacggg caggaaacca gatctcgtct aaaggctatg atgtgatggt caaagatgaa 6480 gatgccaagc tttaccacga gcttttaatg gatgcatgcg cggcccactt aatcgaagac 6540 tggaaaggtg tggtatttgc cgaaatcgta gacggtaaaa ctgttgagtc c gaaaagcca 6600 tatacacctg agaatgcctc aaagcttctt aatcttggtg atattggtat ttcaatctgg 6660 ctattcatta aagaacaggc ccagaagatt caggaagacg cagacaagga caaggcttta 6720 attctgggaa agtcatggag ctctacaaat accaaaaaac gtatgcgtcg aaaacgccgc 6780 acgaaatcga gcaaatcaag ttcttaggcg gccgtattcc ggatccgcca gaatattcgt 6840 atgcggctga t tcaattctt tcggcattta gcactatatg tcgatccaga cgttatgagc 6900 aaagcatacc gttatcttta gatcagcagg ctatcaatgt ctatgctgag cataatgatt 6960 tgccagtggc tgctcatatt tttaatgact gtatttttgc gttggataat ttgtttttgg 7020 aggagt gcca taagaagata tcaaccaaaa gcaaaggtaa gtgaccaaat taggtattgc 7080 cagggactga aaagcctaat ttggtcaaaa cgtcaaaacaa ttaagcagtt gctcttaaac 7140 gcgactcaaa ataacgcagt cgatgttaca aaatacttga tctggattga cagaaaatta 7200 cctttaaggt gttgcgcgtg attatcaaat gatgaataat caccttaccg tcaatatttg 7260 acggttcagc attcttttac t ctttccaag aaccttggtg tttgcttgta tgtgtttaac 7320 attaactgaa gctaaacaaa aacttagagc atttgctaga gatactagca aaatcaagtt 7380 aactgcacat gcaaaagaaa gaatgaaaga acgctgtatc tctatgaagc aaattatttg 7440 ctgttttgag cat ggagata ttactgaggg gccgtacca aatactcgtg gtgattgcca 7500 gttaaatgtt tctgttcgca ctgcaggcga atacataaca acagctgttg caatcaagca 7560 gagcgagaac ggtgaattct cagtagtagt cactacattt agagagtagg ctaaattatg 7620 tatcactatg aagaatgcgg tctgagcaat atttggctgc gcaatggatt tacaattgaa 7680 aatgatgaag actatggtga actcgtatct attgaatctg ttcat gagct tcataatgcc 7740 attgggttgt tcttaattac gcaaaagcct gacttgaatg gtgaggaaat tcgtttttta 7800 cgtaaagaac taaacttgtc acagaagaat cttgctgggc ttttaggagt cagtgagact 7860 agtattagac attgggaagc tgatcgcggt ttaatt ggta aacctactga gctattactt 7920 cgtgcattat ataaagagca tgttcaaggt gatggcaaac taagaagtat gattgagtca 7980 ttaaatcatc aggaacgaac tttagtacca agtgaaatta gtttttcata tggaaataac 8040 cattcatggc atcaaaccaa ttgtgaaata gcttagttag ttttatttga tagaaaccac 8100 cttcgggtgg ttttccttta tgtgacattt agtaaccagt ttgttaa agt tagtacactt 8160 tataacaaac ggtgaaattc atgaaaaaaa tattggctgc gggtttaatt ggtcttgggt 8220 tggtggggtg cgctactcca gcctataatt atcaagctat acctaaaaat ataagcaaac 8280 cgccaattgg atcagttaat aaagcatttg taggggatca aatgcttgaa cagggaatgg 8340 tggttgatcg tgaagttcta aacgtccctg aaaatattaa aattagtttt gcttattcac 8400 ttacttcagg catttactta aaaacaggca aaaatgaaaa agggcaatat tttcagccat 8460 tcaacactgt cagtggtggg gggatggttc agaaaaaccc tttagctgac ccatttaaag 8520 tagttatgtt agatactgaa ggtaagctct gtgtagtaac agtatttaat gcaaaaaact 8580 gtactgataa acatcaagct actatgaaga cagtagcaat tgcatcagat aattccttcc 8640 aacaaacatt aatttatagt ggaaaatttg gaaataaaat taatgtcggg taccgtgaat 8700 tctcaagtaa tcaagcacgt cctgcattca ataatgatgt tgaatatgat ttaagccaat 87 60 ctaagcaaat aggttataaa ggtgctttat tggaagtaat tgatgccact aatcaagata 8820 ttacttacaa agttttgaag aactttaaca aggtagatta agatgagtgc accacaatat 8880 aaaccaatga gagaaagtga agtttgtaat gctatcgggt gggtgttaat agctcttggc 8940 tttatcgcag gttttttatt tattcttgca tttggtcgaa ttgaagtagc ttct tactat 9000 ggtaaagaaa cggtttggtc tggagttatg atagcaacag gaatcggaat tatatttaat 9060 ggattccttg caggctactt atttcaaaaa gtagctagta ttcttcgtta ccatgagaat 9120 aaataatatc ttgcataagc accctaggat gctttttaaa attggtttaa ctacc ctgct 9180 tggtaattat atttaactta aaaagaacta cccactcatt gagtgggttt tttatattgcct 9240 agaggaaagt aaaatggcac aagaatcccg tttggtcatt gttattgatt cgcaaaatgc 9300 tgaacgtaat gcgcgtaatc taggcaatga acttgttagc attgaacgta aaggtgaatt 9360 tgcatctaag tctatggaca gcttgtctgt agccaccaga gctttagctg gacacatggc 9420 t ggtttatta acagtaggtt cagccatttc aaagatggat acatatactg gattacaaaa 9480 tcgccttaag ttagtcacta acaatcaagt tgaactaaat aaagcaacgg aagacacttt 9540 ccgaattgct caaaaaacct attcagcttg ggattctgtg ttacaggttt accagcgttt 9600 tagtgataat gccaaaactt taaacctcac aatggatgac acagcacgtt taactgaaac 9660 agtttctaaa gctgtagcaa ttagtggtgc aagcgcagaa gctgctgatg cagctttagt 9720 tcagttcggg caggccttgg ctagtggaac gttgcgtgga gaagaactta attctgtaat 9780 ggagcaaacc ccagcactag caaaggctat tgctaaaggt atgggtatta ctgtaggtga 9840 attacg ttca gtagcagctg aaggaaaaat tacttcacaa gaaattgtaa aagcgcttag 9900 aaatgtagaa tctgatgttg atgctctttt tgctaaaaca gatatcacaa tcgggcagtc 9960 tctcacactc ctaaacaacg agatcacaaa atttgttggc gaagcaggta agggaagtgg 10020 tgcggcacag gtattagctg gatcagttca aactcttgca agtaatttag atttaattgc 10080 tgatggggct ttagtagttg gtattggata tatcactcgt gcaattttga tgaagagcgc 10140 tgctattaaa gagggaatgg cttcaacttt agcgagccgc caagcatctg tattaaatgc 10200 tcaagcagaa tatgcagaag ctaccgctgc tttgaatgca gcaaaagctc atctcgcgaa 10260 tgtgcgagca a caaatgcag aaacccaagc taaatttggc gcaacagcgg cagcaactcg 10320 atacgcacaa gcacaggcag cagtaactgc tgctacaaat gcacaaacag cagctcaaat 10380 taagctaaat actgcaactt caattgcagg gagactagct aaaggggcgt ttggattaat 10440 tggtgggtgg g ctggagttg caacattagg agtaatggga ttagcggcag cctattctta 10500 ttttaataat aaggcagagg aggcaaagca aaagcttgct gaacaagcta aagttgctga 10560 gaaagctgat gaggagttaa aaaaattaac tggcaatgat aaggctaaag cagttaatga 10620 tttaactact gcttttaatg cacaaaataa agcattagag aaatcatcgc gtgctgtagg 10680 gtctgcatta attgatatcg agaactatgc acga ggaaat agggaggttg aaaaaatttc 10740 ccaagaagcg agaactggaa ctatcagcta tacagaagcc attgaacgtc taaataaaat 10800 taagttgcct acagatctat atgaaaatct gaaaaaacag gctgcgcagt atgatgacaa 10860 tgcatctaaa gcaagtttat cagctga gaa acttaaatta ttaagagttg aagtgaaact 10920 tggaggtaat gaagcacaaa atgcggcaat tcagcatcaa aaacaagcgg atgctttagg 10980 aaatactgct actgaagcag aaaaggcaac taaggctttg caagattatc aagccaagca 11040 aaaagatagc gttattgatt caatctataa atcaggttgg cttgataaag gttacactgt 11100 tgctcaagct aatgccattt tagaactgca aaaagctaaa ggaatgagt g caattttgtc 11160 taaagatgaa attgatagcg cacttagaaa tctcaagatc atcgaagaac aacaggagcg 11220 agaagataaa ttaactgaag ctaaaagaaa gcagacgcag gaaattgaaa aacaagcaaa 11280 acttactaaa cgcttggtcg gtatttccgg tcaatccggt attgg tactg gtccacatct 11340 tgacgtccga tatggtggct cattgtcagg tcagaaagtt tctaatgaac atctggctcg 11400 attacaggcg ggaggaaaac ctttaacttc ctacaagatc agttctaatt atggtccacg 11460 aaaagcccca actaaagggg cttcttcatt tcataaaggt attgattttt caatgcctga 11520 aggaacacca atcacgacca atgttgctgt gaaagatatc aagacatggt at gacagcaa 11580 gggaggtggt tatgtcagtg aagtgatctt tgaggatgga gtgtctctta agcttctaca 11640 tcaatctccc aagatgcaga gcaaggtgaa aggtggtgca agtaaaggaa gtgataaagc 11700 agctggtgat attcaatctc aacttgaacg tcaacaggat ttgcaacggt cacttgaaaa 11760 tgaggtggct agtgaagtcg gacggattaa caataataga aaggcaagac tggaggatgt 11820 tgataaagca aactttagcc cggaacgtac tgcagaaata aaggcggaaa taaatcgtcg 11880 tgcagataat gatattgcta tagccaaaca agcccttaga acgaaattgg aagactataa 11940 ggagttccag aaaaccgagg aacagttact agaagagtcc tttaaccgta aaaagttcaa 12000 tgcagctcat gaccttgaat taagtaagtt tgagcagaag caagctgttg aattgctgga 12060 acagcaaaaa cagcaagagt tagggttatt aaaactagct caggaacagc ggttgtttca 12120 agcccgttta tctctgcttt ctgaaacgca agccatgcag gaac gttaca gactcgaacg 12180 ggaggaaatt cttaagaata ccaagctttc tatagaagag cggcaaaagc taatcgcatt 12240 atctaaagcc aatcaggata aagagacacg cgataaagtg aataatgctg ttcaaaactg 12300 gggtggtatc caagcggata tgaatggtac cggagaattt ttcagacagg atcaggaacg 12360 atttagccgt ttaaatgctg caaatgattt agcagatagt caatttgctg ctactgatct 12420 tga tgaaaaa aatggtttag atgttctaaa tgcacacatg gaagcaggac tcatcaagca 12480 acaggacttc gaaaaccgga aaaacagctat cattcaagct gctcaggacc aacgcaatca 12540 gatcgctgcc gaatatgctc agaatgctca ggatattgaa gataagtatc accaagatcg 12 600 attgaatgct caaattgctc ttggtggcca aatgatgggt tcactcacat cgatgtttgg 12660 ttcaatgttt ggcgagcaat caaaagcata caagatcatg tttgctgctg ataaagctta 12720 tgccattgca gctgcaggta tttctattca gcaaagtatt gcaaaggcgg ctagtgttgg 12780 ttttccagca aatatcccat taattgcaag tgctattgca caaggtgcaa gcatcattgc 12840 aaacatccgg gcaattaa ag atcaaggctt tgctgacggt ggttacactg gatcaggtgg 12900 gaaatatcag cctgctggta ttgtccataa aggagaggtg gtctggtccc aagaagatat 12960 taaacgctgg ggcggtgttg gcttagtcga gaaaatgcgt aagagtgcaa accctgaagc 1302 0 ttttctcaat aacaatgcct tggcagatag tgtcatgcgc cgtgcaatga tgagctctag 13080 tgcctttata gaaagccaaa agcaggctga catctttaat caaccggttc aagatactca 13140 gattatctat aagggtaata gagacacacc taaattagct tcttctggaa atttagactt 13200 attccatgat ggcaaggtct acttctcatc caatggttta gttcaggatc gttcaaatct 13260 ggatgatgtt caggacttta ctttaggaag tact tcacgc cctcaagctg agatgatgcc 13320 