KR101689033B1 - Bacteriophage that kills Propionibacterium acnes - Google Patents

Bacteriophage that kills Propionibacterium acnes Download PDF

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KR101689033B1
KR101689033B1 KR1020140070033A KR20140070033A KR101689033B1 KR 101689033 B1 KR101689033 B1 KR 101689033B1 KR 1020140070033 A KR1020140070033 A KR 1020140070033A KR 20140070033 A KR20140070033 A KR 20140070033A KR 101689033 B1 KR101689033 B1 KR 101689033B1
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김정민
송혜순
이원주
김석호
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Abstract

본 발명은 여드름균을 사멸시키는 여드름균 특이적 박테리오파지에 관한 것으로, 보다 상세하게는 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)에 관한 것이다.
따라서, 피부 질병의 주요 원인이 되는 여드름균을 특이적으로 사멸하는 본 발명의 박테리오파지 Pacnes 2012-15는 보건산업 뿐 아니라 친환경 대체항생제로 이용될 가치가 높다.The present invention relates to an acne-specific bacteriophage which kills an acne bacterium, more particularly to an acne bacterium ( Propionibacterium It relates to KCTC 12569BP): bacteriophage Pacnes 2012-15 (Accession No Seaport of irregularities for the (Siphoviridae) having a specific ability to kill acnes).
Therefore, the bacteriophage Pacnes 2012-15 of the present invention, which specifically kills acne bacterium which is a major cause of skin disease, is highly valued not only in the healthcare industry but also as an environmentally friendly alternative antibiotic.

Description

여드름균을 사멸시키는 여드름균 특이적 박테리오파지{Bacteriophage that kills Propionibacterium acnes}Bacteriophage that kills Propionibacterium acnes < RTI ID = 0.0 >

본 발명은 여드름균을 사멸시키는 여드름균 특이적 박테리오파지에 관한 것으로, 보다 상세하게는 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)에 관한 것이다.
The present invention relates to an acne-specific bacteriophage which kills an acne bacterium, more particularly to an acne bacterium ( Propionibacterium It relates to KCTC 12569BP): bacteriophage Pacnes 2012-15 (Accession No Seaport of irregularities for the (Siphoviridae) having a specific ability to kill acnes).

사람의 피부에는 Staphylococcus , Corynebacterium , Propionibacterium , Micrococcus , Streptococcus, Breyibacterium , Acinetobacterium , Pseudomonas 등의 세균들이 존재한다고 알려져 있으며, 특히 Propionibacterium acnes(여드름균)는 피부에 존재하는 전체 세균들 중 50% 이상을 차지하는 균으로, 사람에 따라 얼굴 피부에 102∼105-6/㎠ 존재한다. 피부뿐만 아니라 구강, 대장, 결막, 외이도 등에서도 발견되는 여드름균은 산소가 거의 존재하지 않는 머리, 얼굴, 등, 가슴, 목 등의 피지선(sebaceous glands)에서 관찰되는 세균으로 포자를 형성하지 않는 비운동성 그람 양성 혐기성균이며, 주로 염증을 일으키는 기회감염세균이다. Bacteria such as Staphylococcus , Corynebacterium , Propionibacterium , Micrococcus , Streptococcus, Breyibacterium , Acinetobacterium , and Pseudomonas are known to be present in human skin, and Propionibacterium Acnes (acne bacteria) is a bacterium that accounts for more than 50% of the total germs present in the skin. It is present in the face skin at 10 2 to 10 5 - 6 / ㎠. Acne bacteria, which are found not only in the skin but also in the oral cavity, colon, conjunctiva, and outer ear canal, are bacteria observed in sebaceous glands such as head, face, back, chest, It is a gram-positive anaerobic bacterium and is an opportunistic infectious bacterium mainly causing inflammation.

피지선은 피부 표피 아래의 두꺼운 층인 진피 부위에 존재하며, 모낭 피지선 단위(pilosebaceous unit)를 형성하고, 모공과 연결되어 있어 친유성의 triglyceride를 함유한 피지를 피부 표면으로 분비한다. The sebaceous gland is located in the dermis, which is a thick layer below the skin epidermis. It forms a pilosebaceous unit, and is linked to the pores to secrete sebum containing lipophilic triglyceride to the skin surface.

여드름을 야기하는 여러 원인들(예, 숙주의 나이, 성별, 특정 신체 부위, 유전적 요인, 생활방식, 직업, 면역체계, 주위 환경 등) 중 여드름균에 의해 유발되는 경우는 여드름균이 모낭 피지선 단위(pilosebaceous unit)를 손상시키는 lipases, proteases, hyaluronidases 등과 같은 효소를 분비함으로써 과도한 피지 생성, 여드름균의 집락화, 숙주의 면역체계를 통한 염증반응, 비정상적인 각질화 등을 유도하는 것으로, 특히 여드름균은 피지선에서 분비되는 triglyceride를 함유한 피지를 가수분해 하여 유리 지방산으로 방출시키고, 방출된 유리 지방산에 여드름균이 결합하여 여드름균의 집락화를 유도함으로써 여드름을 발생시킨다. In cases of acne caused by various causes of acne (eg, age, sex, specific body parts, genetic factors, lifestyle, occupation, immune system, environment, etc.) The secretion of enzymes such as lipases, proteases and hyaluronidases, which damage the pilosebaceous unit, leads to excessive sebum production, colonization of acne bacteria, inflammation through host immune system, abnormal keratinization, The sebum containing triglyceride secreted from the body is hydrolyzed and liberated as free fatty acid. Acid bacteria are bound to the released free fatty acid to induce colonization of acne bacteria, thereby causing acne.

여드름균에 의해 형성된 여드름을 치료하기 위해 지금까지 수십 년 동안 tetracycline, erythromycin, clindamycin, macrolides, penicillin, cephalosporin등의 항생제를 사용하였다. 그 결과 1979년 Crawford 연구팀에 의해 erythromycin과 clindamycin에 내성을 나타내는 여드름균이 발견되었고, 뒤이어 1980년대 초반에는 tetracycline에 내성을 나타내는 여드름균도 확인되었다. Antibiotics such as tetracycline, erythromycin, clindamycin, macrolides, penicillin and cephalosporin have been used for decades to treat acne caused by acne bacteria. As a result, Crawford et al. (1979) found erythromycin and clindamycin resistant acne, followed by tetracycline - resistant acne in the early 1980s.

전 세계적으로 항생제에 대한 여드름 내성균 관련 연구를 지속한 결과 1970년 후반에는 erythromycin, clindamycin 및 tetracycline 항생제에 내성을 나타내는 여드름균의 비율이 약 20% 정도였지만, 1995년에는 약 72.5%까지 내성균의 출현이 높아졌으며, 더욱이 tetracycline에 대한 내성균보다는 erythromycin 및 clindamycin에 대한 혼합된 내성균 출현이 빈번하였다. As a result of continuing researches on acne-resistant bacteria against antibiotics worldwide, the proportion of acne bacteria resistant to erythromycin, clindamycin and tetracycline antibiotics was about 20% in the late 1970s, but the incidence of resistant bacteria was about 72.5% Furthermore, mixed resistant resistant strains of erythromycin and clindamycin were more frequent than tetracycline resistant strains.

여드름균의 경우 항생제를 8 주만 사용하여도 그 항생제에 대한 내성균을 관찰 할 수 있으며, 뒤이어 몇 주 이내 내성균의 수가 점진적으로 증가함을 확인할 수 있다. 이와 같이 항균제 내성균의 출현 및 확산 문제가 심각해서 현재까지 개발되어 사용되고 있는 거의 모든 종류의 항균치료제에 내성을 나타내는 다제내성 세균까지 출현하여, 항생제를 대체할 새로운 치료제의 개발이 시급하고 절실하게 요구되고 있다.In case of acne bacterium, resistant bacteria against antibiotics can be observed even after 8 weeks of antibiotics, and the number of resistant bacteria is gradually increased within several weeks. Thus, the emergence and spreading of antimicrobial-resistant microorganisms are serious and multidrug-resistant bacteria resistant to almost all types of antimicrobial therapeutic agents that have been developed and used so far have appeared, and development of new therapeutic agents to replace antibiotics is urgently required have.

박테리오파지는 세균에 특이적으로 감염하고 용균을 일으키는 바이러스로 1915년 최초발견 이후 지금까지 다양한 세균성 질병의 치료를 위해 연구되어 왔으며, 파지 발견자인 Felix d'Herelle는 1919년에 최초로 파지를 감염질환의 치료 목적으로 사용하였다.Bacteriophage has been studied for the treatment of various bacterial diseases since its first discovery in 1915 as a virus that specifically infects bacteria and causes bacteria. Felix d'Herelle, who was the first to detect phage in 1919, Respectively.

박테리오파지를 이용한 연구는 그루지아, 폴란드와 구소련에서 꾸준히 세균성 감염질환의 치료 목적으로 연구가 진행되고 있었으며, 실제 병원성 미생물에 대한 치료에도 사용되고 있다. 1994년, 위절제술 후에 재발한 횡경막 종양에 감염된 내성 대장균에 박테리오파지를 처리하여 깨끗하게 치료하였고, 1995년에는 급성 만성 비뇨기염증환자 46 명에게 박테리오파지를 처리하여 92%는 임상적으로 회복되었고, 84%의 환자들에서 병원성 미생물이 완벽히 제거되었다. 1999년, 신생아의 수막염을 일으키는 균인 Klebsiella pueumoniae에 항생제 처방이 실패하자 박테리오파지를 구강으로 주입하여 치료에 성공하였다. 2001년, 20 명의 난치 종양환자에게 2~9주 동안 하루에 3 번 구강으로 박테리오파지를 주입하여 치료에 성공하였으며, 2001년에는 54 명의 환자 화상부위에 예방 차원의 파지를 처리하여 Staphylococcus , Streptococcus, Proteus 등의 감염으로부터 보호하였다. 2002년, 박테리오파지와 생물분해성 혼합물을 상처와 종양에 처리하여 환자 96 명 중 67 명이 회복되었다.Research using bacteriophage has been under way in Georgia, Poland and the former Soviet Union for the treatment of bacterial infectious diseases, and it has also been used for the treatment of pathogenic microorganisms. In 1994, bacteriophage-treated infected Escherichia coli infected with recurrent diaphragmatic tumors was treated neatly. In 1995, 46 patients with acute chronic urinary inflammation were treated with bacteriophage, 92% were clinically recovered, and 84% The pathogenic microorganisms were completely removed from the patients. In 1999, Klebsiella , a gonococcal infant of the newborn, When the antibiotic prescription failed in pueumoniae , the bacteriophage was injected into the mouth and the treatment was successful. In 2001, 20 patients were treated with bacteriophage injected three times a day for 2 to 9 weeks. In 2001, 54 patients were treated with prophylactic phage to treat Staphylococcus , Streptococcus, Proteus And the like. In 2002, 67 of 96 patients recovered from bacteriophages and biodegradable mixtures treated with wounds and tumors.