ttcaattgag ccagcttcac cgacaatcaa tttcaaaatt gaagtgatta atcaggtgag 13380 tggggcgaca gttgaagccg aacaactgga cgagcaaaca gtccggatca ttgttaaaga 13440 tgaactggat aagcagcttc caagaacggt acctaagctt gtaagtgatc aaatcgcaaa 13500 tccaaactca accattagtc ggtctttgac tgagaatacg acagcgagaa gaaatcgtac 13560 ttaataattt gaaccctttt cggagggttc attttcataa tatttaaatt tca aggtgat 13620 agagtctgtt ggcattaaaa ttgatggtta agacatgaaa aaaataattg taatttctac 13680 aacactttta ggccttacgg gatgtgccat tcctgcggta aataatctcg taagatccac 13740 aaatatgtat caggatgatg tttcgggaaa tactgcaaat ttaag ggttt atagaagtaa 13800 tattcccatg gtgcagttct atattactta tcaaaataat gagggtgaaa aaatttcaaa 13860 aaacctaata actaagcaga tttcaaataa tttaacaaag tatggctcta tgcatgagcc 13920 caaaaaatta aatatgccta aacccacaat cagtttaaat aatggtgaag agttttttga 13980 gtttaaagta cccgcaaata agaagttaac tttcaggctt acttctgtta ttgggtcaac 14040 tact atgtat agttgtgatg taaaaatgga ctatcagttg gaaagaaatg gaaattatga 14100 attgatccgt ttaaaacaga tcaaagattt tgtgaatcca gctttactga ctgaaccatc 14160 tcaagatgaa gcctactgca agtttgtagt aaaagagatt tttgaagatg gtaa agaaac 14220 tattattaaa tcgatttctt aatgttaaat cgtttttgta attaatttaa atatctaaac 14280 cttatttcat caaaccacct ttcggggtgg ttttttatta cctgaaggaa agttatgtac 14340 aagttaaagc taaatcctca gaccagcggc tatggcgtaa caccgggtga tgatgtgaaa 14400 cgtcagcaga tggatggcgg tcgtggtcgc tattacatcg atgtgaaacg taacagccac 14460 at tgttgatg tgaactggaa cttaagtaaa accgatttca ataaaatgat ggctttctgg 14520 cgggtctacc agaacaaacc agcctcattt tatgcggatt tggtgattga tcagggaaca 14580 cgtcagcaat atctatgcaa tttcattcca aactcgttca agaccaatga agtcaac ggc 14640 aacttatatc gtgtgaacgc gcagctcgaa gttgttcaaa accagcctaa cctgaatgcc 14700 gatatagcat taattaaaga ttgggaggtc taatggataa cgaatatgcc aagttctttt 14760 tcaatcggaa agttgatgtc tatcaactgg agtgtattga gctatcacat ccttctttta 14820 tgaatactta tcgggtagtc cgtaatgatg accgaggtgt ctatgtacaa cataaggaag 14880 gatccggtca ggt ctattat gagttcttgc cagtctctat acaaagatcc ggaatgcttg 14940 gtgatctgga ccagacatta accgtttcta tctctggtct aggtgatgtg atgcctgatg 15000 agtttgaacg ggtaatcgaa gggcaatatc cagatgtaaa gccaaccgta aattaccgga 15 060 tttacagttc agacaatctg aactctccaa tgttttattt acttggactg caactctcaa 15120 gtgtcgccat gaaccataaa gctgtgacat tcaaggctga atcaccacga ttaaatacca 15180 ctaaaactgg ggacattttt gcactggatc gctttagtgg tttgaagggg gctatatgaa 15240 aagtcatgat catttgctcg ataggcaata tgacgaggat cactacaact gtgttcactt 15300 tgttcatgaa gctgcaatgg acctatatgg cat agatcgg gctgaagcgc ttgaactctt 15360 tatgcagcct aagggcaaaa ttactttttt atcttcacgg ttaaaacttt taaatccgct 15420 acccatgccc aaggaaggct gcatagtcgc cttccatccg agacaaagaa ataagccccc 15480 gcatgtgggg ctttt tcgtg ggcaaaagat tcttcacctc atggaaagcg gagtcactta 15540 tttgcctgaa gaggttgtga tggaaatggg gtttaatcgg gtcagttatt atgattaaag 15600 ttatttataa aaaagacgct ttgtctgaag aaaagacaat tgagcaggct caaaccattg 15660 ggcaatggct cacttcaaaa tatgaacata tgcctgagca tgtccgtatc tttcatacta 15720 caagcaatat ggatcatgcc gaaatttcat ttgcgaatga a gtcacacca aagaatgcat 15780 atgacttaaa gcagcttgat ttcttaccgg gcacttttat cgtagttgag aaccctaaat 15840 gggtcgcggc tattgtttcg attgtgatta gtattgcgat cgcattttta atgccaacgc 15900 catcaatagc acaaacgact caaaatacta accagtcttc ttcagcaaac aatgaacttt 15960 ctaaccggga aaacaagatc cgggtgaatg gtcgtattgc tgataactat ggagctgggt 16020 ggaatactcc cgacctaatc gcagtacctt acaaggtata tgaaaacaac gttgaagttg 16080 agcatgtagt gggctgtatt gggcgtggac actataaaat caatggagct tatgacggtg 16140 aaaccaatat tgtcgatatt gctggcgcat cggtagaagt ctttcgacca ggtgtagata 16200 ttgtttcagg tgagccatat ttctcgcttg gtaccgaaat taccacgccg ccactaacgg 16260 ttcagcatca aacttctgtt aatggccaag ttttacgtcc tgctgataca caatctttag 16320 aaggtacgaa ctaccttcat tttgcatatc caa acgagat tcttcgggca acggcaaaca 16380 acacagattt aaccactaag tttgtaagta atgaccgcgt agaaatcacc aatgcctcat 16440 tcacgtttaa tggccagact tttgatttaa atggtactta tagcgttcta tcggtagctg 16500 atgaccgtat gacgttatca aatccggcgg ccgttaatgc taactggtta aagcttaaag 16560 agttaaataa ccaacaaact gcagctttgt caccaaagat cagttcaata ggtgaaaaat 16620 ggattggtcc attcattctg gacaatgttg aacgtagccg ggtgctgtgt aattttgtgg 16680 ccaccaatgg actttatacc gtttcttcag gtgggtatca ggccgctgtt aatgtcacga 16740 ttgaagttga agtaacaccg gtaaatgaat ctggtg cagc gattggtaat ccgatgctga 16800 agcagatcat tttgaaaggt tcggcaaagt cacgtcagac cgttggtgca acacttgata 16860 tggtcacgtt tcaggggcgt tgtagtgtcc gtgcacgccg tttaactccg actccgacag 16920 tcacaacagt tgttgatgaa gtaaagtggc aggcgcttta cggtgcttat cctttacaaa 16980 gcacagtgta tgaacatgaa acggtttttc gtgcgcgtac ttatgcaacc act ggagctt 17040 tatctgttaa gtcccgcaag atcaattttg atcttcagcg aatgttgccg acttataaaa 17100 acggggcaat gacaacagag ctatatccaa cgtctagctt tgctgatgct ttggtatcta 17160 tggcactcga tgacaagatt ggccgccgtt cgatc gatga gattgatctt gaaaaacatct 17220 atcggaccta taatgatgta gttgattatt ttggtacgcc gctagcggct gagttctgta 17280 ctaccattga tgatacgaat ctatcttttg aagagctggt taccaatctt tgtgatgcgg 17340 tgttttgtac tgcatatcgg caaaacaata agctcaagct ttattttgaa cggccaactg 17400 ataactcggt aatgctgttt aacttcagga atatcattcc ggatagttac aagcatgacc 17460 tgacc tttgg cgtgatggat gactacgacg gactgatcta tgaatacacg gatccgaccg 17520 acgatagccg tatcaatatc tatttaccgg ataaagggc caaaaaccca aaagaggtga 17580 aatctgttgg tgtacgaaac aagtggcaag cgcatttcaa tgcataccgg atttggaaca 176 40 agatgcgctt ccagcgcaaa tccattacct ttgatgcggc accagaatca gaattactgg 17700 ttttacgtga ccggattgct gtagcggatt atcgcaatgg tattcatcaa agcggtgagg 17760 tggtacagca agaaggttta gtcctcacct taagccatga tgtagatttc attgcaggca 17820 agagctatgt gatttatctg caaatggcgg atggcacagt ggacctgatt cctgttacac 17880 cgggttcagc caaaaataag gtggttttag ggcggttgcc gaacggggcc ttaaagctaa 17940 gtcctgatga ttttgtaaat accatctata cagtagttaa tgatgatact aaaggttcat 18000 tgccttatct ggttgcaaaa agagaaccgg ttgaccagtt ctctaatact attacagcaa 18060 tta attacga tgagcgctat tacctcaacg ataaagactt tattgacgtg ccggttgatg 18120 attctccaat ttacattcga tatgaccagc tggatattaa tctggcgcgt ttatatcaga 18180 tgcaaagagg ggatttgcca acgactggcg aaatcagttt tgtagttgaa tctggtgcac 18240 tagtttctag ttcgagttct tatcgaccgg aaaccagatt tgtctataaa ttcgactaca 18300 actccagtcc gccgaaac ag gaatttattg cccctgcagc gactgaacta cccgccattg 18360 atactggtga gttcccacct gatctggtgg taaatctgac tattaaaggt gctgttgttg 18420 ggcgtggtgg tgatggcggt ttacctcatt tggcatttgg cgcatgggag tccgatccgg 18480 attaca actt tactaaaacc cgacgtgatg ggtttcaggg agcacccggt ttattgaacc 18540 ggcacagcaa actaaacctg attattgatg gcggcactct agctcgaggt ggatctggtg 18600 gtggagcaac accaagcggt atttacactg ggttgtctta tggtgttcaa ggtattccgg 18660 gtggagctgg tgcaccattt ggacgggtca tgacaggcca gccaatttca agcgactcac 18720 aagattggcg ctggtatttt ggaagttact tca atgtctt aaaaattact gatgccgaag 18780 cttcggtacc cggaaaaggc taccgaaccc aaaatgaccg ttatggatcc ccattatcag 18840 gtgatggcgg aaactggggc gaacgtggta ccaagtctac taatgatgga acatggaact 18900 ggaaatacca tggcacaact gaaggtca gc cggggccagg tggacctgca attgtgggag 18960 ttgcaccact gacaactcaa ttgattaatg gagggaaaat cttacaaacc ctttaaacct 19020 tataagaact ttgagcaccc aattcgggtg cttttttatt acctaaattt tctggagaaa 19080 ttaatggaac cagtttccac tagcggtttt acagcacttt taaaattata tgggattgca 19140 atcatggtga ctttagcagt cggtttggtt gcagcagttg tatta atgac tcgtatgcca 19200 cgctcaccac aagagtgggc agttggtttg atctgtacgg ttgtatcaag tttggctggc 19260 ggctcattca ttattgtgaa gtggggactt catgaatggg ttactgatgt atggggatg 19320 attgctctag gtgggttctt ctttgtttgt ggtttacccg gttgggcttt agtccgttgg 19380 atttttaatt ttatagataa acaggaaggt aaaacgatcg ttgaagtgat caaagagttt 19440 aagaaagcca gaaaagacat tgaaaacagc taatgccgcc ttcgggcggt tttttacatc 19500 tgaaggaaac cgaaatgaac attgaacaat atctggacga gttaattaag cgtgagggcg 19560 ggtacgtaaa caacccagca gatcgaggcg gtgaaacaaa gtacggtatt actgaagcag 1 9620 tagcacgtac taacggcttt aagggcaaca tgaaagattt accgcttgat gtggccaaag 19680 ccatttataa aaagcagtat tggacagatc cgcgatttga tcaagtgaat gtaattagct 19740 cgttagttgc tgaagagctt ttagatactg gggtaaattg cggtaccgga ttt gcaaaac 19800 cactcttaca gcgtgcttta aatttgctga ataaccaagg taaagcaggt tggccagatt 19860 taacagttga cggaatttat ggtccagcaa ctcttaatgc actcaaaact tatctggcca 19920 agcgtggaaa agacggcgaa aaagtcctgg tgcgtgttct taatatcatg caagggcaac 19980 gttacattga aatctgtgaa cgcaatccta gccaggaaca gtttttctat ggttggatc g 20040 ccaatcgagt tgttatatga aagtctttca ttgcagacga tcaaagatag ctttaacaat 20100 tacattgctg tgcattctat tttcaggatg cacagctcat acgatcaata gcaatgtcaa 20160 tgtctcaatt tgcgctagag cattataaaa aaaagccctg aatgatca gg gctatttaat 20220 aaacttcaat tcacatactt ctacaaagct cgagtagtct tatgtttgtt attgtatagc 20280 ttgataatcc tctatctttc atcctagggt tgtgcacata cttctatcct taaattgtgt 20340 aatgaaattt cttctgttgt agttgagaag cttttcaatc tgttaaaaga atccaaaaag 20400 catcaaatga ataaagaaac tacttattta acttgaatca tcattttctg tttactaata 20460 aatgaaagtg cttggatgta tagggattgt ttttttaatg ttatgttata atataacctt 20520 ttcttaaaaa agggggggat tatgaaacct ttggcagctt taccgttaat ttttatagca 20580 attcagcaag tgcaagctga ggagagaatt gcaattttaa agcctcttgt ttttaaggca 20640 aatgcat taa aggaaaaaaaa ttatgtggtg gacaaagaaa aagtagaaag ttccaataca 20700 ataggtgatg ctcttaaaaa tataacaggt atacaaagta cttcatttgg acccaatgca 20760 ggtgcaccag ttatacgtag tttgagtgga aatcgggttg gagtaattga aaatggagaa 20820 tttattaatg gaatgaatgc atttagtgga aatattaata taccattcga tccaattttt 20880 atagaaaaag tgatagtgaa caa aaataca gataatattc gttatggcgg aaatgcaata 20940 ggcgggagtg ttcaaataga atcgggttta attcctaaaa aaattgaaga aaagccaaac 21000 aaattagata ttgtctttcg gaaaggattt aatgattttg atgtaaaggg gttcaatttt 21060 aacatcaatg atca aaaaaa ctggtctaca aatataagat attcagaata tgaaatttct 21120 tcttataaaa ttccaggaaa tagtaaagcc aaattatgtg aagaccagat tttttcaaat 21180 tcaggtggga tcaatagtgc attagcagct tcctgtcaaa aagatagtag agtccaacat 21240 atttataaca agtcgtcaca accatacata gataaattta tgactgagaa tcctgattgg 21300 gcagatggcg atttttcttt ttatacagat a agcccacat ctatatgggg aggaaaaaca 21360 tatataaatc caaaaaatcc agagtacata cctaatactc cgcaaaatac aataaaaaag 21420 atcaatacgg atgttacacc aaattatttt aaaaaattag gtaacagtta tgctcagaat 21480 gagaatattg ggtttggaac aacatacttt tttgata aag gtttcattgg attgagtgca 21540 gataagaaaa aaagtgaata tggtgtacca ggattttcat tacaaaatca atcttttgct 21600 gattcttatg aaacattacc ggttggtgtg aaaatagatc aaaatcgttt tgtattaaat 21660 tccaatttta tccaaccaat ttcctctgca gaagagataa gtttgaattt tcaacagctt 21720 tctaataaat ctggagaata tgttggtact gcaaa agcta atgagtataa aattgataat 21780 caattaattg aattaataat gaaacagtca tcctttaagg gattagatgg gatacttggt 21840 tttagcctta aaaataggaa tatcgaagga agtggtactc agcgctattt acctaatgta 21900 agtactatta gtaaagctat attcttacaa gaagaattaa at atcaaaca atttacttta 21960 aatacgggct atcgttttga aagaattgaa catgagcttc aagataatga ttttaaacta 22020 gcaagaaatg ctagtaattc aagaatagaa aatagaaaat ataatttaaa ccaatatttt 22080 atcggaggag aatataaggt taataatttt ataaatttaa aagttgatta tggtatttca 22140 gaaagagcac ctgaagtgaa tgagctctat tcaagtaatg ttcactattc tgttatggca 22200 caagaagaag gcgaccagaa tctcaaacca gaaaaaatcta aaagtttaga gttaggtatg 22260 tttttgaatt ggaataattg ggtcatgcaa cttgttgggt atcaaatgga ttttgaaaat 22320 tatatgtatt tatctcattc aggtgttgct gtgcaaaatc gattacc ttt aaaatactgg 22380 aaacagacag acactgacgt caaagggttt gaaattgatt taatttatga ttttaatcta 22440 gctcatattg ggaatattaa actaggtggt ttagctgatt ttgttaaaaa taaggctgtt 22500 aatcctacag atataaggtt agctaatgat ggagtttacc taccaaatat gcctactaat 22560 cgttatggca tgtttcttga gtggagaaat gattcttgga aaggtaaaat ttcaagtatt 2 2620 tactacgatg agccaagata tctaggtaag aatgtaatac aggaagttcc tttatctggt 22680 tacaacttac ttgaatttaa gatagataaa aaattaaaga ttaaaaatgc ttcatttgat 22740 atatttttaa atggtacaaa tctgctgaac gaagaggcta gaccacaaaa ctctcctcta 22800 aaatatattg cccctctacc agggcgagca tttcaactgg ggataactat gcatatttag 22860 gttgctaaag atataaagtt agttcttatc tcctgtcttc aaatttagta ataaaaatat 22920 agtcttaaag ccgaataatt aatcggtttt aagattttaa aataatcaat tataaagttt 22980 aaaatttttt atttataaaa tgtgttcaaa taatgaactg attttttagc tcaaggagcc 23 040 atcgtcatat aaataaagaa tattacaaag gttctttttt aatttttctt taaggtatgg 23100 tatctaatct tagcattttt tatatttaat ggtttttaaa aatggcactt aatgttttta 23160 aattcaaaaa aatatgcaag gatgttacac tattaaattt taatttgctt ttatct atct 23220 ggctaggttt atttctgaat ataggttttt ttaaaaaaaat ccatcaactt acaccttata 23280 atggtattaa gtcagttctt ttcttagggg cgacattagt tattttaata gcggcatata 23340 atttaatttt tcaattaata aattggaaat ggactgccaa aatctttgca attttattga 23400 tatttattgg tggctttagc tcttattttg taaacacatt gggtgtcatt atttcacccg 23460 accaaattca aaatatggtg caga ccgatg tttcggaatt taccgatcta atctctttac 23520 gctttgtttt atggacagtt ttttttgtta ttttgcccat ttttttaatt actcaagtta 23580 aatttaaaca agaaaaagca tcacggttgt tattgaagaa agtattctca ctggtagctt 23640 catttgcagt ggtcggtgtt ttacttttta cttactatgt cgatttcgct gcaatatttc 23700 gtgagcatcg tgatttaaaa gggatgattt caccgcaaaa tagtatttca tcgcttatgt 23760 cttactatca taagaaggct ccgaagaaaa atctgcctct tgtgatatat ggacaagatg 23820 ctcatcaagt tcagcaagta caaaagaacc tccctaagtt aatgatactt gttgtaggtg 23880 aaacggcacg tgccga aagt ttctctctaa atgggtatgc aaaaaatacg aatccggagc 23940 tttctaaaca agatattttc aacttttcgc aagtgagctc atgcggtacg gcgacagctg 24000 tttctgtgcc atgtatgttc tcgggtatgc cacgtgtaga ttatgatgag caatta gcta 24060 gtcaccgcga aggtttatta gatattgcaa aacgtgcggg ttaccaagtg acttggattg 24120 ataataactc gggttgtaaa ggtgcatgtg atcgcgttga acaataccag attccagaaa 24180 acttaaagaa aaaatggtgt aaagatggcg aatgttatga tgacattctc attgacagct 24240 taaagcagta tttggctact attgccaaag atgatgatcg tccgcgtttg attgttctgc 24300 atcaagtggg tagtcatgga cctgcat att acaagcgtgc acctgaggca tatcaacctt 24360 ttaaaccgac ttgtgatact aatgcgatac agggctgttc gcaaactgaa ttgctaaata 24420 gttatgataa tacaattgta tatacagacc atgtattaag ccaaatgatt ctctgtacac 24480 gacaaatttc acaga accct tatcctatca gggttctgcc ttcttaaaat tgccaaaatt 24540 tccttaaact cttctttttt cccaaaacca attaaacgct gaatcgccat ttgaacatag 24600 tctaaaccat agcgaaataa actcattgag agtcgtccat gcttctttat ttttatcgct 24660 tttttttgat catgttgcca ttcacccgtt aagtaacacc aacagaagct tatagctaac 24720 accgcaatca attttttcac tcgtctag gg tctgtcaagc gcgtattttc aagattaaac 24780 ccgcgtcctt tgagacaact gaataaggtt tcaatttccc agcgtaatgc ataatcctga 24840 atagcattgg cattaaactg aggagaaacg acgagtaaaa gctctccatt ttctaactgt 24900 agtgcactta ta tatagttt cacccgacca accaaaatcc gtcgtttacg acattcaatt 24960 tgaccaactt taagatggcg aaataaatca ctaattttat gattctttcc taaatgattg 25020 gtgacaatga agttttttta acacgaatgc agaagttgat gtcttgttca attaaccatg 25080 taaaccactg ctcaccgata aactctctgt ctgcgaacac attcacaata cggtctttac 25140 caaaaatggc tataaagcgt tgaatcaaag caatacgctc ttt cgtatct gaatttccac 25200 gtttattaag caatgtccaa aggataggta tcgctattcc acgataaacg attgcgagca 25260 tcaggatatt aatatttcgt tttccccatt tccaattggt tctatctaaa gtcagttgca 25320 cttggtcgaa tgaaaacata ttgaaaatca act gagaaat ttgacgataa tcaaaatact 25380 gacctgcaaa gaagcgctgc atacgtcgat aaaatgattg tggtaagcac ttgatgggca 25440 aggctttaga tgcagaagaa agattacatg tttgctttaa aataatcaca agcatgatga 25500 gcgcaaagca ctttaaatgt gacttgttcc attttagata tttgtttaag ataagatata 25560 actcattgag atgtgtcata gtattcgtcg ttagaaaaca attattatga cattatttca 25 620 atgagttatc tatttttatc gtgtacagag caaatgatta atactctaaa agaaatatca 25680 aagtatcaga caggtttatg gtatttatct gatcatggcg aatcaaccgg agaacatggt 25740 ttatattatac atggttcacc ttatgcaatc gcaccgagcc aacaaacaca tgtaccaatg 25800 attatgtggt tctctgaaag ttggaaacaa cataatcttg ctcaagtgaa ttgtttaagc 25860 caacaaacta aacaaaagtt aagtcaggat aatttattcc caagtttgtt aagtttgctg 25920 gatgtaaaaa ctcaggtagt aaataacaaa cttgatatgt tgagccaatg taaataaata 25980 tatttttaat ttatataaaa cgaagcaaaa tagacttgct tcgttttata aaatgtattg 2 6040 gttcttttat atttaaaaaa taagagggca gtcgtaaccc ggataaacac cattcttata 26100 gtcgaatgtc ggttcgaata gatctagtag gtgaactcga tctttattta taggttcata 26160 gttcgcgcac atacaaagta acctctttat gattttcgaa attacttttc catcata act 26220 aatataaata aaaagagggt aaataataga ctgtagacgc tattattcac cctcatggta 26280 tatatcttta acgccagcta ttcggaactt tgaatttacc tgtaggcatt ggagaaccca 26340 gaacatactt aacgttgtaa attaaaccag gcaaaacagt gtttggcttt tcattaaagc 26400 aaacataggt attgtttctg gatggtttaa ttaacttata ttgtgtacca gcacttgaga 26460 cataatagac accatttggg gtagtcttaa ggccagcatc aactttagaa atattttgat 26520 tgtaactctg gcttgtattg ttaatagctg agaaataact acaccctagc gatttagata 26580 cttcagcagc tttacgtaat gcgtactggt ttgctatcga tttatgggta tatccgttta 26640 caga tgcgcg tacttgaaag acattatcat caataatagt ggcttcaacg ccaccagaag 26700 cccccatttc ttgataaggt gtagtacagg cttgtaaacc aattgttgct aaagcagcta 26760 aaaatatctt tttcataatt tatataaagt gataaatgcg tcacattaat tttaactatt 26820 tagaagaatt tttcaattac ttaaggattt cttaaaactt gagttctaaa aatctagaat 26880 ttggcctgcc attttaaagt tatctaac ac ttgaatgtgg tggttaatta attcttgagc 26940 ctgatttctc gattcatttt tctcgaaata taagcgactt ttgattaatg cttttactgg 27000 ttcagaaata