2007년은 미국에서 파지가 약제로서 처음 허가된 해로, 식품의약품안전청(FDA)이 당뇨성 발 괴사의 세균감염 치료를 위한 파지 사용 1 단계 임상실험을 승인하여, 파지를 이용한 동물의 감염질환 치료 뿐 아니라 사람에게도 치료목적으로 사용할 수 있는 길이 열렸다. 미국 FDA는 2008년에 닭고기 식품 처리과정 중 살모넬라 특이적 박테리오파지를 이용한 살모넬라 오염을 저감하는 방법을 승인하였다. 2007 was the first year phage was approved as a pharmacological agent in the United States. The Food and Drug Administration (FDA) approved Phase 1 clinical trials for the treatment of bacterial infections of diabetic foot necrosis, It also opened the way for people to use it for therapeutic purposes. In 2008, the US Food and Drug Administration approved a method to reduce salmonella contamination using salmonella-specific bacteriophage during chicken meat processing.

이에 본 발명자들은 환자로부터 분리된 박테리오파지 Pacnes 2012-15이 여드름균을 특이적으로 사멸시키는 것을 발견하여 본 발명을 완성하게 되었다.
Accordingly, the present inventors have found that Pacnes 2012-15, a bacteriophage isolated from a patient, specifically kills acne bacteria, thereby completing the present invention.

따라서 본 발명의 목적은 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:기탁번호:KCTC 12569BP)를 제공하는 것이다.
Accordingly, an object of the present invention is to provide a bacteriophage Pacnes 2012-15 (accession number: KCTC 12569BP) of Siphoviridae having a specific killing activity against Propionibacterium acnes .

본 발명의 다른 목적은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 질환의 예방 및 치료용 약학적 조성물을 제공하는 것이다.
Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of diseases caused by an acne bacterium ( Propionibacterium acnes ) containing bacteriophage Pacnes 2012-15 as an active ingredient.

본 발명의 다른 목적은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 화장료 조성물을 제공하는 것이다.
Another object of the present invention is to provide a cosmetic composition for improving skin troubles induced by an acne bacterium ( Propionibacterium acnes ) containing bacteriophage Pacnes 2012-15 as an active ingredient.

본 발명의 다른 목적은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 의약외품을 제공하는 것이다.
Another object of the present invention is to provide a method for treating acne bacteria ( Propionibacterium < RTI ID = 0.0 > acnes ) for improving skin troubles.

본 발명의 다른 목적은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 항생제를 제공하는 것이다.
Another object of the present invention is to provide antibiotics comprising bacteriophage Pacnes 2012-15 as an active ingredient.

상기의 목적을 달성하기 위하여, 본 발명은 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)를 제공한다.
In order to achieve the above object, the present invention provides a bacteriophage Pacnes 2012-15 (accession number: KCTC 12569BP) of Siphoviridae having a specific killing ability against Propionibacterium acnes .

본 발명의 다른 목적을 달성하기 위하여, 본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 질환의 예방 및 치료용 약학적 조성물을 제공한다.
In order to accomplish still another object of the present invention, the present invention provides a pharmaceutical composition for the prevention and treatment of diseases caused by an acne bacterium ( Propionibacterium acnes ) comprising the bacteriophage Pacnes 2012-15 as an active ingredient.

본 발명의 다른 목적을 달성하기 위하여, 본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 화장료 조성물을 제공한다.
In order to accomplish still another object of the present invention, the present invention provides a cosmetic composition for improving skin troubles caused by Propionibacterium acnes containing bacteriophage Pacnes 2012-15 as an active ingredient.

본 발명의 다른 목적을 달성하기 위하여, 본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 의약외품을 제공한다.
In order to accomplish another object of the present invention, the present invention provides a quasi-drug for improving skin troubles caused by Propionibacterium acnes containing bacteriophage Pacnes 2012-15 as an active ingredient.

본 발명의 다른 목적을 달성하기 위하여, 본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 항생제를 제공한다.
In order to accomplish still another object of the present invention, the present invention provides an antibiotic comprising Pacnes 2012-15 as an active ingredient.

이하 본 발명을 상세히 설명한다.
Hereinafter, the present invention will be described in detail.

본 발명은 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)를 제공한다.
The present invention relates to a method for treating acne bacteria ( Propionibacterium provides KCTC 12569BP): bacteriophage Pacnes 2012-15 (Accession No Seaport of irregularities for the (Siphoviridae) having a specific ability to kill acnes).

상기 박테리오파지 Pacnes 2012-15는 한국 생명공학연구원의 유전자은행에 2014년 4월 2일자로 기탁하였다.
Pacnes 2012-15, the bacteriophage, was deposited on April 2, 2014 in the Gene Bank of the Korea Biotechnology Research Institute.

상기 박테리오파지 Pacnes 2012-15는 서열번호 1로 표시되는 전장 유전체를 갖는 것을 특징으로 한다.The bacteriophage Pacnes 2012-15 is characterized by having a full-length dielectric represented by SEQ ID NO: 1.

본 발명의 상기 박테리오파지 Pacnes 2012-15은 본 발명에서 처음으로 분리 동정된 것으로서, 그 유전체의 서열 또한 본 발명자에 의해 처음으로 밝혀졌다.
The bacteriophage Pacnes 2012-15 of the present invention was first isolated and identified in the present invention, and the sequence of its genome was also discovered for the first time by the present inventors.

이와 같은 본 발명의 특징은 본 발명의 실시예들에 잘 나타나 있다.
These features of the present invention are well illustrated in embodiments of the present invention.

본 발명자들은 분리된 박테리오파지 Pacnes 2012-15의 전장 유전체를 분리하고 이에 대한 염기 서열을 결정함으로써 파지의 유전체가 29,741 bp 크기인 이중 가닥 DNA이며 46 개의 단백질 암호화 부위(open reading frame, ORF)를 가짐을 확인하였다(실시예 1 및 실시예 4 참조).We isolated and sequenced the full-length genome of the isolated bacteriophage Pacnes 2012-15 and determined that the phage had double-stranded DNA of 29,741 bp in its genome and 46 open reading frames (ORFs) (See Examples 1 and 4).

또한, 여러 가지 세균에 대한 숙주특이성 및 사멸능을 확인한 결과, 본 발명에서 분리된 박테리오파지 Pacnes 2012-15는 여드름균을 특이적으로 사멸함을 확인하였다(실시예 2 참조).
As a result of confirming the host specificity and killing ability against various bacteria, it was confirmed that the bacteriophage Pacnes 2012-15 isolated in the present invention specifically killed acne bacteria (see Example 2).

본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 질환의 예방 및 치료용 약학적 조성물을 제공한다.
The present invention provides a pharmaceutical composition for the prevention and treatment of diseases caused by an acne bacterium ( Propionibacterium acnes ) comprising the bacteriophage Pacnes 2012-15 as an active ingredient.

또한 본 발명에서 상기 여드름균(Propionibacterium acnes)에 의해 유발되는 질환은 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택되는 것을 특징으로 한다.
In the present invention, the above-mentioned acne bacteria ( Propionibacterium acnes is characterized in that the disease is selected from the group consisting of inflammation, acne, cottonseed, papule, rash, blister, nodule, cyst and false cyst.

본 발명에서 사용된 ‘치료’라는 용어는 여드름균에 의해 유발된 질환의 예방, 여드름균에 의해 유발된 질환의 억제 및 여드름균에 의해 유발된 질환의 경감을 의미한다.
The term " treatment " used in the present invention means prevention of diseases caused by acne bacteria, inhibition of diseases caused by acne bacteria, and alleviation of diseases caused by acne bacteria.

본 발명에 따른 약학적 조성물은 본 발명의 박테리오파지 Pacnes 2012-15 또는 이들의 약학적으로 허용가능한 염을 단독으로 함유하거나 또는 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 함유할 수 있다.The pharmaceutical composition according to the present invention may contain the bacteriophage Pacnes 2012-15 of the present invention alone or a pharmaceutically acceptable salt thereof, or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents .

본 발명의 박테리오파지 Pacnes 2012-15는 그 자체 또는 염, 바람직하게는 약학적으로 허용가능한 염의 형태로 사용될 수 있다. 본 발명에서 '약학적으로 허용가능한'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 말하며, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하다. 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다.The bacteriophage Pacnes 2012-15 of the present invention may be used as such or in the form of a salt, preferably a pharmaceutically acceptable salt. The term " pharmaceutically acceptable " as used herein means physiologically acceptable and does not normally cause an allergic reaction or a similar reaction when administered to humans, and the salt includes a pharmaceutically acceptable free acid ) Are preferred. As the free acid, an organic acid and an inorganic acid can be used. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methosulfonic, glycolic, succinic, Glutamic acid and aspartic acid. The inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.

약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다. 또한, 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로 부탄올이 있다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).

본 발명의 여드름균(Propionibacterium acnes)에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물은 비경구적인 투여방법으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다. 바람직하게는 본 발명의 약학적 조성물은 경피 투여될 수 있다. 상기에서 경피 투여란 본 발명의 약학적 조성물을 세포 또는 피부에 투여하여 본 발명 조성물에 함유된 활성성분이 피부 내로 전달되도록 하는 것을 말하다. 예컨대, 본 발명의 약학적 조성물을 주사형 제형으로 제조하여 이를 30 게이지의 가는 주사 바늘로 피부를 가볍게 단자(prick)하는 방법, 또는 피부에 직접적으로 도포하는 방법으로 투여될 수 있다.The acne bacteria of the present invention ( Propionibacterium The pharmaceutical composition for preventing or treating diseases caused by acnes may be administered by a parenteral administration method. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration Lt; / RTI > Preferably, the pharmaceutical composition of the present invention can be transdermally administered. In the above, transdermal administration refers to administration of the pharmaceutical composition of the present invention to cells or skin to allow the active ingredient contained in the composition of the present invention to be delivered into the skin. For example, the pharmaceutical composition of the present invention can be administered in a scanning type formulation, pricking the skin lightly with a 30 gauge needle, or directly applying it to the skin.

본 발명의 약학적 조성물은 상술한 바와 같이 비경구 투여용 제제로 제형화 할 수 있다.The pharmaceutical composition of the present invention can be formulated into parenteral administration preparations as described above.