atcacgtctt caatcatatt catagctttc tttaaatcat cgaaagaaac 27060 ttgaatatat ccatcagtca catcgttatc atcatcgtca gtggtatggt taattagcct 27120 tttaatcgta tagcttccta tggccaagct gttcgcgata gtgccaaagg tgcggcgtaa 27180 atcatggaac gtaaattcga taccagaatt ctcagttact ttgtcacgtg ctgctcggcg 27240 gtctgaaata tgggaaacac catttctatc ggtaaagaca tatttgttat caccggcacg 27300 tttttttcgt tcacgcataa tgtgccaaag ggtatcaccc at aggtagca aaagatcctc 27360 atggtttttc gtattaataa ttttgatggt accaaattga agatctacat ttttccattc 27420 aacagattct gcttcactac gtctaaaacc agttagagca agtaagaata aaaagtcttg 27480 gtttgtgtac gctctaaaat cgttattttg ttcacccatc caataagtag tggccacagc 27540 caatgcccat gcttcgcgct gatctgcacg aacatggcct tttctacgtt taattttatt 2 7600 gaaagctttt tcttctttaa cgataacaac cgggtttttt atatttagaa ttttattccc 27660 ggactcatcc ttatacctgc taatcgtatg gttaaagaga gcatgtaaaa attttgatgc 27720 aagattagct cgggaagggc ttgctttcga aagcttcaga tgacga tcaa taatcattgc 27780 actggtgatt tggtcaagtt ttaaatcttt ccaatcacta aagtagtttt ctatgcatcc 27840 gtcataggca attaaagatg tttccgccag ctttttacgc aatttatagt attggtaagc 27900 ttcactaagg gtagggacta gcttttgtaa ggcatcattt tgaattgctg aagctcgtaa 27960 atcacgcttt tgcttaactg gatctacacc ttcatccatc aagataagaa gccgtttagc 28020 ttca gttctg gcttgttcta atgtatagac gccatgtttt ccaataactt tacgtttaga 28080 cttgccatta ggcattttct tttcagcaaa atagctttta gttttgccca cacataagcc 28140 aaatcctata gttactgtat ctctgtaaaa gatttgtttc tcttcagaca aaggaata ga 28200 gtctattacc gatttagtaa atttaatgtg ttgagccatc tttaaattaa gcaatacaaa 28260 gcaataccta acgatacaat acaataattg tgaagtctat taagagtcta ttttgaaggt 28320 ttggtctatt aaaaaagaga gttttaagta ggggattttg ttttaagtta ttgttatcta 28380 ttaaaaataa atgctccgaa gatgccgctg catgtcgtta cccttgaacc ctaaagttca 28440 gcgggtcttt ctcaattcta gcaatacatt gcaatattaa gcaataccta gcgatattaa 28500 aaaatcaata tttttaataa tttatattaa agcaatacaa tgcaatatta cacaatcttt 28560 agcaatacaa aaatagtcta ttaatggtct attttgataa atacggtcta tttttcaagt 28620 ttaagtctat ta aaggtcta tttttggtga ttaaaaaagc ggcacttagc cgcttatgct 28680 gtatgtgcca ttttgttttg ttcaatataa gccaaaacat cagacttcat ataatttact 28740 tgtcgtttat gaggtttaga gaatggaatg ccgccacctt cacatctttt cttctgcaac 28800 cacggtaagg atacgtgcat aacaatagct actgtttcag gtggaaaagt ttgattatca 28860 gcagcttccc aaaattcctt cttagca gcc tctttttctg catgagtcat acgatctaat 28920 ttagttaaac gtgacattta tttctcctta ctttccgctt taggatttgc ccaccaaagt 28980 acagggccat cttctgaatc aaatgctgca attaaaaaga gtccttgttc tggcggtttc tggcggttct 29040 ggcttccag t ttggccaaac tactgcatct tccggtatat ttggtatttc atcgtaatct 29100 aatagttgag tttcaatttc aactctaaga ttcatttgaa gttgtgccca ctgttctctt 29160 gtataggctt cagctccttc ttcaatggtg tcaaacaatt caatatctgg atgaaaccaa 29220 ttgaaaaggt tttcaggtgg ttctattggc tggatctgat atttaaaacc cgtctcacta 29280 gatccataaa atagttttgc ttcatcaaag cttt tggtta caagaggggc agagcctttc 29340 ttgtagcaaa ttactatttc atcaaattta aaaacacgtt cagctgtctt caaatcaaag 29400 cattggtaca taggttcact aaaccaactc tcaacataaa atagattttt aatatgatct 29460 ttgcgggaac cgtgccattt ctgaactt tg ataacatcat caaaaatttc taagaaaaag 29520 ttgttgcctt ccttttcatg catttttcta taacgctcaa cagctcgctc agctatctct 29580 tttgaagctg ctggcgtttg cttaaaaggg ctgtaacctt caggtcgcat tgcaaccgcc 29640 cataaagttg attcactcat ccttcagctc ccgattcgct aacacccaac ttaatgcaac 29700 cttcctcagg taaatcagca taccaacagt agtatccttc accgtcataa ccatcttgga 29760 gccatttgat ggtcatttca gtttccatct ggaattgatc tttttcccca tctggcgcac 29820 caaaatcaaa ggcttctttt agttcagcgc aagttagagt gacactaggg gtgggagtat 29880 ctggcaccgt ctcggct ttg gctttattcc ataactgcca agcatcatta gttacaatat 29940 tgaaatagcc attcattgtt tcactgaatg ctaggatgtc atttttacga atagcacttt 30000 cacgtttaaa aatttctgta gttttgaatt gtgattcaaa agggatacgt tcatttacctg 30060 tcatttaagc caccatctct gcatattctt ctttagtcca ttcaacaaac tctttataaa 30120 gctgctgcgc gggtttatt aaccggttgt gatagtcgat cgttatgcgg cg ccaagcga 30180 ctggtaccgc ataatgcttg gttagaaaca tcgcttgatc catgccttgc cggactatta 30240 cgtagcccag caattgcaag tagtacataa aaccaagcat gtgtttttgg ctcactttct 30300 tgtactgatc tttcatatta gaaaccgtct cctaataaat aat caggctc agcctcttga 30360 agtggcgtag atgtagggtt ctctaattca aagcggcgtt tcttaacaaa gtccatgagt 30420 cgtgattgaa tctgtggatc tcgtgcggcc acatctattt ccaaagcatc taatgttgtg 30480 agatcgggcg cgttttggat ctggaccatt agtgaaggtg gttcagttgc ttgcgcctta 30540 gatttttcga gctcttcaag acgtttgtga gttgcaagta g caaaggctc catttgttta 30600 tcagaccaag tgcgtgtata tcgataaact gcatttactt cgtctggtgt ttttgagtcc 30660 ttaactcgtt gcagcagggt atcaagtttc ttctgatatt ctgaatcagc ggtttctgat 30720 tcaatagccg gctcagctg t ttgtgctttt tctacaacct ctggttttga atttttaact 30780 tttagagatt ccgcatgact ttctgaaggc ttttcttctt cgacttcttc agtaggctta 30840 tttagaagtt ttagaatgtc ttccgcaaac tcaccaccgc tgattttaat aatcgcgcag 30900 caatgagcaa atgcattatc aaaacttgag tgaacttggc catgctggag catgcgcaat 30960 tgtcctttag atccattcca cttaaactgc tgcacaccta attcaacagt tgggctaggg 31020 taagagcaag taga accttt ttctggcgca actcttaatg gttctggtac ctcaaattca 31080 ccaataaaaa tagttctagg ctttaattga aattcgaatt tatcaaaaac atcaaagcca 31140 aagtcataag ggttaaatgg ttcccagcca ttacgctcag tattatttac taaaagtaat 31200 tcaccgttgg cccaagcaag tttggcttca actttattta gaattttcat gctgtcatcc 31260 ccgttttcgc taaggtttca atttcttgtt taactgcagt tagttttgcc gcttcaattt 31320 ggatcagggc atctatgccg aagtgctcac aaactgtttt tacatcgagg ccacgttcag 31380 caataaagtt ttgaagttca tctctttgtt gatctgagat accgttaaat tctggtggac 31440 taatccaag t gccacgttgt ttatcaaacg tgcaattcaa tgctttagct ctcatttaaca 31500 ttgcttggcg catgttctgg taatacatgt gttctttatc aagcgactca gttaattgat 31560 taaggtcacc tgcatgctca gcttcttcac agctttgttt ccagttttct agctct tctt 31620 gggctttagc tgctgcaagt tgtgcaggcg ttaaggtgtt aatgtgatct ttagcttgag 31680 taatcaggtc agccaagaaa gtaggatgtg ctttaagatc tggtacccat acttcaccag 31740 tttcaccacc taaagcacct gagtttttcg catgatgtgt aggcgagggt ttaaaattaa 31800 taacgcgggc atttttacct tcacctgtag taacagttgt tagataaccc atcaaatctg 31860 cgatacggta aagctcgtta cggtttttac cacctagatc tgggcggtaa ataatttgat 31920 caccgttttg atcttctgat gcgtgtgcaa tgaaaacaac atctttacct aaactgatca 31980 aagtattgat gtattgcttg aacgtttggt tcgctaaacc ttgagccttt aactttaaag 32040 agccatctt t ttgacggtta ttagcagtta gcaatagatg ggttttaatg cattcaagca 32100 ttgcacccac ggtatcaatg actacggttt tatatggtgc taagtcctgc ggagtaaggt 32160 ttgcaacatc actccattgt tgaacctgta caaccgcacc acgacgtaat tcaccagtac 32220 ggtgagcacc acggtcaaag tcaaaagaaa ttgctttttc cgcagtaaag cccatcgatg 32280 atttacctaa acccggatca gcgtataggt acacaataat tgcttgaacc aataaagttt 32340 ggtcagcagt aataatcggt aacgccattt ttcttatcct catctagagc cggtgaagcc 32400 gcgtttttgc ttatatgctt tgcggtcata agtagggatg tttgtttcac gcagttttat 32460 tgc gagctgc tttctgcgtt ggaaatcgat ttcttgggtg agttcattcc aaacttttgg 32520 ataagaagtt tggaacctga acacatttaa aggcgtctta actccgtctt taactttgta 32580 aagaactgag ccattagcat tagatgcgta cacttgccag ccaatgcgga cagagtagag 32640 gcccttatca tcacggccta aaaatgacat gtagccgtca gggtgttttt tgaaattaga 32700 catgttcagc ctccttacat tcgcatgtac caacaaaggc atacgtaagc gggc taggag 32760 catctacagg tgagacgtcc ctaatattta aaggaataat ttctttgcga tatttaacta 32820 aaaccacatc accttcacgg caattgacaa ttccttctct agaagaaaaa cgtgcagatt 32880 tagaagattg ggttactctg caaaatgaaa cctcatcacc agctttgatt ttt gaacggt 32940 caacaggaat catcttcttg caagtagggc agttataatc tttcattagg ctgcctccaa 33000 ccagttatta cggtcgatat agccagccaa taaaatattt atatttttat ggtcatcatg 33060 attggtaaag tcattgaaag acttcccgct tagatccgtt actgaatcaa tagccaaatt 33120 tgtaatttca gcagttgtaa agtcagatcc agctacgccg tagctatcag ctacaccgtc 33 180 aaaatcgaag ctcacgttta atttgaagcc gtcaatgcgg ataactgctt caccagattt 33240 ttctccagtt ttcttaacag ccagaagttc atattcagaa gcaacgactt gctcgctttc 33300 atatgagtaa ttagaaggga cgctagaatt agcagttcga tattcacaag aact caaggc 33360 tacaagtaca gcaattgctg taactccagt taccttatgc ttgtttgaaa aggtttttac 33420 gttcataatt gatctcgcag ttttgcaaaa gcacatcgga cctggggagg ggcggtgtgc 33480 ttttttgttg tctgtgagat aaatattagg taaacctaat tattaagtca ataggtattc 33540 ctaacaaaat tagaaatacc taatttttgt gttttaatag acaaaagaaa acccacacgt 33600 ggtggtgggt agattagatg aattggatcg ctttttactt attgctcaat acttttgctt 33660 ttgcctctct tgattctttg cgatctttta atgttttttc aagcaaagag atttctctta 33720 agtcagacca agctaagaag aagctaaaaa ttgaggtgag tccaacagaa agtattagag 33780 ctaaaagatg cttagctgaa agtaagccta ataaattaag tatatacata ctaaaaaacaa 33840 gaataataaa