비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다.In the case of a preparation for parenteral administration, it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate. These formulations are described in Remington's Pharmaceutical Science, 15th edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a commonly known formulary for all pharmaceutical chemistries.

본 발명의 약학적 조성물의 적합한 도포, 분무 및 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 질병 증상의 정도, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 일반적으로, 본 발명의 약학적 조성물은 1 × 103 내지 1 × 1011 pfu/㎖의 박테리오파지를 포함한다.Suitable application, spray, and dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, disease symptom, food, administration time, administration route, , And the ordinarily skilled physician can readily determine and prescribe dosages effective for the desired treatment. In general, the pharmaceutical composition of the present invention comprises 1 x 10 3 to 1 x 10 11 pfu / ml bacteriophage.

본 발명의 약학적 조성물은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 됨으로써 단위 용량 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.
The pharmaceutical composition of the present invention may be formulated into pharmaceutically acceptable carriers and / or excipients according to a method which can be easily carried out by those skilled in the art, Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.

본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 화장료 조성물을 제공한다.
The present invention provides a cosmetic composition for improving skin troubles caused by an acne bacterium ( Propionibacterium acnes ) containing bacteriophage Pacnes 2012-15 as an active ingredient.

또한 본 발명에서 상기 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블은 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택되는 것을 특징으로 한다.
In the present invention, the above-mentioned acne bacteria ( Propionibacterium acnes are characterized in that they are selected from the group consisting of inflammation, acne, cottonseed, papules, rash, blisters, nodules, cysts and false cysts.

상기 본 발명의 화장료 조성물은 박테리오파지 Pacnes 2012-15를 유효성분으로 함유하며 피부학적으로 허용 가능한 부형제와 함께 기초 화장품 조성물(화장수, 크림, 에센스, 클렌징폼 및 클렌징 워터와 같은 세안제, 팩, 보디오일), 색조 화장품 조성물(화운데이션, 립스틱, 마스카라, 메이크업 베이스), 두발 제품 조성물(샴푸, 린스, 헤어컨디셔너, 헤어젤) 및 비누 등의 형태로 제조될 수 있다.The cosmetic composition of the present invention contains bacteriophage Pacnes 2012-15 as an active ingredient, together with dermatologically acceptable excipients, basic cosmetic composition (cleanser, pack, body oil such as lotion, cream, essence, cleansing foam and cleansing water) , A color cosmetic composition (foundation, lipstick, mascara, makeup base), a hair product composition (shampoo, rinse, hair conditioner, hair gel) and soap.

상기 부형제로는 이에 한정되지는 않으나 예를 들어, 피부연화제, 피부 침투 증강제, 착색제, 방향제, 유화제, 농화제 및 용매를 포함할 수 있다. 또한, 향료, 색소, 살균제, 산화방지제, 방부제 및 보습제 등을 추가로 포함할 수 있으며, 물성개선을 목적으로 점증제, 무기염류, 합성 고분자 물질 등을 포함할 수 있다. 예를 들면, 본 발명의 화장료 조성물로 세안제 및 비누를 제조하는 경우에는 통상의 세안제 및 비누 베이스에 박테리오파지 Pacnes 2012-15를 첨가하여 용이하게 제조할 수 있다. 크림을 제조하는 경우에는 일반적인 수중유적형(O/W)의 크림베이스에 박테리오파지 Pacnes 2012-15를 첨가하여 제조할 수 있다. 여기에 향료, 킬레이트제, 색소, 산화방지제, 방부제 등과 물성개선을 목적으로 한 단백질, 미네랄, 비타민 등 합성 또는 천연소재를 추가로 첨가할 수 있다.Such excipients include, but are not limited to, emollients, skin penetration enhancers, colorants, perfumes, emulsifiers, thickeners and solvents. In addition, it may further contain flavors, pigments, bactericides, antioxidants, preservatives, moisturizers and the like, and may include thickeners, inorganic salts and synthetic polymeric substances for the purpose of improving physical properties. For example, when the facial composition of the present invention is used to make a facial cleanser and a soap, a bacteriophage Pacnes 2012-15 can be easily added to a common facial cleanser and a soap base. Cream can be prepared by adding bacteriophage Pacnes 2012-15 to a cream base of a typical underwater type (O / W). A synthetic or natural material such as a flavor, a chelating agent, a coloring matter, an antioxidant, an antiseptic, and a protein, a mineral, and a vitamin for the purpose of improving a physical property may be further added.

본 발명의 화장료 조성물에 함유되는 박테리오파지 Pacnes 2012-15의 함량은 이에 한정되지 않지만 1 × 103 내지 1 × 1011 pfu/㎖의 박테리오파지를 포함하는 것이 바람직하다.
The content of the bacteriophage Pacnes 2012-15 contained in the cosmetic composition of the present invention is not limited thereto, but it preferably contains bacteriophage of 1 x 10 3 to 1 x 10 11 pfu / ml.

본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블 개선용 의약외품을 제공한다. The present invention provides a quasi-drug for improving skin troubles caused by an acne bacterium ( Propionibacterium acnes ) containing bacteriophage Pacnes 2012-15 as an active ingredient.

상기 의약외품이란 질병을 치료하거나 예방하기 위해 쓰는 의약품보다는 인체에 대한 작용이 경미한 물품에 대해 보건복지부가 따로 정한 분류 기준에 의한 약품을 지칭하는 것이다. 약사법에 따르면 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 섬유ㆍ고무 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않으며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염병을 막기 위한 살균ㆍ살충제 등이 포함될 수 있다.
The quasi-quasi-drugs refer to drugs classified by the Ministry of Health and Welfare for products that have a slight effect on the human body, rather than medicines used to treat or prevent diseases. According to the Pharmaceutical Affairs Law, textile or rubber products used for the treatment or prevention of diseases of humans or animals, excluding those used for medicinal purposes, , Sterilization and insecticides to prevent infectious diseases, and the like.

또한 본 발명에서 상기 여드름균(Propionibacterium acnes)에 의해 유발되는 피부 트러블은 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택되는 것을 특징으로 한다.
In the present invention, the above-mentioned acne bacteria ( Propionibacterium acnes are characterized in that they are selected from the group consisting of inflammation, acne, cottonseed, papules, rash, blisters, nodules, cysts and false cysts.

본 발명은 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 항생제를 제공한다. 상기 항생제는 방부제, 살균제 및 항균제일 수 있다.
The present invention provides antibiotics comprising the bacteriophage Pacnes 2012-15 as an active ingredient. The antibiotics may be preservatives, bactericides and antimicrobial agents.

본 발명은 여드름균을 사멸시키는 여드름균 특이적 박테리오파지에 관한 것으로, 보다 상세하게는 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)에 관한 것이다.The present invention relates to an acne-specific bacteriophage which kills an acne bacterium, more particularly to an acne bacterium ( Propionibacterium It relates to KCTC 12569BP): bacteriophage Pacnes 2012-15 (Accession No Seaport of irregularities for the (Siphoviridae) having a specific ability to kill acnes).

따라서, 피부 질병의 주요 원인이 되는 여드름균을 특이적으로 사멸하는 본 발명의 박테리오파지 Pacnes 2012-15는 보건산업 뿐 아니라 친환경 대체항생제로 이용될 가치가 높다.
Therefore, the bacteriophage Pacnes 2012-15 of the present invention, which specifically kills acne bacterium which is a major cause of skin disease, is highly valued not only in the healthcare industry but also as an environmentally friendly alternative antibiotic.

도 1은 박테리오파지 Pacnes 2012-15의 현미경 사진이다.Figure 1 is a photomicrograph of a bacteriophage Pacnes 2012-15.

이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

<< 실시예Example 1>  1>

PacnesPacnes 2012-15 파지의 생산 및 분리 Production and separation of phage 2012-15

본 발명에서 사용한 파지분리를 위하여 얼굴의 여드름 부위를 면봉으로 채취하여 아래와 같이 분리하였다. BHI 배지 4.5 ml에 생장기의 여드름균 (Propionibacterium acnes) 0.5 ml을 첨가하고 면봉에 있는 샘플을 넣어 37℃에서 3 일 동안 혐기성 조건에서 배양하였다. 3 일 후 클로로포름 200 ㎕를 넣어 혼합한 뒤 4℃에서 2 시간 정치배양하고 10,000 rpm으로 10 분간 원심분리 후 상층액을 0.45 ㎛ 구멍크기의 필터로 걸렀다. In order to separate the phage used in the present invention, the acne area of the face was sampled and separated as follows. BHI medium (4.5 ml) was cultivated in a growth medium ( Propionibacterium acnes ) was added and the sample in the swab was added and incubated at 37 ° C for 3 days under anaerobic conditions. After 3 days, 200 μl of chloroform was added and mixed. The mixture was incubated at 4 ° C for 2 hours, centrifuged at 10,000 rpm for 10 minutes, and then the supernatant was passed through a 0.45 μm-hole filter.

상기 용액에서 파지의 존재를 확인하기 위하여 여드름균을 포함한 여러 가지 세균을 가지고 BHI 고체배지에 균을 도말한 다음에 5 분간 말리고 용액을 점적하여 다시 말린 후, 37℃ 배양기에 넣어 3 일 동안 혐기 배양하였다. 용액이 떨어진 부위가 투명하게 보이는 것을 세균의 용혈이 일어난 것으로 판정하였다. In order to confirm the presence of phage in the solution, the bacteria were plated on BHI solid medium with various bacteria including acne bacteria, followed by drying for 5 minutes. After the solution was dropped and dried, it was placed in a 37 ° C. incubator and anaerobically cultured for 3 days Respectively. It was judged that the hemolysis of the bacteria occurred because the part of the solution appeared to be transparent.

여드름균 특이적 파지의 순수분리를 위하여 위 용혈이 일어난 부위에서 파지를 분리하여 대수기로 증식한 여드름균 배양액과 혼합하고 0.7% agar를 함유하는 top LB agar 3 ml과 혼합한 후, BHI agar plate에 부어 잘 굳게 하였다. 37℃ incubator에서 혐기성 상태로 배양한 후에 plaque 형성 유무를 관찰하였다. plaque를 각각 분리하여 앞서 파지 분리에 사용한 여드름균을 이용하여 파지를 증폭하고 이러한 과정을 반복하여 파지를 순수분리 및 정제하였다. Stock phage는 7% DMSO가 첨가된 SM 완충용액 (100 mM NaCl, 8.1 mM MgSO4H2O, 50 mM Trisl (pH 7.5), 0.01% gelatin)로 용해하여 4℃에 보관하였다.
For pure isolation of acne-specific phage, the phage were separated from the hemolysis site and mixed with acne culture medium grown in logarithmic phase, mixed with 3 ml of top LB agar containing 0.7% agar, He poured it well. After incubation at 37 ℃ in an anaerobic condition, plaque formation was observed. plaque were separated and amplified phage using acne bacteria used for phage separation, and this procedure was repeated to purify and purify the phage. Stock phage was dissolved in SM buffer (100 mM NaCl, 8.1 mM MgSO 4 H 2 O, 50 mM Trisl (pH 7.5), 0.01% gelatin) supplemented with 7% DMSO and stored at 4 ° C.