aagcatagcc acatataaag atgacttact tcttatgtcc acagttgaag 33900 tcaacctatc tcgttctgac tgatttaaac catcaagctt taatgcatcg agcatacctt 33960 tataagccaa ataaatttga cttaaaggga gaagcagtac aaatgaaaat tgaaccagat 34020 ttatattgtaat atttaactct aaatatttaa aaattattga aaatatagca aacagaccga 34080 ctaacactag tgcgataaat ctagcattat tgtagaaggg taagtagcgt ttagccatat 34140 tagtcaccaa aatttatatt ggtagtcatc caattataca attgaacttt taggccgtcg 34200 ttataaactt tattattgat tgtttca act gaaatcttgc cgctcatttt tagattatca 34260 gccgtaacct tggtcccatc ctcaagagta ataacataat catcattatg tcgcatggat 34320 gaagctacag tatcaataac tttttgccca ctttttgagg ttttgcggtt gtatgtaagt 34380 gttaatttta actttaggtt tgcgtcatca agcccatcct ctagttttaa attttctaaa 34440 tcaactccaa aagctgactt aagcacatca accacattat cttcaatttt atagtcaatt 34500 ttcgcaggta tgcttgattc gacagtatga acaggttgaa gttctgttga cccaatgcca 34560 gatgagattg aaatagtttt agctggagtt gattcaagct tttgcttaac agtgggattt 34620 gg agcatctt ttaatattaa tgcactattc tctggcaatg ctttggctgc ttcacccaaa 34680 agccagccca aatatgactc caaggttcta gcggtaagtg atcttgattg aatgattgcg 34740 acatggttat caataacacc aaagtaaaga acactatcaa taaactcttt tcttacaacc 34800 tctgtagcgt caacgccatc ttcatcatct ggcagatcat ctgttaaata ggttttaatg 34860 ggaaattcag tagcatcatc actgtctatc tttaataca g cctgagcttt gcctgactca 34920 acaataatca actcgccaaa gaacatgctt tggtgtgaac tagcatgatt aattagaata 34980 aaatcatctt ttgttgcgga gacaaattgt tgacgattta tggctttata gtaaaaagaa 35040 tccttatcca gcaattgtgc ttttagtaat tgacctagat tggcgccttt tagaaaatct 35100 acttttttgt agtgtactgt tttgtctttt actactgttt tactcattat ttcctcctcc 35160 cgaatcgctc taaagtactg tgtagggttc acaacttatt aatctttggt gttgttaatt 35220 ttatgcccaa gctttccttc ttttaccaac tgcactactt gttcatttgt aaggactgga 35280 ataaagactt tatcaccaat gtcctttgag aggatcttca cttcttcggc tgttagcacc 35340 aaagcttcac catgtttcgc agcatcattg atgcgagcaa taatctggtt gattggtcgt 35400 tttgaattgt ccataagtct tcctgtgatt aatgcgaata aggatgttct tgtctatgct 35460 gacttggc gg cacgatatct gtaatagcgg taatactttc aacctcgtcc atttcaaaga 35520 aaaatcgctc accaccattc acagaaagca aacttaaaac cccaccattg atgccgacaa 35580 attctttaat tgtgcatctt ccatccttca agcacacctg aacaaactca ttcggcacaa 35640 gatctgcatc agggtcgcac acaacgtacc aaccattacg aattgctgga aacattgagt 35700 cgccagtgcc tttaatgcca taggctcttg gtcctgctga gtggg ttgga acatatccat 35760 caccagcatt tccttcataa cccatgtcag taaaataacc atccatccc atcttggagt 35820 acgcctttac aggaacccaa cgtttagatg atggggtaaa aggtttttcg ataattgttg 35880 aaaataaaag agcttcatca ctatcactaa tgtt gtattt ctttttgaat gcttcaatat 35940 ccagttgttt aaatttatct ctcgtgcttg attgaatctc tcctgtgcca gatgcaagcc 36000 aagaaggatt aacattcaaa aattttgaag cacgtaataa attttcacct tccattgttt 36060 tggattttcc agacagccaa tcactcacag aaggaggttt gactcctact gcacgagcaa 36120 gctcaacacc tttaatcttt ttaggtggca aaacttccat agcataccta agtcgttca g 36180 caagagtatt catacaacta tcctcacaat gttaggaaat cctaacataa ataaaattag 36240 gtattcctat tgatttatca taaggaatgc ctaataatta aagaaaaatt aggagcacgt 36300 tatgaatgac gcacaactta tagacaagct aggtggtgtc acagcggtag caagacttct 36 360 agggattact ccgccatcag ttagtggatg gaaagctatt ccccttgata aaaaaatcag 36420 gttagcagtt attgctgaag atcttggttt aacaacacga aaagagcttt tccctgataa 36480 ctatcaagat atttggattg aactacgtcc ccagacgaca aaaagtagaa accttggatc 36540 attaaccgct taggacctta accatgagca aagtatcaaa tgaattgcct gcaagcgcta 36600 g caataacga atcgctcata ttgcaagcgc taaatactag caaccaaaga caagtagccg 36660 agaaggtggg aatagatgca agcaccttgt cgagaatgaa aaatgacaag aaaaacaatg 36720 gattgacaga gattgaattt attagctctt tgttgacagc cattggattg aaggtggtgc 3678 0 cagaaagtga tgtgtattgc tcacctgaaa ttgcagaagc aacgcgagtt tatttagcac 36840 atgcattcac ttcacctgaa tacatgcgga ttttattcaa ataaaaaacc actacctgcg 36900 ggaacaggag tggttaggca ttcaaatgag gtggatcaaa tgaacacaaa caatttatca 36960 gaacaaccaa tcgaactcaa ctcaccagat tttttaatag gtgacgttgt agtacttact 37020 aaagagtg tc gaagttttaa atcaaacgat ttatttgagg ttaaaaataa aactttgact 37080 aggttgtgga ctatcaaatc ggagaatcat ttgattctgg tttcatcaaa agaaatccgt 37140 acagcaacag tagcagagct caacgctaaa cgccgcctaa caaaagctga gcaagcatta 3720 0 gcggaggtgt catgaatagt caatttaagt ataaacctga gtacaaacag actcaggaaa 37260 ttcagtcctt ctttgatcca gcgttagtga ttctcaatga gctacatgat cgtaaccgta 37320 aaaatctaag agccaaaggt tatgacgaaa ataatgctgc aataacgcgt gaagaatttt 37380 cacaaactat ggcacagcgt tttcgcatta atcagtggtt agcagggcag atcgttaata 37440 gtttggctaa tgctgacttg gttcaaaaat ttggtgggta tgtaaagcct aaggtcggtg 37500 tacatgagta attttgtgcc taattccttt caagtgccta atgcatttgt tgacgaggtt 37560 ttaaataaaa tctctgatgc tgcatgcaaa atttatttag ttatttgccg taaaactcg t 37620 ggctggaata aggagatgga ttccatctct ttaactcaat ttgaagagat tacagggaag 37680 agtagaccga cagttgttaa atgccttaat gaattaatta aagttggttt agtcgtggaa 37740 caaccaagca caattcatgg aaatacattc aaattaggta acgatactag cgttggttta 37800 gtgcttaaat tccctagtaa aaatttttta ctacctgaaa tttatggcca aactagtaaa 37860 aattctttac cactgctagt taaaaatttt aactac acta gtaaaaattt tttaccgcta 37920 ctagtaaaaa tttttaacac acaaagtatc actatcaaaa acaactctca aagtaataaa 37980 aaaataaata aaaaaagaga gcctgtttct gaaaaaccta aatcagaaaa accaactgaa 38040 tttaatccac gtttagttga actaccagca tgtgtagatc cagagctgtg gaacaatttt 38100 gttgatatgc gtatcagcat caaaaaacca ctttctgaaa atgcagtaaa gctaatcctt 38160 aaaaaactta tctcgtttgg ccctttggct aaccaatcac tggaaaactc aattatcgga 38220 aattatcagg gtgtatttga gcctcgccaa aatcaaattc aggaaaccc acaatctcat 38280 aacgttcctg aagaaccggg ttatttcact caaatg tacg ctgagagcaa ccgttcaaac 38340 gtgattgacg ttacgccagt gtcacaagat tttggaggct attaatcatg aatgaattag 38400 caccatttga aagtttttta aaagaactaa ttgcggctta cagaactaaa tacgctgttc 38460 agttcaataa gaattttc ca gtagagggga aaaatgccgt tccaatgcaa atcgttgaac 38520 agcagcttgc taaagcattg gttggggtta cacctaacca acttcaaaga ggcttagcgc 38580 tattttacgc aagtacaaat acatacatgc ctaacttcgc tgaattccgt gctatgtgca 38640 tgggtgatga ttggtggagc gctgagaagg cttgggttaa ggcttgtgaa tacactcaga 38700 tctctcaaca caaaaaagtg acattgccag acggaagaga gcaga accaa gaaattacaa 38760 ccttgaccaa atttgtttta gaccaagttt attcactaat ccaagatggt gaaatgtaca 38820 aagccaaaat ggaatttatc aaaatctatg atgaatacaa ggctgaagca caactgaagg 38880 gtaaaaccca agcttggtac caagaaccaa ttttattagc tca gaaaaat gagcaaaagg 38940 tgcataagcc tgtttcaaat gacgaagcgc aaaagcatct ccaatcattg atggaacgtt 39000 taaaaatcaa tggtcgtaaa cctgtaccag tacaaaagct taaggctaag gaaaaaagagc 39060 cagaactcaa acaagagcta ggtccagatc cttttgacaa tccgcacgaa tacgcagaga 39120 tgtgccgccg tgaaggtatg ccaattccta gaaatattct taagttaatt gatgggg cga 39180 atatatgaat aaattcgaga ttttagcgtg gggtttactc atttcatttt ttacagcagc 39240 tattagcggt gcggtggttt ggtggtggtt ggcgcgtaaa gagcttgatg agaaaggagc 39300 cagccatgaa agcaactaaa ttgattagag ataaagg act gcaatacgcg aaggaaatcg 39360 tagattcagc acccgataac gcaactgaat ggaacgaggg ttatgagttc caatgtggtc 39420 aaagtgtaga aatcagccca gcagatcgtg agaagtattt tgtagatttg gttgagctta 39480 aacgtctggt ggagtctttg aaaatcatca acgatttagg tggagttgag aagctaacgc 39540 ctgcattcat tacgacagat aagcatgttg gttacacgca tgttcgcatg gtggga aatg 39600 ggagatgag ctttcttgat gatttttgcg acttcattcc agatggttcc atttcaatta 39660 agcgtgtgat gactgctatc cgcgaccacg aatcaatata cggaggcggt gaatctcatg 39720 ccaactagat ataacacagg cgagtatagc tacgatcttg aatatcacta tggagatatg 39780 tcagcaagca tggagatgct tagagcacgt ttaattgaat tgttgactcc tcatctgtct 39840 ggccgttatg tgaaatggag agaagcatat ttcacatggt ttacaaagtg cggcggggat 39900 tcggggtgga tgttttgtgt aggtccacac gaatttcata ttgatggggc gttaaggcgc 39960 tattactcag gttctattga tattacctac aaccagaaag atcgatattt cttggtgggt 40020 gagaaaa aga aagtcaaatg taaggcttgt aaggggtttg gcttcattcg agatgatggg 40080 tgggggcata tagataaatg tgaaatgtgt gatgcagaaa aaggagccag ccatgagtga 40140 gtttgagggt aaatctggaa agtgggcttg ggagattcaa aaagaacaac aagcga aagt 40200 ggaggagctg caaaagcgtt tagatggggc attaaaagag actcaatatg ctttgcagta 40260 tgttgaagaa gacatgcgcg gcaatcatga atttctacaa atggcaatga ttcgaaccct 40320 taaagctata gagcaagtgc tcaaaggtgg tgcttgatgt catcagtcag cattgctgaa 40380 taccgcaagt tatttcccat aaagaaaaat aaaaagcgcc gttcagcaaa gcaagttgcc 40440 agacaaccaa gtgtggg tga agtggttctg gcaacgcatt taagagcatg caagattgga 40500 tttgaacagg aatataagtt ccatcctgaa cgcaaatgga gagcagattt tttaataaag 40560 ggttcaaaga ttttgattga ggtagaaggc gggatctgga gcggaggccg tcacacaaga 40620 ggtaagggct atttagggga tatggagaaa tacaactccg cagcaatgat gggttttaca 40680 gttttacggt tcagcacaga gcaagtgaaa tccggtatgg cattaaagca aattgaatta 4074 0 ttaattaagg gtaaatagga aggcgattat gttggttgaa aagtttgatt ttattgagtt 40800 acttcgcctt gctattgctc aaggcaaagc tgaaggtaag aaaatttcta aagatgtagt 40860 tttaggtgaa ttagcgctgt tatcgccagc tgcaaagctt tgggccactg t cttgattga 40920 aaaggttgat tttgagcgaa tcgcaataat taccccagca caaaaacaga ctgaaacttt 40980 ttacagtaag tatgacttta attttcaaac tgaacgccgt attgaagata ttccgggcaa 41040 ggttgagttt gttcgtggtg agattaaatc aggtaatttt ttcagagcgc gaaataaatt 41100 agcggtagag attcataaag aaatggtaaa gaaaaaattt acccctacta atgcccaagg 41160 tgatcttact aatctggcaa aaggtatggc tgagattatt ttgcgtggcc atgtttttgt 41220 taaggctatg tgtggagtct gccaagggtt gggtaaaatt gagacatttg gtttaaatgg 41280 ctttccaaat ggggcaaggt tttgtgaaaa atgtaatggt actggaaaac gaccatatac 41340 gttgaaagag aaaatgaata ttgctggcat tgatgcaacc aaaacagctt atataaagag 41400 ttatcagaaa tttgagctgt ttggagaatc aatcgttgct gaatgggaaa atgaaattag 41460 aacgcgtatt tctcgatcat tccgttttga acttcctgat agtcaagaaa cttacgcttg 41520 acagttgggt atacacttga gtataaagat ttctaaaatg ggcgaaatgt aaagtaatcg 415 80 ccagaatgaa tttaagagct cgccaatcgg tgggcttttt tatttttaaa tatttcagta 41640 ttatcagtgt gttgctttaa gtaacactaa accttattga tcagcgcaaa tatcaaaaaa 41700 aagggggagc ttgcctacta ggcaagcttt ttaaattgat gatttaaaca caata atcca 41760 ttttaaagct caatagaaag atcaaacttc catagctttt atttgtacta atttattgaa 41820 tataatcgtt tttataattt ttaaaatttt cttaaactaa aaatggaaaa tttcttgttg 41880 caacattgtt ataataggac taccttaaga aaaatacttt ataaaaatga ggagctgctg 41940 aaatgacaca gtatctcatg tttgcggaaa atatttataa caaaattaaa gatgaggaat 42000 tgttttcaca tgactgtatt ga aaatatga acttacttat gacatgtata cgcagagaaa 42060 ttaagggaac agaatttaaa ttaaaatata attttattga ttttgttgaa ttgtttagta 42120 gaccattaga tgaatgtaaa gtaaaaatag atgttagttt gattcctcct cataattcag 42180 aaggtgagta tattttatgg t tagctggat taatcgaaaa aattacagaa ggtggaccta 42240 aaccacctcc gcctataaag aagtttattc cagagtatat gagcttgaaa tttgaattag 42300 attttttacc cttaaatgag gaaaaaattc aaaacgaagg taaagaaatt acggattact 42360 ttaattcaaa gctttataag gcaactttta agaagtaata ctatattgcc tgtgagttta 42420 gccaccgcct aagggcggtt ttttttatgg gtaagaataa tggattctac agaatacttt 42480 tggcttactc ggaaaaaaga acctaaaact aaacctaaaa gccggccatt gcctaaggcg 42540 aagcaaaaat atctcgaggc tgaggcaaca cttaaggaag agcttgagga tttggcgatt 42600 ggatttgaaa gtaagtttca gccgatccat accaaac act ggcgctttga ttttcatata 42660 gtgaaattgc gtttgctcat tgaaattgag ggtggtccct ggtctggtgg gcgtggtgga 42720 aagctgtcaa ataaagcatg gagtcttaat cgatatgatc atgctgaaga gatgggttac 42780 aaaatagagc gctttcatcc agattctatt ttgtcgggat atgtcatcaa ctggataaaa 42840 agtgaattag cgagaattga agatggagca gatcagacca tt tccaccga ctgattttat 42900 tgatcaagct gaagaagagg aagcaattag actaacacca gcaccggact taaaaaaatg 42960 ggttgtggct aattacttaa ctattggggg tcctattttat aatccagatc atgatcatat 43020 tgctgagctg cttcatgata atgacgagtt tttagcattc g cgtgggcct cttctgcata 43080 taaaagcaag caagctatgg tgttaggcca gtgcgaaaaa gtcatgttca atgttggtgg 43140 ctggcgtaaa gctcgacaag agcaacagat gcgtgattgg tttggttttg tacctactta 43200 tttaataact gtcgacgctt ctttctgtga gcgtgcaaac gatacagagt tctgttactt 43260 acttgaacat gagctttacc acattggagt gatgagagac gaggac ggag aaattgttta 43320 tagcgatagt tctggtcttc ctaagcacta tcttgctggt catgacgttg aagagtttat 43380 tggcgtagtt aaacgttatg gaccaagcaa aaatgttaag cgacttattg aagtcgcaaa 43440 aaatccgccg tttgtttcga atcttgata t ttcaaaatgc tgcggcaact gtgtaatcaa 43500 ttgagcctaa tggctctttt ttttgcccat tttgttatac gtagttatac gatgaggaag 43560 ttatggcgac actaaaagag cctgtgaaaa tctttatagt tcagtctctt gcttgtcgtg 43620 atacacctca agaagtggct gaactcgtaa aacaagagtt tggcgttgat atagatcgtg 43680 ttcaagttgc aacttatgac cctacaaagg ttgctggtaa gaact taagc aaaaagtatg 43740 tcgaactatt tgaaaaaacc agagatgagt ttgataaagg cttaattgat attccaattg 43800 ctaataagta ctaccgattg aagcaatacc aaagacaact tgagaagact agaaacgtca 43860 aaacagcctt aaaaattctt gagcaagccg ctaaagacat tggtgg tcaa tttactaatc 43920 gccaagaaat tacaggcaaa gacggcggac cagtccaaac agttaattca gaaattccag 43980 ttccaatgga agattactta aaagcgcgga gggaagtctt agatgagtac tgatgcggct 44040 cgggataaag ccatccggat cgaggcgcaa gaagatttat atttcttcac aaggtacatg 44100 tttaaggagc gccgtggtta taaatggatg caaaattggc accacttaga aatctgcgaa 441 60 gctttaatga aagtttatcg cggagagata aagcggttaa ttattaacgt tccaccacga 44220 tattctaaaa ctgaaattgc tgtaattaat ttcatggctt ggtgttttgg taagaatcca 44280 gactgtgagt ttattcatat cagttactcg gcaatgcttg ccgcaaataa tgccttcc aa 44340 atacgaactc ttgtacaaga agaggcgtat agaaaagtct ttcctgagct tacattgcgt 44400 gatgatagta aggctaaaga cttctggaga acttctcaag gcggtgtctg ctatgcgaca 44460 ggtacaggcg gtacgattac tggttttggt gcaggaaaac ttcgtaaagg ctttggtggc 44520 tgcattatta ttgatgaccc acataaagca catgaagctt catcaaaaac tattcgagaa 44580 gggg taattg attggtttca gaacacactc gaatcgcgta ctaactcgcc agatacgccg 44640 atcattgtga ttatgcagcg acttcatgaa gatgatttag ctggatggtt gctaggtgat 44700 agaaaagacg gcgttcctgt agctggtggt aacggtgaag tgtgggagca t ctatgtctt 44760 tcagctattc aggaagacgg atccgcactg tggccagcaa aacacaatat ccaaaaattg 44820 aggctaatgg agcaagcagc accatatgta tttgccgggc agtaccgaca aatgccatca 44880 ccgccagcag gcggtttttt taagcccgac aatattcaaa ttgttgatgc tttgcctgcg 44940 gatgtagtga aacaagttag ggcttgggat tttggggcta ccgaaaatga gggcgacttt 45000 acagtaggtg tgcgagaagc tctaggcgca gatggtttta cttacattgt cgatgtaact 45060 agaggacagc ttggacctga caatgtgaat aagcgcttag aacaaacagc aaaaatagat 45120 gggaaaaaag tttctgtgcg tctaccacaa gatcccggtc aagctggtaa atcacaag ct 45180 agttcatttg tgaagcttct tgcgggttat agcgtgatag ctaagccaat ttcaggtgac 45240 aagcttacac gtgcacaacc atttgcggcc caagttaacg taggaaatgt acgaatgctc 45300 aaaggtgaat ggaataagga ttttattgat gagcttcgtc attttcctaa tggcacacat 45360 gacgaccaag tggatgcagc ttcagatgcg tttaatgaat tacatgaagg ttttgaagcc 45420 ttctttgctg atatgggatt tgctc gatga gtgatgtaac ttttcaacat gctgaatatg 45480 ttaagaactt gccatactgg caaaaacttg atgatgtttg tgaaggtgaa gatgcagtta 45540 aggctaaagg tgaaaaatat ttgccgatgc caaatgcaca tgataaatca cctgcaaata 45600 aaagcgctta tgaggcttat cttacccgtg cagtctttta tgaagtaaca gggactacat 45660 taaatagttt agttggtgca gcttttgcaa ccgatccaag ttttaaattt cctccggaac 45720 ttgctcattt agaacgtaat gcaaatggtg ctggtttaag tacttatcaa ttggctcaaa 45780 atggaattcg ccatttatg aagcattatc gttgtgcttt atatgtagat tatcctgatg 45840 tgccgccagc tcgtaatcta gcggaattta a agcacaaaa agcctatccg atgattcatt 45900 tactaaatgc ccttgatgta gtgaattggg attcagtaat gatcgataac cagaaaaagc 45960 tttgcttagt ggttatacgt gaatttaagt ctgagcgcgg tgctgatgga tttagtaaaa 46020 ccgaacaaga gcaatat cgt gtacttcgtt tagagcaaga gggaaatggg gaatatattt 46080 attccgttca ggtgtacaca aagggtgaaa agggtaactg ggttggcgga gagaagaagt 46140 ttccaacaga ttacaacggg aatttctgga cctatatacc ttttacattt gtaggtgcaa 46200 ttgataattc agaagagatt aaaaagccac cattacttcc tttggctaat ctcaatttag 46260 cccattacag agacagtgcg gactttcaag agtccgtttt ttatatgggg caacctcaat 46320 attatgcgaa gggtgttaat tggggagtggt atgaccaagc caagaaacgt ggcatctaca 46380 ttggagcgaa agtacttttg cctttacctg aaaatggtgg tttaggaatt gtacaagccg 46440 accctaatac tcttgcccgg gaagcgatga aagataagt g ggaaaaaatg aaggagatgg 46500 gggcgcgttt aattgagaag ggctcgggaa gtaaaaagac cgctaccgaa gcgaatagtg 46560 atgacgccgt tcagcattca gttctttcgc tctgtgtcgt taatatgaat gaagccttgt 46620 cagcagcatt acgatgggct gctaagtttg taacgcctaa tgtggatgtt ctaactaaag 46680 atgatttgat gttcgaaatc agtcaagaat ttaacaaaca gggttattta gctgagttag 46740 ctcgacagtt atttgaagca gctctacaag gccgatcttc atttaaatca tggtgggaat 46800 acaaccaaac aggtatgttc cctaaacaaa aatatgaaga agagcttcag aatgttgaag 46860 cagagcaaga tgggacttta aatcaaaagg tagag tgaga tggcaacaga tatcaaaaaa 46920 ctatttgaag tactcactca gcaccaggcc tatctttatc gtgcttcatc aaaaacggta 46980 aatgagttat tggctttatt caatgatgat acgagcaaga tgctatctaa gcttcgggat 47040 ttattggatg agcttaatga gtcggagaaa gttgctttag ctggtggtaa atatacaact 47100 tcaaatttaa gggaaattag ggatttgatt gcccaatggt ttgccagtgt taatttagca 47160 ttacctgaag cttttgccgt ttctgctacg gcgctggctg tttatgaggc caattacgta 47220 gctaagctct atggagcaaa aattaataag cctgatgggg aaaaactatt cttatccgct 47280 aaaaaagttc cgttggcagg tggcgctctt gtcgatgatc tgctttcaag aattgct gaa 47340 agtgcccgtc aaaaggttga gtatgcaatt cgagatggta ttaattcagg caaaactaac 47400 caagaaattg ttcagcgtat tcgtggtacc aaacggctta actatgaaga tgggatctta 47460 aatggtacca aaactgatat tgagcgaacg gtaagaactg tgcgaagtca tgtagctaat 47520 caagcctatc taaatagctt caaccaaatt