<< 실시예Example 2>  2>

PacnesPacnes 2012-15의 여러 가지 세균에 대한 숙주특이성 및  Host specificity for several bacteria in 2012-15 and 사멸능Destructiveness

상기 실시예 1에서 얻은 순수 분리된 파지용액을 이용하여 영양배지에서 배양한 여드름균 등 여러 가지 세균들을 BHI broth에서 1시간 교반배양 후 BHI agar plate에 도말하고 Pacnes 2012-15 파지용액을 떨어뜨린 후, 37℃ 배양기에서 18 시간 동안 배양하여 세균용혈의 정도를 확인하였다(표 1 및 표 2 참조).
Using the purely isolated phage solution obtained in Example 1, various bacteria such as acne bacteria cultured in a nutrient medium were incubated in a BHI broth for 1 hour, then stained on a BHI agar plate, dropped in Pacnes 2012-15 phage solution , And cultured for 18 hours in a 37 ° C. incubator to confirm the degree of bacterial hemolysis (see Table 1 and Table 2).

Spot test 결과Spot test results SpeciesSpecies Strain or
isolateStrain or
isolate Spot test
result a Spot test
result a SourceSource PropionibacteriumPropionibacterium acnesacnes ATCC 11828ATCC 11828 ++ ATCC b ATCC b 28742874 ++ GNUH c -NCCP d GNUH c -NCCP d 28752875 ++ GNUH-NCCPGNUH-NCCP 28762876 ++ GNUH-NCCPGNUH-NCCP 28772877 ++ GNUH-NCCPGNUH-NCCP 28782878 -- GNUH-NCCPGNUH-NCCP 391391 ++ JBNUH e -NCCP d JBNUH e -NCCP d 893893 ++ JBNUH-NCCPJBNUH-NCCP 14751475 ++ JBNUH-NCCPJBNUH-NCCP 14901490 ++ JBNUH-NCCPJBNUH-NCCP 19121912 ++ JBNUH-NCCPJBNUH-NCCP 105105 ++ KNUH f -NCCP d KNUH f -NCCP d 106106 ++ KNUH-NCCPKNUH-NCCP 109109 ++ KNUH-NCCPKNUH-NCCP 112112 ++ KNUH-NCCPKNUH-NCCP 113113 -- KNUH-NCCPKNUH-NCCP 114114 ++ KNUH-NCCPKNUH-NCCP 116116 ++ KNUH-NCCPKNUH-NCCP PropionibacteriumPropionibacterium avidumavidum 111111 -- KNUH f KNUH f StaphylococcusStaphylococcus epidermidisepidermidis 107107 -- KNUH f KNUH f 108108 -- KNUH f KNUH f 115115 -- KNUH f KNUH f KNUH-180KNUH-180 -- Laboratory collectionLaboratory collection KNUH-184KNUH-184 -- Laboratory collectionLaboratory collection 1One -- Laboratory collectionLaboratory collection StaphylococcusStaphylococcus aureusaureus ATCC 29213ATCC 29213 -- ATCC b ATCC b KNUH-539KNUH-539 -- Laboratory collectionLaboratory collection KNUH-541KNUH-541 -- Laboratory collectionLaboratory collection KNUH-584KNUH-584 -- Laboratory collectionLaboratory collection KNUH-585KNUH-585 -- Laboratory collectionLaboratory collection KNUH-589KNUH-589 -- Laboratory collectionLaboratory collection StaphylococcusStaphylococcus aureusaureus MRSAMRSA 1One -- Laboratory collectionLaboratory collection PseudomonasPseudomonas aeruginosaaeruginosa 1One -- Laboratory collectionLaboratory collection KNUH-558KNUH-558 -- Laboratory collectionLaboratory collection KNUH-563KNUH-563 -- Laboratory collectionLaboratory collection KNUH-564KNUH-564 -- Laboratory collectionLaboratory collection KNUH-567KNUH-567 -- Laboratory collectionLaboratory collection KNUH-582KNUH-582 -- Laboratory collectionLaboratory collection

Spot test 결과Spot test results SpeciesSpecies Strain or
isolateStrain or
isolate Spot test
resultSpot test
result SourceSource Corynebacterium Corynebacterium 1One -- Laboratory collectionLaboratory collection KNUH-188KNUH-188 -- Laboratory collectionLaboratory collection KNUH-309KNUH-309 -- Laboratory collectionLaboratory collection KNUH-576KNUH-576 -- Laboratory collectionLaboratory collection Candida albicansCandida albicans 1One -- Laboratory collectionLaboratory collection KNUH-16KNUH-16 -- Laboratory collectionLaboratory collection KNUH-74KNUH-74 -- Laboratory collectionLaboratory collection Acinetobacter baumannii Acinetobacter baumannii 1One -- Laboratory collectionLaboratory collection KNUH-770KNUH-770 -- Laboratory collectionLaboratory collection KNUH-822KNUH-822 -- Laboratory collectionLaboratory collection EnterococcusEnterococcus faeciumfaecium KNUH-1107KNUH-1107 -- Laboratory collectionLaboratory collection KNUH-1120KNUH-1120 -- Laboratory collectionLaboratory collection KNUH-1134KNUH-1134 -- Laboratory collectionLaboratory collection KNUH-1143KNUH-1143 -- Laboratory collectionLaboratory collection KNUH-1144KNUH-1144 -- Laboratory collectionLaboratory collection EscherichiaEscherichia .. colicoli ATCC 25922ATCC 25922 -- ATCC b ATCC b KNUH-9KNUH-9 -- Laboratory collectionLaboratory collection KNUH-33KNUH-33 -- Laboratory collectionLaboratory collection KNUH-39KNUH-39 -- Laboratory collectionLaboratory collection KNUH-42KNUH-42 -- Laboratory collectionLaboratory collection 1One -- Laboratory collectionLaboratory collection EscherichiaEscherichia .. colicoli DH5DH5 αalpha -- invitrogeninvitrogen BacillusBacillus 1One -- Laboratory collectionLaboratory collection

a +, lysis; -, no lysis.a +, lysis; -, no lysis.

b ATCC, American Type Culture Collection.b ATCC, American Type Culture Collection.

c GNUH, Gyeongsang National University Hospital. c GNUH, Gyeongsang National University Hospital.

d National Culture Collection for Pathogens. d National Culture Collection for Pathogens.

e JBNUH, Chonbuk National University Hospital. e JBNUH, Chonbuk National University Hospital.

f KNUH, Kyungpook National University Hospital.
f KNUH, Kyungpook National University Hospital.

그 결과, Pacnes 2012-15 파지는 Propionibacterium avidum , Staphylococcus epidermidis , Staphylococcus aureus , Methicillin - resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Corynebacterium , Candida albicans , Acinetobacter baumannii , Enterococcus faecium, E. coli DH5α, Bacillus 등을 사멸시키지 못하고 여드름균만 특이적으로 사멸시켰다. 이와 같은 결과를 통해 Pacnes 2012-15 파지는 여드름균을 숙주로 하며, 이 균을 특이적으로 사멸시키는 파지임을 확인하였다.
As a result, Pacnes 2012-15 phage was found in Propionibacterium avidum , Staphylococcus epidermidis , Staphylococcus aureus , Methicillin - resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Corynebacterium , Candida albicans , Acinetobacter baumannii , Enterococcus faecium, E. coli DH5α, Bacillus , and so on. As a result, Pacnes 2012-15 phage was found to be a phage that specifically killed acnes bacterium as a host.

<< 실시예Example 3>  3>

전자현미경을 이용한 Electron microscope PacnesPacnes 2012-15의 형태관찰 Morphological observation of 2012-15

본 발명에서는 파지의 모양을 관찰하기 위하여 주사전자현미경을 사용하였다. 순수분리된 파지를 탄소로 코팅된 구리판에 바른 후, 2%의 uranyl acetate로 염색하고 주사전자현미경(Philips EM 300)을 사용하여 관찰하였다.In the present invention, a scanning electron microscope was used to observe the shape of the phage. The purely separated phages were applied to a carbon coated copper plate, stained with 2% uranyl acetate and observed using a scanning electron microscope (Philips EM 300).

관찰결과, 시포비리데(Siphoviridae)에 속하는 것과 같이 각이 진 머리(icosahedral head)와 긴 하나의 꼬리가 관찰되었다(도 1 참조).
As a result of observation, an icosahedral head and a long tail were observed as belonging to Siphoviridae (see Fig. 1).

<< 실시예Example 4>  4>

PacnesPacnes 2012-15의 유전학적 특성 분석 Genetic characterization of 2012-15

본 발명에서 파지의 유전체는 Phage DNA Isolation Kit (NORGENBIOTEK)를 사용하여 순수 분리하였다. 분리된 파지 유전체는 전체 유전자 염기서열 결정을 위하여 천랩에 맡겼다. 전체 염기서열 결정은 454 및 Illumina sequencing platforms의 혼합 방법과 CodonCode Aligner 3.7.1 에 의하여 수행되었다. In the present invention, the phage DNA was purified by using Phage DNA Isolation Kit (NORGENBIOTEK). Separated phage genomes were left in chunks for the entire genome sequencing. All sequencing was performed by mixing 454 and Illumina sequencing platforms and CodonCode Aligner 3.7.1.

실험결과, 파지의 유전체는 이중가닥 DNA로 크기가 29,741 bp이고, 46 개의 ORF로 구성되어 있었다. 서열번호 1로 표시되는 전체 염기서열을 미국 NCBI의 BLAST 검색을 한 결과, 여드름균을 사멸시키는 PHL113M01, PHL073M02, P1.1, PA6, P100 A등을 포함한 16종류의 파지들과 87%∼89%의 유사도를 나타내며 이들은 모두 시포비리데 (Siphoviridae)에 속하는 파지들인 것으로 확인되었다.
As a result, the genome of the phage was double stranded DNA, 29,741 bp in size, and consisted of 46 ORFs. As a result of BLAST search of the NCBI in USA, the whole base sequence shown in SEQ ID NO: 1 was found to be 87% to 89% in 16 kinds of phages including PHL113M01, PHL073M02, P1.1, PA6, And they were all found to be phages belonging to Siphoviridae.