ggctttgaat atgtccgatt tgttagcgtt 47580 ttagatggac gaactt ctaa gctttgcgct tcattagatg gttcagtgtg ggaaataaat 47640 gatccggcaa agcgagtgcc gccgttacat cctaactgtc gcagtatctt ggttccggtc 47700 gagaaggacg gtcaacttgt tggcgaacgg ccatttgtaa tggacgaacg tagagttaaa 4776 0 gacatcccca aagaagagcg aagccagtta ataggacagt tagatgcaaa caccacattc 47820 aaagagttct ttaagaaaac agatgatttc tttcaaaggg agtggctagg gccaaagcgc 47880 tttaagctct ataaagatgg gaaatttgat tttgataagt tctttgatcc tgaaggccgt 47940 ttctatagct tagatgattt gagaaagttg gatgaaaaag cttttaaaaa gttgggtctg 48000 taatttttct tat gttatat tttttaaaac atcagaattt atacaatatg aaaacaatag 48060 cttttgtatg tctaacccta atttccatca cttgtttagc tgaaccaagt caaaaatatc 48120 ttaaagaata tgatcgattg tctgaagctt tggagtcagc aatggcaaat gcatattctt 48180 ttga tcctgc aactggtcaa gtaaaacagg ctactcaagg tttagaagct aaaaataatt 48240 tatgtagagc tgcccaggcg aaactaaacc tcaccacgtt tttaaaagac aatttagagg 48300 aatctaaaga gctttataaa tctattgatg gtgcagagac tctagataaa aattatctta 48360 gtggacaaca gcaggaacaa caaaatctcg tttcaaattt gaaaaaagac cttgttggaa 48420 ctggatttaa ctgtgagtaa ttatgccga tta caggtaa ttctaaactc acttaagaca 48480 caattttcac ctatataagc gcccaaatgg cgcttttgtc atttatggag tttggcttat 48540 gagtgaatca aaagttagac atttggtact taaaagagtt tcagataaat cttctcatct 48600 tgctctttgt gacgaggaaa caggt attcc attagctgga ttaaccgctg taaaaatgaa 48660 ttgtagtgtt tttgagggtc cagcgactat cacggcaaca tttgatgtag gtggtcctca 48720 aggcatccgc ttagttggtg atgaacctag acaaaaggtt tggagtgcaa aggaaacgta 48780 gcgaaaggca ctacaaatgc ctgaaaagca aatcaatatg tcagatgctc aatatattct 48840 gagcacaaaa tgaattctgg tgccatttct tcaaattaag g tttcaagcc atggcaattt 48900 atggttttac ttttgaaaga ttaaaagcaa ttgcactcat caaatagaac ttaattttta 48960 accatagcac cttcgggtgc tttttttgcg agaagaaaat gccaagccct attatccaat 49020 atttccaata tgaacattta cctgaacatt tg cagcaagt tagtaagcca attggtgatt 49080 tagctcggca aatggatgag caacttcctg acgggcctga aaaatccaca ggattaagaa 49140 agctacttga agcaaaagat gcatttgtac gccaagcttt aagtaaataa tcatttatag 49200 aaatgaagcg tcctaaaggg cgctttttta ttgcctgccg aaagcggatg ctaacggcga 49260 atccgggcgg atgcccattt tgtatatata ggttggatga cca atgaaac ttaaaacagt 49320 aacaatcgac ggtaaagttt atgcggaagt agacggtgat aagccgatct atattcatga 49380 tgacggcaaa gaaatgccac atgatgcacc acactcggta gcaacaattg cacgcttaaa 49440 caatgaagct aaaacacatc gtgaagccaa aga agcagcc gaaaaagcat taaaagcttt 49500 tgaaggaatt gaagacccag cggcagctaa aaaggcatta caaacaatcc aaaatctcga 49560 tgataaaaag ctggtggatg ccggtgaagt tgagaaagtt aaagctgaag ctatcaaagc 49620 agttgaggaa aaatatgccc cgattgttgc gcaacgtgat gctctagaag cctctttaca 49680 taaagaactt atcggcggtg gttttgctcg ttctaagtac attca agaca acattgcagt 49740 acctgtggac atggttcagg caacctttgg tcatcacttc aaaatcgaag aaggcaaggt 49800 ggttgcatat gatccgaacg gcgaaaagat ttattcacgt gtccgcccgg gtgaacttgc 49860 aaatgttgat gaagctttag agtcat tggt tggtggatac cagcataaag acttaattct 49920 taaaggtggt aaaggaactg gtggcggttt tcaaggtggg ggcaaaggtg gagcacctac 49980 tggaatgaaa cgcagtgaaa tgtctgtttc tcagaaagca gattacatca aagaacatgg 50040 caatgatgcc ttcctaaaac taccgaacta atcattaaat atttggagat aagtagttat 50100 gactacgaca gttaattcag acatgatcat ctataatcaa ttggctcaaa ctgcttattt 50160 agagcgt ttg caagataatt tgaatgtatt taaccaagcc tctaatggtg caattgttta 50220 tcgcaatgag atcattgaag gtgatttcaa taaagaagca ttctacaaag tgggcggtag 50280 catcaaacat cgtgatgtga attcaaccgc caaagtagtt ccagagaaaa ttggttctgg 50340 tga gtctgta ggcgtaaaag tcccatataa atatggtcct tatgcatcaa ctgaagaggc 50400 atttaagcgc cgtgctcgta caccagaaga atttgctatg gttgttggtt acgatcttgc 50460 agatgcattg gttgcaggcc gattagagta cagtttagct tctttaaaag ctgctatttc 50520 tagcaatcca gacatggttg caaaaggtag tatcgttgtt gatggccgca aagcattgac 50580 t cgtggtatg cgaaagtttg gtgataagtt tggccgcatt ggcttatggg tgatgaactc 50640 agatacatat ttcgatattg tcgatgatgc aatcactaag caaatttatg gtgaatctga 50700 aatcgttatc tacggtggtt taccgggaac cttaggaaag ccggtcttgg t gacggacgc 50760 tgtaggtgat aacgatgctt ttggtttgca gtatggcgct gtcactgtaa ctgaatcaca 50820 agtaccgggc ttccgagctt atgacatcaa tgatgaagaa aacttagcaa tcggtatgcg 50880 tgctgaaggt gcatttaact tagatattct tggttatagt tgggataca 50929 <210> 2 <211> 588 <212> DNA <213> Artificial Sequence <220> <223> Ab endolysin <400> 2 atgccgcctt cgggc ggttt tttacatctg aaggaaaccg aaatgaacat tgaacaatat 60 ctggacgagt taattaagcg tgagggcggg tacgtaaaca acccagcaga tcgaggcggt 120 gaaacaaaagt acggtattac tgaagcagta gcacgtacta acggctttaa gggcaacatg 180 aaagatttac cgcttgatgt ggccaaagcc atttataaaa agcagtattg gacagatccg 240 cgatttgatc aagtgaatgt aattagctcg t tagttgctg aagagctttt agatactggg 300 gtaaattgcg gtaccggatt tgcaaaacca ctcttacagc gtgctttaaa tttgctgaat 360 aaccaaggta aagcaggttg gccagattta acagttgacg gaatttatgg tccagcaact 420 cttaatgcac tcaaaactta tctggccaag cg tggaaaaag acggcgaaaa agtcctggtg 480 cgtgttctta atatcatgca agggcaacgt tacattgaaa tctgtgaacg caatcctagc 540 caggaacagt ttttctatgg ttggatcgcc aatcgagttg ttatatga 588 <210> 3 <211> 195 <212> PRT <213> Artificial Sequence <220> <223> Ab endolysin <400> 3 Met Pro Pro Ser Gly Gly Phe Leu His Leu Lys Glu Thr Glu Met Asn 1 5 10 15 Ile Glu Gln Tyr Leu Asp Glu Leu Ile Lys Arg Glu Gly Gly Tyr Val 20 25 30 Asn Asn Pro Ala Asp Arg Gly Gly Glu Thr Lys Tyr Gly Ile Thr Glu 35 40 45 Ala Val Ala Arg Thr Asn Gly Phe Lys Gly Asn Met Lys Asp Leu Pro 50 55 60 Leu Asp Val Ala Lys Ala Ile Tyr Lys Lys Gln Tyr Trp Thr Asp Pro 65 70 75 80 Arg Phe Asp Gln Val Asn Val Ile Ser Ser Leu Val Ala Glu Glu Leu 85 90 95 Leu Asp Thr Gly Val Asn Cys Gly Thr Gly Phe Ala Lys Pro Leu Leu 100 105 110 Gln Arg Ala Leu Asn Leu Leu Asn Asn Gln Gly Lys Ala Gly Trp Pro 115 120 125 Asp Leu Thr Val Asp Gly Ile Tyr Gly Pro Ala Thr Leu Asn Ala Leu 130 135 140 Lys Thr Tyr Leu Ala Lys Arg Gly Lys Asp Gly Glu Lys Val Leu Val 145 150 155 160 Arg Val Leu Asn Ile Met Gln Gly Gln Arg Tyr Ile Glu Ile Cys Glu 165 170 175 Arg Asn Pro Ser Gln Glu Gln Phe Phe Tyr Gly Trp Ile Ala Asn Arg 180 185 190 Val Val Ile 195 <210> 4 <211> 7882 <212> DNA <213> Artificial Sequence <220> <223> pB4_Ab endolysin <400> 4 taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60 tgtttaactt taagaaggag atatacatat gggcagcagc aatcatcatc atcatcacgg 120 taccaaaact gaagaaggta aactggtaat ctggattaac ggcgataaag gctataacgg 180 tctcgctgaa gtc ggtaaga aattcgagaa agataccgga attaaagtca ccgttgagca 240 tccggataaa ctggaagaga aattcccaca ggttgcggca actggcgatg gccctgacat 300 tatcttctgg gcacacgacc gctttggtgg ctacgctcaa tctggcctgt tggctgaaat 360 caccccggac aaag cgttcc aggacaagct gtatccgttt acctgggatg ccgtacgtta 420 caacggcaag ctgattgctt acccgatcgc tgttgaagcg ttatcgctga tttataacaa 480 agatctgctg ccgaacccgc caaaaacctg ggaagagatc ccggcgctgg ataaagaact 540 gaaagcgaaa ggtaagagcg cgctgatgtt caacctgcaa gaaccgtact tca cctggcc 600 gctgattgct gctgacgggg gttatgcgtt caagtatgaa aacggcaagt acgacattaa 660 agacgtgggc gtggataacg ctggcgcgaa agcgggtctg accttcctgg ttgacctgat 720 taaaaacaaa cacatgaatg cagacaccga ttactccatc gcagaag ctg cctttaataa 780 aggcgaaaca gcgatgacca tcaacggccc gtgggcatgg tccaacatcg acaccagcaa 840 agtgaattat ggtgtaacgg tactgccgac cttcaagggt caaccatcca aaccgttcgt 900 tggcgtgctg agcgcaggta ttaacgccgc cagtccgaac aaagagctgg caaaagagtt 960 cctcgaaaac tatctgctga ctgatgaagg tctggaagcg gttaataaag acaaaccgct 10 20 gggtgccgta gcgctgaagt cttacgagga agagttggcg aaagatccac gtattgccgc 1080 caccatggaa aacgcccaga aaggtgaaat catgccgaac atcccgcaga tgtccgcttt 1140 ctggtatgcc gtgcgtactg cggtgatcaa cgccgccagc ggtc gtcaga ctgtcgatga 1200 agccctgaaa gacgcgcaga ctggtaccga ttacgatatc ccaacgaccg aaaaccttta 1260 cttccagggc ggcggtggtg gcggcccatg ccgccttcgg gcggtttttt acatctgaag 1320 gaaaccgaaa tgaacattga acaatatctg gacgagttaa ttaagcgtga gggcgggtac 1380 gtaaacaacc cagcagatcg aggcggtgaa acaaagtacg gtattactga agcagtagca 1440 cgtact aacg gctttaaggg caacatgaaa gatttaccgc ttgatgtggc caaagccatt 1500 tataaaaagc agtattggac agatccgcga tttgatcaag tgaatgtaat tagctcgtta 1560 gttgctgaag agcttttaga tactggggta aattgcggta ccggatttgc aaaaccactc 1620 ttacagcgtg ctttaaattt gctgaataac caaggtaaag caggttggcc agatttaaca 1 680 gttgacggaa tttatggtcc agcaactctt aatgcactca aaacttatct ggccaagcgt 1740 ggaaaagacg gcgaaaaagt cctggtgcgt gttcttaata tcatgcaagg gcaacgttac 1800 attgaaatct gtgaacgcaa tcctagccag gaacagtttt tctatggtt g gatcgccaat 1860 cgagttgtta tatgaggcgc aaaggagaag aactgttcac tggtgttgtc ccaattcttg 1920 ttgaattaga tggtgatgtt aatgggcaca aattttctgt