<< 제조예Manufacturing example 1>  1>

PacnesPacnes 2012-15를 유효성분으로 포함하는 크림의 제조 Manufacture of cream containing 2012-15 as active ingredient

Pacnes 2012-15를 유효성분으로 포함하는 크림의 제조는 통상적인 방법에 따라, 상기 <실시예 1>에서 분리한 Pacnes 2012-15 10 중량%, 1,3-부틸렌글리콜 6 중량%, 글리세린 4 중량%, 유동파라핀 5 중량%, 스쿠알렌 3 중량%, 폴리솔베이트60 1.5 중량%, 및 정제수 잔량을 혼합하여 영양크림을 제조하였다.
Pacnes 2012-15 as an active ingredient was prepared according to a conventional method by mixing 10% by weight of Pacnes 2012-15, 6% by weight of 1,3-butylene glycol, glycerin 4 By weight, 5% by weight of liquid paraffin, 3% by weight of squalene, 1.5% by weight of Polysorbate 60, and purified water.

이상 살펴본 바와 같이, 본 발명은 여드름균을 사멸시키는 여드름균 특이적 박테리오파지에 관한 것으로, 보다 상세하게는 여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP)에 관한 것이다. As described above, the present invention relates to an acne-specific bacteriophage that kills an acne bacterium, more particularly, to an acne bacterium ( Propionibacterium It relates to KCTC 12569BP): bacteriophage Pacnes 2012-15 (Accession No Seaport of irregularities for the (Siphoviridae) having a specific ability to kill acnes).

따라서, 피부 질병의 주요 원인이 되는 여드름균을 특이적으로 사멸하는 본 발명의 박테리오파지 Pacnes 2012-15는 보건산업 뿐 아니라 친환경 대체항생제로 이용될 가치가 높다.
Therefore, the bacteriophage Pacnes 2012-15 of the present invention, which specifically kills acne bacterium which is a major cause of skin disease, is highly valued not only in the healthcare industry but also as an environmentally friendly alternative antibiotic.

한국생명공학연구원Korea Biotechnology Research Institute KCTC12569BPKCTC12569BP 2014040220140402

<110> Kyungpook National University Industry-Academic Cooperation Foundation <120> A bacteriophage that kills Propionibacterium acnes <130> NP14-0023 <160> 1 <170> KopatentIn 2.0 <210> 1 <211> 29741 <212> DNA <213> Artificial Sequence <220> <223> Bacteriophage Pacnes 2012-15 <400> 1 ggtcttgcac gggtgtgcag ggggtggtcc gggtgggggt ttgcgggttt gtcaccatga 60 aactaatgtt tttgtggttt gttgttggaa ttgaatgttt ggttgtgttc tgttgccttt 120 gcttctgttg catgttctgc agatgatttg gccgttgtcg agggtgttga gtcctcccct 180 gctgacgggt gtgatgtggt cggcttcggg gctggttggt agctggtggg tgtcccaggt 240 gatggtggct ccgcagagtg ggcaggcgac ctggccttgt tgtcgggctt gggtgatgag 300 tcgttgccgc cagcggcggt gggcggagga tgcggtgcgg ttggtgtgtg ccatcacgcc 360 tccgctcccc aatagtgcct ctatgggctc tggttgcctc tgtaacggcc tggaatgtgt 420 tgggggtatg aataccttgc ccttgccccg ctgttcgatt ctaggggcct ttttgtgcgt 480 ttgagggggt gttctgtttg tgtcggggtg tttgttttct cttcctaccc ccacggttgt 540 gagaaagatc acattgcccc ccagcggtgt caaaagaaga aaggacacgg aagaaaacgg 600 gggagtgggt gttcgcactt cacggcttag cgcttggcgc ctagcggtgt agaacacagc 660 caaaacgtgt acacccttaa ggtttttaaa gtcttctaca tataatatac actttaagtc 720 ttacctggcg ttaagggttt acgtgtgaca cgccgtacgc cttcagccga acacgccaag 780 gtttgaagga agaacacggg tagagtgagt gtggggagtg tgcgatggga gcttgcgacc 840 aagcacacga gtcacacggt aaaagatcat cggcgctgat ggtaaaggtt cctcttctcc 900 cctgatgaag aaaagaagag aagagagaaa gaaccaaaga gagtagagaa gtaaagaagt 960 taacccctta gctcttctaa aacttttata acttatataa ttatattata ttataatacc 1020 tataagcttt aagacttata ggttataata ttaaagttta agactgatgg ttaactttaa 1080 gtatttaaag ctttaatgtt ttatagttac ttaaagtatt aaagcttata agtatttata 1140 tttactttaa gttttaaagt cttacacact gatgtaaagt ttatatcctt aagtgctaag 1200 cctttaaggt tttatactta acttaggtgt taaggtttaa agttttaaac gtttaactgt 1260 taaggtttta tatttacttt aagacttaaa ggctttaatg tttatttata accttaagtg 1320 ttaagtactt aaggttactt aaagtgttta aagcttataa gtctttaagt attaatattt 1380 actttaagtg tttaaggctt taaggctgat gccgagccct tgaggggctc ggtgctcagc 1440 gttaaggtct taagggctta gcgctaagcc ttgaagcttt aaagtgtttg gtagactgat 1500 ggatgtaagg gtgaaagccg cgtcagcgga tttcggcctt gcgtccagct ggctacctgt 1560 ccagcctatc atatgccacc tgggatgagt caaacacggt ggtttggctc tataggcggg 1620 tttgaggggt gtaaacgggt gtttttggta gtaaaggtcc aaaaattaaa cctaaacttt 1680 tccttaaatt ttcttagagt cttgtaacct ttgagggtgg ttaaggctga aacccctagc 1740 cagaacgggt ttcactccca gacagctgtc acactgtacc cctgtgtcct ttccggacac 1800 gctaggtgtt cagtgctgat gggtgttccc tcaggctttc gagtactcgt cgctaaggct 1860 cctcgtactc tcaagccttc cctgatggcg tgtacccctt tcagggctgt gcctcatcgg 1920 ctgagcctgt tcgggctgat gccgagccct tgaggggctc ggtgctaagt gctcaacccc 1980 tcagtgctaa gaccttaaag cttgaaggtg tgaaggctga tgctccccct tctttcttgt 2040 accgtgtcct tcttcccccc acagtatccc acactgtcca catagttgag gcttagctaa 2100 ccaagatagg tactcatggt ctatgccgag accgctcatc tcatacaagc ctcctgtagg 2160 cgtctagaat cgatcagaat gtgctggggg tataaatacc tagcccccac ccggcaaggc 2220 gctcctaggc gccatgcaga ggctttaaac agcatttctg ggctacactc tctacgctag 2280 atcggcagag tagcctcgag ggtgcacacc aagccaggag gatgtgatac atctcacaca 2340 gtatgagggt gtagattcca tgcccagatg gggtaccccc acttttgcga tgcagacctg 2400 catcagcctg tcaatccatc taccgaacct gctatcaccc agacataccc ctgggacgcc 2460 ctagaagtgg cctagaatcg atcagcaggg tcaaccctat ataatcctac ccccagaaga 2520 tttgaggcgc ttagaggagc aataaaggct taagtgatat acgccacacc ctatgccaca 2580 tccacatgaa acgctcacaa ccgttgagcg tagccttgac cttgatgccc cacctcaacc 2640 atcatgggat cctgtcggca caaccacaca ccccgatgaa aggacaacac gatggcctac 2700 acgctcatca cccccagctt caccaccctc tacaggcaaa ccgaaatcga tccactcaac 2760 ctccacaaca ccatcggaga ctacagtgac aacatcgatc tcgacatggt gcagcgcctc 2820 taccacgccc aagtagaaca atccatacgc ctcatccgcc cacactggat agtcaccctc 2880 gacggagccg tatacgggcc acccgactgg cagtcactca ccgagaaaga agccgaagag 2940 ttgcacgaca tcatcgacat gatcgatctt gactccatca tcgccgcatc aacccgataa 3000 acccaacaca aacccgcaac aaccaacaca agagtaaagg acatgatcat gcagaagatc 3060 gccaaccact tcacccagct ctacaccccc acccaggact gccctgagcc tttcgacctg 3120 acacgcctcg aaaacctcca ctgcgaccac atggattttg agggcctcgc cgaagcctac 3180 cggcagcgcg tagagattga actccacaag ctacgccccc acacattcat cgcatccgac 3240 ggcaccgtgt tcagctacga cgagtggaag ccactgacac agacagaggc gacacaactc 3300 tactggaatg tgacacgcat caacatcgga agcctgctcg ccctgttcac ccgataaaac 3360 cccaaccaca cacaacgagc ctagaatcgc ctagaaatac ctgacctata taatcctacc 3420 cccaagggct gaaaggccct aaattagcat taccgccaac cgtataatcg aaaataggag 3480 cacatatgca atggcaatgt cgcaaatgcg ataccacaat catcggatac aagccagaac 3540 actgcacagt ctgccacgag acattcacta gtaccacctc aggcgatatg caccgtgtag 3600 gtgatcacgg ggttaaggaa ggcaccaatc gccgcagatg cctcacggtg gacgagatgc 3660 tcaccaaggg catgcagcgt aacaaactcg gctactggac cagcggcggt acctcatact 3720 gggtgaaaga agcataaccc caagccacac accaaacgct cactgggtat gagcgcacac 3780 ttgacatggg gaaccatcca cgccatgatt aatcatgtca acaacgaaca aaccccagaa 3840 aggggacaac agtcatgaac aagaaaaacg gctacaccat cgcaggcatc acagccgcca 3900 tcatcgcagc cgcctccttc ctcccagccc cagacgacaa cccgccactc acctcacagc 3960 ccgcaccaca ggtaaccaca gccaacaccg aatggacacc tgaaaccgcc cagcagcgca 4020 aggctgagaa gaaagcacgg caagccgcag cagtccactc cctacaagca gaacagcagc 4080 gcgcccaccg gcaagcccaa gccaggggtg aagaaacctc cacaggtctc accatgctca 4140 ccgccgcaca cgcctgcaac cagaaagtca cccagcaagc cgccacacaa ggcgtcaaat 4200 ggaacggcaa cccggacatc gacctcttcc tccacaaagt gatcggcagc aaaaaagaca 4260 ccttctcgat cgcctacggg gctacggcac gccaacccgg cgcctccaag acgcaggtga 4320 aagtcttctg ccaagtctcc ggcacagaag acaacccaca ggtagatgac ctgtccatca 4380 acccagcacg ctaaggacgt ccaatgtctc tcatgtcaga ctacacagcc aaagtcggcc 4440 tctccgatat cggccacatc atccacggcg ccgaactctc actccaaaca gccactgaca 4500 tcgcttccag aatcgacacc ctcaagcaag aaatcaacct cacaaacgaa ataaacacac 4560 tactggaaat cgaagcacaa ctgtacaaca tttataaaac aatcaacacg aaaacaaggg 4620 aatacaatga acaatcacac caaaacaacc ggtgaactcc acagctacga aaccttcttc 4680 accagcctcg cctggatcca aggcgccctc atcacatgga tgtacgcaac cggcaccagc 4740 cacaaagccg ccctcgccat caccgccgcc tgcgccctcg ccaccctgct cggcgcatca 4800 accctcacct accagcccaa agaccacaca tgattacaac acccatactg atcgcagaaa 4860 ccctcgccat cattattctc gccgccgcac tcgcccacaa caacaaccag taacccacgc 4920 ttaaggagca cacacctcat ggatgagccc acccgcatat acaccaaccc caacaccggt 4980 gcccgaaaag aactcaaact gtgcaggctc tccctcatcg accccgcatc cctccacgcc 5040 ctcggcgagg ttgcaggcta cggtgccacc aaatacggcg acaataactg gaccggagga 5100 tacccctggt gtcacagtgt cgacgccctc taccgccatg tgcttgcctg gcagcaagga 5160 aacaacctcg accacgaatc acatctgccg catctggccc acgccgcctg gcactgcctc 5220 gcactcctcg cctaccagca acacgatgcc ggccaagaca cccgcaaccc atggaacaca 5280 cacaaaggcg accagtaatg cccctagcac aaaaacccgc tatcatcgac ctacccgacc 5340 acatctcatt ctcaagcctg acacagtggg tagaatgcgg cgaaaaatgg cgactcatgc 5400 acggctacca cgccacagcc cacacctggt atgccaccat agccggaagc gtcatccacg 5460 ccatcactga aacctgggat aaaaaccttt accaccaaac cgatgcggac atcccaccct 5520 ttggcgacct gttcaccgaa gagatcatcc gccaagtcgg tgatggcgaa gacattcgac 5580 cctcaggacg cacctgcaaa accgtctgcg aaagtggagg accccataag aaagactatg 5640 attggtggat gcactacggg cccatctacg tggaaaggtg gacaacctgg aggaagaggc 5700 acaccgagta tgagatcgcc accatcgacg gccagcccgg catcgaatac cccgtcgaag 5760 ccaccctcga caatgacacc cgggtagtag gatacattga caggatcctc cacaacccca 5820 ccaccggcga atacaccatc ctcgacctca aaaccggggc cataccgcaa ggaaacctgc 5880 aactctacac ctaccggcac ctactccatc tcaaagatga tatacagccg gcgtatggca 5940 tgttttggac acccagccac aaaacaacct ccggcgacac caacaccgga tacgacaccg 6000 ggcccatccc gctagacacc gaggctgcac gccacatcgg ggtcatgtat actagcgcca 6060 tgcaaggaat cgcccacaac gtgttcgtgc cccacgtcac cccgatgtgt aaaggctgcc 6120 ccgtccgaga ctcatgctgg gcctacgggg gcgcgcaagc ctaccggtac cccaccaaaa 6180 ccatcaccca gccacgcaac aacaaggagg ataactgagc atgcaagaca acacagacga 6240 cgaccgattc acgatcaccc tcaaatacgg tggagactac gccgcaccct ggaccgtcat 6300 ccgcggagac accgccgacc aggtaaagaa agccatcatc gacctgttag gcggactcaa 6360 aaacagctcc gcggcaagga actgggacct ggcaaccctg atcgccacag catccatcat 6420 cctccaagac cgatacaacc aggccgccaa agactacgta gacaacatcg catcagaagg 6480 aaacaacacc atcatcgaca aaattaacaa tgccacaagc aaggcacagc tagcagacct 6540 tctgaaacag tacaagaaga ccatcactag taacagtgac gtgtcagagg cgttccgcag 6600 caaacgaaac agcctcaccc gataaaaacc gacacaaacc aacaaaacag taaaggaaac 6660 aacaatggga ctcgccaact accgaaacaa cagcaacagc accttcttca acccgtcccg 6720 aaaccaggac gccaccgcca tcgccttcaa agtccacgat gtggaacaca acactgaagg 6780 atacggcgga caaaccgcag accgcatcta cgctgatgtc accatcttcc acaccctaga 6840 cgacctcaac aacggcaccc cagaaaccat ccccaacgcc atcatcgaaa aagtgcgagg 6900 caacaacgac cggccacact ccatgatccg cgatttagag gcatatcttg gcgaggagca 6960 ggccttcaaa ctagccaccg tgcgcaccaa aaacggcttc aacgcggtcg tactcaaacc 7020 attagacgac gctatctacg acaaggtggc cgaatatgtg gacaaacgcg ataacggcca 7080 gctagacgac accacagcct ctactgacat cgatatcgac tccatctgac catccacaac 7140 caaccgatag acagatagat taaggtcccg atgctctctc