cagtggagag ggtgaaggtg 1980 atgcaacata cggaaaactt acccttaaat ttatttgcac tactggaaaa ctacctgttc 2040 catggccaac acttgtcact actttctctt atggtgttca atgcttttcc cgttatccgg 21 00 atcacatgaa acggcatgac tttttcaaga gtgccatgcc cgaaggttat gtacaggaac 2160 gcactatatc tttcaaagat gacgggaact acaagacgcg tgctgaagtc aagtttgaag 2220 gtgataccct tgttaatcgt atcgagttaa aaggtattga ttttaaagaa gatggaa aca 2280 ttctcggaca caaactcgag tacaactata actcacacaa tgtatacatc acggcagaca 2340 aacaaaagaa tggaatcaaa gctaacttca aaattcgcca caacattgaa gatggctccg 2400 ttcaactagc agaccattat caacaaaata ctccaattgg cgatggccct gtccttttac 2460 cagacaacca ttacctgtcg acacaatctg ccctttcgaa agatcccaac gaaaagcgtg 2520 accacatggt cctt cttgag tttgtaactg ctgctgggat tacacatggc atggatgagc 2580 tctacaaata agcttgcggc cgcactcgag caccaccacc accaccactg agatccggct 2640 gctacaaag cccgaaagga agctgagttg gctgctgcca ccgctgagca ataactagca 2700 taacccctt g gggcctctaa acgggtcttg agggggtttt ttgctgaaaa ggaggaacta 2760 tatcccggat tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 2820 tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 2880 tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcggggggc 29 40 tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 3000 gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 3060 agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaac actc aaccctatct 3120 cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 3180 agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 3240 tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 3300 aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 3360 gaagagtatg agtattcaac atttcc gtgt cgcccttatt cccttttttg cggcattttg 3420 ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 3480 gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 3540 t cgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 3600 attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 3660 tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 3720 agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 3780 aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 3840 tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 3900 cacgatgcct gcagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 3960 tctagcttcc cggcaacaat taatagactg g atggaggcg gataaagttg caggaccact 4020 tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 4080 tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 4140 tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 4200 aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atat acttta 4260 gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 4320 tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 4380 aaagatcaaa ggatcttctt gagatccttt ttttctgcgc g taatctgct gcttgcaaac 4440 aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 4500 tccgaaggta actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc 4560 gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 4620 cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 4 680 acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 4740 cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 4800 cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtc ggaac 4860 aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 4920 gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 4980 atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 5040 tcacatgttc tttcctgcgt tatcccctga ttctgtggat a accgtatta ccgcctttga 5100 gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 5160 agcggaagag cgcctgatgc ggtattttct ccttacgcat ctgtgcggta tttcacaccg 5220 caatggtgca ctct cagtac aatctgctct gatgccgcat agttaagcca gtatacactc 5280 cgctatcgct acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg 5340 cgccctgacg ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg 5400 ggagctgcat gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt 5460 aaagctcatc agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca 5520 gctcgttgag tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa 5580 gggcggtttt ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg 5640 gggtaatgat accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac 5700 atgcccggtt actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc 5760 agagaaaaat cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac 5820 agggtagcca gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact 5880 tccgcgtttc cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg 5940 tcgcagacgt tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct 6000 gctaaccagt aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca 6060 tgcgcacccg tggggccgcc atgccggcga taatggcctg cttctcgccg aaacg tttgg 6120 tggcgggacc agtgacgaag gcttgagcga gggcgtgcaa gattccgaat accgcaagcg 6180 acaggccgat catcgtcgcg ctccagcgaa agcggtcctc gccgaaaatg acccagagcg 6240 ctgccggcac ctgtcctacg agttgcatga taaagaagac agtcataagt gcggcgacga 6300 tagtcatgcc ccgcgcccac cggaaggagc tgactgggtt gaaggctctc aagggcatcg 6360 gtcgagatcc cggtgcctaa t gagtgagct aacttacatt aattgcgttg cgctcactgc 6420 ccgctttcca gtcgggaaac ctgtcgtgcc agctgcatta atgaatcggc caacgcgcgg 6480 ggagaggcgg tttgcgtatt gggcgccagg gtggtttttc ttttcaccag tgagacgggc 6540 aacagctgat tgcccttcac cgcctggccc tgagagagtt gcagcaagcg gtccacgctg 6600 gtttgcccca gcaggcgaaa atcctgtttg atggtggtta acggcgggat ataacatgag 6660 ctgtcttcgg tatcgtcgta tcccactacc gagatatccg caccaacgcg cagcccggac 6720 tcggtaatgg cgcgcattgc gcccagcgcc atctgatcgt tggcaaccag catcgcagtg 6780 ggaacgatgc cctcattcag catttgcatg gttt gttgaa aaccggacat ggcactccag 6840 tcgccttccc gttccgctat cggctgaatt tgattgcgag tgagatattt atgccagcca 6900 gccagacgca gacgcgccga gacagaactt aatgggcccg ctaacagcgc gatttgctgg 6960 tgacccaatg cgaccagatg ct ccacgccc agtcgcgtac cgtcttcatg ggagaaaata 7020 atactgttga tgggtgtctg gtcagagaca tcaagaaata acgccggaac attagtgcag 7080 gcagcttcca cagcaatggc atcctggtca tccagcggat agttaatgat cagcccactg 7140 acgcgttgcg cgagaagatt gtgcaccgcc gctttacagg cttcgacgcc gcttcgttct 7200 accatcgaca ccaccacgct ggcacccagt tgatcggcgc gagatttaat cgccgcgaca 7260 atttgcgacg gcgcgtgcag ggccagactg gaggtggcaa cgccaatcag caacgactgt 7320 ttgcccgcca gttgttgtgc cacgcggttg ggaatgtaat tcagctccgc catcgccgct 7380 tccacttttt cccg cgtttt cgcagaaacg tggctggcct ggttcaccac gcgggaaacg 7440 gtctgataag agacaccggc atactctgcg acatcgtata acgttactgg tttcacattc 7500 accaccctga attgactctc ttccgggcgc tatcatgcca taccgcgaaa ggttttgcgc 7560 cattcgatgg tgtccgggat ctcgacgctc tcccttatgc gactcctgca ttaggaagca 7620 gcccagtagt aggttgaggc cgttgagcac cgccgccgca aggaat ggtg catgcaagga 7680 gatggcgccc aacagtcccc cggccacggg gcctgccacc atacccacgc cgaaacaagc 7740 gctcatgagc ccgaagtggc gagcccgatc ttccccatcg gtgatgtcgg cgatataggc 7800 gccagcaacc gcacctgtgg cgccggtgat gcc ggccacg atgcgtccgg cgtagaggat 7860 cgagatctcg atcccgcgaa at 7882 <210> 5 <211> 35 <212> DNA <213> Artificial Sequence <220> <223> Ab_endolysin_LIC_F <400> 5 gggcggcggt ggtggcggca tgccgccttc gggcg 35 <210> 6 <211> 43 <212> DNA <213> Artificial Sequence <220> < 223> Ab_endolysin_LIC_R <400> 6 gttcttctcc tttgcgccct atataacaac tcgattggcg atc 43 <210> 7 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> pB4_seq_F <400> 7 gtcagactgt cgat gaag 18 <210> 8 <211 > 19 <212> DNA <213> Artificial Sequence <220> <223> pB4_seq_R<400> 8 catcaccatc taattcaac 19
Claims (8)
It has a killing ability against Acinetobacter baumannii ATCC 17978, has a genome consisting of a base sequence represented by SEQ ID NO: 1, is isolated from Acinetobacter baumannii 1656-2, and is Bacteriophage Ab1656-2 (KCTC 14314BP), belonging to Siphoviridae.
An antibiotic comprising the bacteriophage Ab1656-2 (KCTC 14314BP) of claim 1, the Ab endolysin protein isolated therefrom, and Zn 2+ as a cofactor.
A disinfectant containing as active ingredients the bacteriophage Ab1656-2 (KCTC 14314BP) of claim 1, the Ab endolysin protein isolated therefrom, and Zn 2+ as a cofactor.
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| PCT/KR2021/013191 WO2022065969A1 (en) | 2020-09-28 | 2021-09-28 | Bacteriophage having potential of killing acinetobacter baumannii and composition comprising same |
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| KR20220042688A (en) | 2022-04-05 |
| WO2022065969A1 (en) | 2022-03-31 |
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