tacaacgatc cttcgagaga 7200 gcctcccaaa cagccgccga gctgccccgc ataccacaac tcgcacccct atacgataac 7260 caagacttgc acatccacaa aggggacctg gtgatgattg cggggcgctc aggcagccaa 7320 aaatcagggc tagccatgtt catcacagca atgctcaacc agcccaccct ctacatatca 7380 ggggacatga caccctggga ggcctccaca cgaatcatct cactcaacac ccaacacacc 7440 accacacaga tacaacaaaa catcgacgac tacgggccag aatactatcg agacaccatc 7500 cggcacggcg aacgcatcac attctcattc cagtcaccca tcacctggac agacatcacc 7560 atggagctac aagcctacat ggaaatgtgg aaccgtttcc ccgacatcat cgtcatcgac 7620 aacctgatgg acatccaaga ctgcgagagt gactatcagg cccagcagga agccatgcaa 7680 tggatcacag ccctcggccg cgacacagga tccaccatca tcgtcaccca ccacgcaacc 7740 gacaaaacag gaaccgacat cgaacacccc ccggcacgcc gcgaaatcaa aaacggcctc 7800 tccgaaaaac cacaactcat cctcggagtc tcactctacg gtggcgaaga caacggcaac 7860 gggctcacca tacccgccga agcccgcatc gcagtgttga aacagcgcac cggcaaatcc 7920 agcccagacg gcacccgata cgaaagacta cgagcctacc ccgaatacac attcttcgga 7980 ccactggtag aaaaacagcc atggaacatg accccaacac acaaaggact atcatgtcga 8040 cacagcaatc acgcaaccgc cgggccggag ccgaatggga aacccgactc ctccaccagc 8100 tacgagacac cggccatgat atagagcgcc tccacctcaa cggcagagaa gatgagggag 8160 acctgattct caaaaccggc aacaaaacct atataatcga agcgaaagcc ggccagcagc 8220 atttggccca attcgtgaaa gaagccacaa ccgaggcacg caactatgag caacaccgca 8280 accgagaaaa ccagtccacc ataggactcg ccgtcatgaa acaacgcaac aagccatgga 8340 gcgaagccta tgtggtatca accctcaacg agctcctccc acacctctga cacctgccgc 8400 ctcctcgaca tctaccggat acgctacaac ccgtccaaaa acgagcagca catcctgtgc 8460 ccgttccacg acgaccacca gccctccatg agcatcaacc tcgacaaggg cgtctggtac 8520 tgccacacat gcggtgtcgg aggcggactc gcccaactga aacaacgatt agaagaagaa 8580 aacccgaatg tacgacagca tacgcccata caacattgtg gaacgccgcc gaattcagaa 8640 agcctcggcc ctctacgaaa cccacctcga aaacattctc gacctgctct cagcaagagg 8700 catcagcgaa gaaacagcac gctaccacca ccttggatac atcgacaatg accccatccc 8760 aggccacgaa aactacaacc agtgcatcac catcccctac atgtaccccg tttggggcgg 8820 cccagccgaa atacgaaaaa tgcgtttccg ctgctcactc ccgcacgact gcaaaaccca 8880 caaccacccc aaatacctaa ccccagccgg ggacacaggc tccatctaca acatggccgc 8940 catggccaac ctggcagccg aaatgcacat ttgcgaaggc gaattcgact ccatgatcct 9000 agaacaatgc ggatggccag cagtagccat ccccggcgcc acctcgtggc aaaacttctg 9060 gaccaaattc ttcgaaggct acgaccacat ctacatctgg tccgacccag acaaagcggg 9120 agaccagatg gcccaaaccc tccagacggc actcccccaa gccactcatg tgcccctcac 9180 catcggcgat gtgacagaca cctacctaaa aaccggcaaa acagggttga cacaagccct 9240 caacacagtg ctacaataaa accacaccaa cagcccaaac aaagaaaggt acactaaaac 9300 atcatggatc ccctcgacac gtgccccatc cccaaccggc gcaacattag ccaagcagcc 9360 aggaggcgta tccgcctcgc catctgtgca gaaaaatggg ctgatggtga agaccccacc 9420 tacatcatgc acacctgggg caccacctat gatgggatgc gatccatgat ccgcgccaac 9480 cccgacatta aactacccga cgacatggcc aaacgtttac acaaagtatg ccgggaagcc 9540 taccccaaaa accagccaaa caggcaccga agcggatggg acgcctacga gaaaaactac 9600 tacacccacg aaatactctt cctcgactcg tttaacgtgc cagccctcga aatcctcaac 9660 cggctcgacg tgtcatgggc catgtggaaa caaatcctcg cagagcagca cctgacccgg 9720 ctccagcagg agaccgacaa cgcctgccag tgggcaaacc tgcgaaagca gcaccccgat 9780 aagactgatc aagaaatcac tcagatgatg tatagtaacc aggtgacgtt tagcaaggtg 9840 atgaaaacca tacccgcata aacactcatg acacctgcat agtatttgca cactctttca 9900 caaataggag acatgatggt cgccaaaacc caacacttga tcgacatgca cggggacaac 9960 aacaacgata agtttcccga gcacctacgt gacgtcatgt gcggccgtgc catcatccac 10020 gatgccggcg aagtctcatg gtgcacccgc aaaccaggac acgacggcga ctgccgcaca 10080 ggatggcagc ccaccacaca accgttagga caccatggca accaaaactg aaacactcat 10140 ccaacgatac ggggccaaag ccgccgacgt cctcgccgac aaaaccatcc ccgcctcatg 10200 gctcgcaaaa cagctcaccc aagccggata ccccatctcc gccaccgtca tcaaagacca 10260 cagacgcaaa ctcaaccacc agaaaggaga cacacaatga tcgacaacat tgacaggctc 10320 ctcgcacagc tagcccaaca caacaccgaa gcagacacca tccacgatga tctcgccaac 10380 ggcaccgtac gacgaacacg catctccgaa tggacactcc ccaacggaga aaccggccga 10440 tcaatccaaa aaatcatcga ccaccagcca gaaacagacc catacccggt cgacgaactc 10500 gtagctaagc tagccgaatg gacaccaccc aaaccagaaa ccaacaccca aagcagtgac 10560 gagaccgcgt ttgtcatagg ggcgggcgac ttccaaatcg gcaaaggcat cccccagggt 10620 gaaaccgcac acttcgcaga cgactatctt cgatccctca cagccgccac acactactgg 10680 caacaggcag gcaaacccga acgagtccac atcgcattcc tcggcgacat gatcgaagga 10740 tacgtgtcac aaggaggcaa caacgcctgg cgcacacaaa cacccttgac ggaacaaatc 10800 aggctcaccc gcatggccat gatgcaactc atccaccaat tcgaccactg cgccaacgtg 10860 acggtcacat ccatccccgg aaaccacgga gaagccgtgc gcttcggtaa aggcgtcacc 10920 acctacgacg acagttttga tgtggactgc tgccgcgcca tcgcagaagc ctaccaactc 10980 accaacaact accctaacct ccacttttat ttcccccacc gggacgaaat gaccaccacc 11040 gtcaacgtag ccggggccac catcctgcac gcccacggac accaatggcg caacaaccaa 11100 cactacgaat ggtggcgcgg ccaagaattc cacaacggca ccgtatccca tatactcatg 11160 gcaggacacc gacaccacct ccacatatct gagcaaggac aacgcacctt catccaatgc 11220 ccatccatgg aaggagaatc cgtctggtac cgacacaaga cgggcaccac cggcaacccc 11280 ggactcgtgt gctacactat ccaccataaa acaccaaaca actaccagat agcccgataa 11340 aagagatgcc atgagcagac gaccaaccaa agtccaacaa gccacaaccg ccaactgggg 11400 gtgggcaacc ccccaccacc aacaccagct acacaaagcc tgcaccaaca ttgcgcgcca 11460 ctacccggcc gtcaaccccg acgacctcta ccaagacgca ctcctctaca tagccgtacg 11520 caaccaatac caccaactca caggcaacca gtggacccaa atgtgctacc gtgtagccca 11580 acggctagca aacaaaacag tccaacacct cgacctaccc aaacccgtac acgaaatcac 11640 agccatagcc gacagccaaa ccagcaacta aggagaaccc cccatggtta tcaccatcct 11700 cgacgacgga acccaaacca ccaggctaca aacagtaggc tccaccacca ccgccatcat 11760 caccaacaca gaaacacccg aaaccatcac cgccaaatac accatcgcaa aagatggcac 11820 agccacctac agcatcagcg gaaacaccta cctcggcgac caccaacaca tcatcaaact 11880 catgtacgac tactgccact gcgtaggacg attcgacacc accaacacca gcaacccaga 11940 caacttcgac aacctgttca gggggtgacc agtgaaccga acctacacca cagccgacat 12000 catccaagcc gcccaatgga tctggaacgg cggcccatgg aaaccatcag tcgagccagg 12060 catgccaccc ccaccaaccg cgccacaaca ccacggaaac aacatcgtct ccatgatcga 12120 cctgcagctc gccatcgacg actacaccct cacctgccag ccatccaagc agcggaaacg 12180 gctagcacgg ttggcagcct tccgggaagt atacgggtac gaccaaacat atgcgtcggc 12240 cgcccaacga ttgggtgtca cccggcaaac cgtgaaacag tgggcagacc aaacactgat 12300 gacactcacc gaatacgcaa acagcacata ctacatgcca gacgataacg aaggaatggc 12360 ataacacgat gaacaacaca cacaatatcc cctacaccgc cctcaaaaca gcggtacacc 12420 gcatcgtcca acaacagccc accaacatgc agcagctgga aaacattgtt gacggtgtcg 12480 aaaaccagta ccatgtaccc atctccctcg acaacgtgaa cctcaccatc aaagaagtca 12540 gcctcgacaa ccttgctatc gaccaggaca cgctagacga gtgcagcgaa atcctgtggg 12600 actgcgacag tgcaggacac cccacaaaca accagcagcc gaaggcaagc caggaagcca 12660 tagactggct agcccgaatc gcataccaaa ccaaactact gcaagcagag gccgacgata 12720 tcatgcggtc catcctctgc caccgcgaca accacaaaaa tgttatcggc caggatgttc 12780 tgcaccaggc caacgaaact atctcagcct gcctccacct ggaccagctc atcgaagaca 12840 ccctagacga caacctgtaa aacccctgca gacacaaaaa gagtgcccca gcagcagcca 12900 ccacacaaac atggcagcac cgctggggca ctcttttatc aatattcact tatcacacaa 12960 caggcgattc tatcgtgcaa acctccgact cggctgcacg cctcggcaca tagcccgcaa 13020 caccagtatc gtccatcggc tcgatcatgc caggatccga cacatcaacc aggtgagact 13080 ccactattcc cggatcgtcg ggtggaacaa gcccggcatc aacaaccgta gtcttcggct 13140 tgccagccac aaacgaaggg ttaccaaacg aagtagccac cgacaggaca gcagcaaccg 13200 tggccgtgat cagggcagac tcccacggca aaccgcgaaa cgactccgcc gtataggtga 13260 cacccgccgt cacacccaac acagcaacaa acgtttgaat aaaagttttc agggcacgct 13320 ccaacaggcc caaccaaaac tgtttaccca tcacacatca ccatcacttt ttcaaccggt 13380 taacgtccgc ctcaagccgg gcaagacggc tgcgacactc caacacgtaa taccagacac 13440 tccacagggc atccttagta cgccacagct tccccgtcac cggattcttc acccacgaca 13500 aagcctccac acggcgcgct agatcaccat tctgaacctg aaccacaccc acatcgtgat 13560 gcagcttatt caccgactgg gccacctgcc cagacaactg tttaatctga tcatgtaacg 13620 ctttcacatc agccatactc aactctccac tctctccact gccgccgttg acgacggcca 13680 taaacctgtc ccacggaaac catggccccg gatcgtcatg atccgactga tgccacgcat 13740 ccgtcacatc cacatgcccg cacacgccac gcctgccagc cttcaaatcg gccacagaca 13800 gtttcctctt cggaacacca tgcttgtcac acaactgccg gcacagcaca gcagccttct 13860 ccaccgcagg ccacacccga gggtcaagcc actgctcccg agtataagca tgccccggca 13920 ccctaaacga ggcgtgcgaa cccccatcag cacaaatctc tatacccaaa gaatgcggat 13980 taggtggggc atgccaacca atcgtagact cagacaagca ctgcaccgtc tcagagacat 14040 cgcacacata gtgtgcagaa ccccccgaag aaggactcgc aaaatagttt gctgtagaca 14100 ccgcccgccc tttacgggaa gcggacggaa accccacatc cgggcatgtc gcatgaatca 14160 caaccctatt caccggatga ttagagccgg ccgagtgatg cgccgcagga atgtatctca 14220 ccgcatgtca ccaccaaaca ccactatcaa catcagtaac acccttccac tatcattcat 14280 ttgcgggatg acacggtaac cacaggtgat ggtttcacat cctggcaggc tgcagaaccc 14340 gctatggtag aggccgtacc gtcatcatat ttgacgatca ggcggccccc ggaacagtac 14400 acggacacca cagagcggcc atcacgccca tctttgccat ccttaccgtc cttaccattc 14460 acaccgtcta caccggcaga accctgcaga ccctgaggcc caacagggcc acgctcaccc 14520 tgtgcacctt gcggaccggc agggccacgg ccaccatcag ccccatcagc gccatcccta 14580 cctggcacac catctttgcc atcagcgccg tcaacacctg cacgtcccgg aacaccatca 14640 cggccatcct taccgtcact gccgggcagc ccgtcaggac ctttcacacc attcaaaccc 14700 ggggaaccct gcggaccaac agggccaacc agcccagcag aaccatcaac accattacgg 14760 ccatcaacac cggcaacacc tgcagggcct tgcggtcccc gtacaccggc cgggccaggc 14820 acaccctgca cgctacgctc aacacgttga gcatccacac acaagccaga ctggtgaagc 14880 cgcaccgact cccggccacc agaggcacac gcctgccgca cacggctagc caacccttta 14940 gccgccgtac cattcgactg ggctcgagcc tgctccgaat ccctttgcga agccacagcc 15000 ccgaaacgta aagcaccccc ggcaaccacc gccaacagta caagcgacag gaacaacaac 15060 accatggaag ccttctcaaa cgagcggcgc tgccgcttct cctcctccaa ctccctcaca 15120 attcaccccc caccgctatc aacagtatcc ttcaaaaact cgggcaaatc aggcatcttc 15180 acaggctcaa cattatccgg cagattcgcg ttataacggt gaacaatatg gcgaatattc 15240 cacgtgtatt cttccatagc atcaacctgc gcagacaact gcctcagcct cttcttcgac 15300 ctgtacgtaa ccgcctgaat cgaaccaaga acagtagcga tagcggtaca aagagaggct 15360 acgagtgtgg gtgtaaacca tgacactaca gccccctacc actacaacca ccacaacacg 15420 tcacataccc gcaagccgcg cattacacgc cgacagcaat ccaattagcc accgcaggaa 15480 caccagacgg cttcgaacca tcattcgtaa taaacgccaa accaaaatcc ttggtagtga 15540 tattgtaggc tttcacatca atttgggtgg tacccccagc agccgtggcc atagacgcca 15600 ccaccaccgg cggggtagca aactggcgat caaacggaac agtataggca tacacattcg 15660 aaccgccaaa cttgatagac ttagtgccag tctcaatcct cggggacaac aacatccact 15720 tgtcggcatg gttagcccac acagcccccg aaggcaccat cacccggtca ccctccacag 15780 gggtagggtc acaggcggca gactccccaa acgccaccct agccgctata gcacgcctat 15840 ccagctgctg ctgcaacccg tcagacgaca acaccaaagt cgccaacagc tgctgatgaa 15900 acacgccagg ctcggcacgc aacacgtcac gggcacgctc cgaagagccg ccaggaacaa 15960 tctccaacct ggcagtattc tcctgccaat ccctggacag gacaacatag tcgtaccttg 16020 gcttccccgg acccggaagc tgctccgtca ccgtctcaac actattcgac gtacacatca 16080 ccccgtgagc ccacgcctgc cccggcagga cctcacacaa caccgtggca ccctgaaccg 16140 tagtgccaac cctgaaatcg tcagggccct tcacagacgg catattaccc atcagaccag 16200 acatttgagc ccaatcatac tcggtcaaca caccatcaaa acccttacac acaataccca 16260 caacacaccc ctcacaatta gaacttttgc aaatcccgca cacccgcagc caaaccagcc 16320 acacgccgcg ccaacagggc cgacggatta tcctcataat caccggcaac cggtgtcact 16380 ttcgtccacc cgtcacccgg cgatacacac tccacatcaa tctgccgaac aatctccgcg 16440 atagggccag aacccacatc aacataaatc aaatccccag gcatcagatt gccgggccca 16500 aaacgcaaca catccgactc agccaactcg atcttaaaac cagacgtggc ctgtgattcc 16560 gacaacacct gctcagcctc atcgtaaaga gacaccttct ctgaatccgt gttacgggca 16620 tccttaaaca cctcgacacg atcaaaccag cccccctcgg ccatcgaatc aacatcctca 16680 caaaacagcc gatcccgacc ctcgccgcgc cccccaacaa ccaccgatgt ggccttcggg 16740 gcgtcacgca catactccca cgacacaatc gaacccgact cggacgtcaa cacatgttta 16800 cgcgtcaccg cgggcacaca atcaaacacc aaaccccgct gatcaaactt cgcatcctca 16860 aactggttca ccgaaacagt catatgagcc cacgacaaca ccggcaacaa tttatcggca 16920 aacacgtgaa accgcacctg aaaatcctta atatagcgtc cacgacgctc atcatcgttc 16980 ataaacaaat ccggaggaaa acgccacgca ttatccccca acacctgctt agccaccgac 17040 tccgccgcac ccgaatagtg agcataatca cggtccgcac gccactccga accaaccaaa 17100 ccggggcgat aattcacagg ccacatcaac atacgccaca acagccgaat atcatcctca 17160 cacgtgatag tcacacgcga agaacgccaa ggacccacac catgcaccct acgcacaggc 17220 ccagaaaaaa tctggccacc accataatca acaaccaggc gtgcaccagg cttcgtcaac 17280 ccgtcaagcc ttgaatgatc cccagacacc accaactcca gcgtcgacaa accattccac 17340 ttcaacgaca acttgagcga ctcaaaaaaa ttgataggcg ccacccgatg atagtctggc 17400 gtaaacaatg ttatctgcgg gacaagacca gccacaatat attcaccaag ccctcaaaaa 17460 cctgtactgc accgacacaa caatggcacc caaaccaacc atctcaatat tcacactctt 17520 agaaccgcca ggcgggatag gcgcaaactc ccactccttc aaacgatcca tcacatcctc 17580 aaacccgttc aacaatgcag actgtttgcg aggatccgta tcaatagtaa tccaatcaaa 17640 ctcctcgaca ggatagtctg atgacacacg caaaccatca atctgcacag accacgaatc 17700 caacggaccc tcaacacgaa tcacaggcca cgcaggcaca tcacccctgt tagacaagtt 17760 atcccagcca gaccccacac ccggtgtcaa caccacagga aacgcggtac catccttgcc 17820 gacagggccg ccacccaacc aatcctgcaa cttcgcgtta ctaaaacgaa acctctgctc 17880 atccccatac caaaacggat cataagccgt caaatgcaac agataacgcg catagccgcg 17940 gttcaccgga tcagttgtga acgtgtcatc agccgaatca aaccggcagt gtagcacacg 18000 ctctttgccg gcaggagtct tcaccgacag ttccccctcc tccccaggag gaaaagcaga 18060 ccacaactcg tcataggctt tcaaaaaacc gtcacgaaac ccgcccgccg gatcctcgtc 18120 gacacccgac accagcaccg gcagcgtcac ctcccggggc ttcacattaa acccgcgcca 18180 ctccgagccg tgcacaccaa catgagtttg agaaaactgc tccacctcag gcatacccag 18240 gccgcgcaac gaatcattca acaacatgac aggagacgac cccgtataat ccgtcaaatg 18300 aagcacacgc tccggagcat tacccaccaa cggaaacatc gtccaatcca cagtcaaacc 18360 ggcacgatca gaagggtcag gaataaacat gcacaacacc ccctcaatca catgtaagcc 18420 aacgcgttca acgcgtcacg ctgctgccgc tcaatccgct tagcaaactc ggcaggatca 18480 ccatacgtcg ggccgttcac attcaccaca acactcttat cattcgcacg ctgatacctg 18540 ccatacgggg taaacgagcc caccgatgat cgcacaccaa accgggcatc aaccgcatca 18600 ggcagacttc cagccacacc agacatagca tccaacgcca aacccgcatt acctgttatc 18660 ccctcagcca aaccggcaac aacctgacgg ccaacctcgt cacgaaacac ccgagacggg 18720 gaatgaatac ccagagcaga cttcgccgcg ttcgcaatct gggaacccat gttacgcaca 18780 gtatccaaca agccactcaa agcactctta ataccgttac ccaaaccaga caccacgtca 18840 cggccagcag acaccaacaa ggaccccata ctacccaagg cacccctaat attgctgggc 18900 agattccgga aaaaacctat cacactatgc acaccgctag acacagccga acccatagca 18960 tgcatagcag aagaagccgc accacgagcc gcgttaaacc cactagaggc tgcgctacga 19020 accctagacg ccatagagcc aaagaacgag cccaccgcgg acgccaccga agacaccaca 19080 ctacgtatcc cgttcatcgc agccgaaaca gcgccacggg ccgcgttaaa ccccgacctc 19140 acatgggagg caaccgacaa accaagccgc gtaaaaaacc ccacaacagc ggcaacgccg 19200 ccagaaatga tcgacttaaa accgcccata aacgccgacg taaacgccct aatacgattc 19260 cagccattca gtatagccga acccatatgc gccacaccag acaccaaatg gcccacaacc 19320 catgagatga cacgggcaac agcagcaatc acacgggcca cagcagacac gacagcacca 19380 acaatacggg caacaaaccc caccacagca gccaccatcg gagccacaac agcaagaata 19440 cgggccacca cctgtatcac aaccgcaaca acctgaacca ccacacgcat aaccgccgca 19500 atcacaggca tcaacgaccg gatcaaacca ataataggtg gcagcacaga catgaccgca 19560 cccaaaatct gctgaatcac aggcatcaac accggcacca actgcatgac cacgccaaca 19620 acctgccgta tcacagccac aacagcctgc aacaccggca tcaacgtagg cagcaacatg 19680 gccgcaacct gcgtcaccat gccaataatc tgcgtgatca caggaaccag acgggccacc 19740 agcataccaa tcacaggcat caactgggca gccaacccgg caaccatacc aataatctgg 19800 gcaaacactg gcgccaacct ggcaaccagc cccgcaacaa tcccgaacag cggctgcaag 19860 gcggccataa tctgccccag ggcctggcca accacagcca caagctgcat cacagcggca 19920 cggaactggg cgttcgtcgc aaacattgcc gcaaacaagc cgatcacaac accgacaggg 19980 ccacccaagg cacggaacac gccgccaagc cccccggcgg cacccttcaa agcaccaaac 20040 gatggtagca gattcttcaa cgacaccgcc aacggggcaa accctgcaac cagttttccc 20100 acacccgcag caacaatacc aaacacggcg gtgccgccag caaacatggc agccaaattc 20160 accttcggaa ccggcaaatg cagcctcgca aaaatgccct tcaactgctc cgccttggcg 20220 cgcatctgtg cattcattcg agtgatcata gcgggcatcc ggttaatcca cgccaaaata 20280 gacggcatca cccgctgaat accctgatca acagaagcaa acaaaggctt cacagaatcc 20340 gtgacagact tgataaccgg attcaacgca acaaaaatct gccgcaaccc gttaagaaac 20400 ggcgccatag ccgtagcacc aagataaccc agggcaccct taacattctt catagcgccc 20460 tcaaacgtct gaccagacgc ctgcgcagca ccacccatac caagcttcat cgcagccgca 20520 aacgtggcaa aatcaatctg ccccttcgac accatctgcg acacctcagc cgacgtttta 20580 cccgtctgcc tggcaagcaa agacaggaca ggcacacccg ccatagtaag ctgcaacatg 20640 tcatcgccct gcaacttacc gcgagccata accgacgtga aaatagcgcc cgtatcctga 20700 aacgacttac ccgaaatata cgacacatcg gcgacagtct tcaacacgtc agtcatctgc 20760 ccgccagact tcacaccaga agcagacaac gcggcagccg tagaagccgc atcccccaga 20820 gcatacgacg tgccagtcac agcctcaata gccgaattca taatcgaaga cgtgtcagaa 20880 gacgtatgac ccaaaccagt cagtttagcc tgcgcctcat cgatagccat agccctagca 20940 ataccgccac caatagtcac atcatagata gacttgaggc ccttcttagc aacattgatg 21000 gcacccatca ttgcggcgcc acccaaagcc aacttcatcc cggaagcaaa aagactaccc 21060 gaacgctgac cctcagccgg cataacaccc gacaactgtt taccaacatc agccttcaaa 21120 ccgggcatct tcgtatacaa cgacacatat gcggaagcaa tctcaccaga catacactat 21180 tcaccccaac acatcaatct cgcgagacac cccgccaccg gcacgaacac gcgccaaaat 21240 atcgtccacc tgcccagacg taaaccttgc cctacgctca tccgtcggcc tcgccacagg 21300 ctccggctgc ccctcactat tagcagacct gtaatgatcc aacacgtcca acaccgccca 21360 ctcgcaccac tcaaacgggc gctgccaacc attgagatgg gccgccaact ggctagacgt 21420 atcagtacac aacacgccag ccagccggac agcctcaccc caacacatta cagggccacc 21480 aacatcataa acagagcaac cgaaccgggt cctccaatca tattcgatgg ccccacgata 21540 atcatcaatc aggccgtgga gccaaactat tcccccaaag aggcaccctt accgtcaggc 21600 ttgtattcca tccactcacg gaaaatctcg gcaacacgaa ccataggaag cccctccaaa 21660 gcctccacag catccgctgg ggcggcagcc tccaacatag aaaacatcac ctcaacctgg 21720 gcgaaatcag ccgactcccc cgactgggca atcttggcgg cacggcgaaa aacacgggca 21780 ggaacagcct gcgccgtctc ctccgcatca gccaacaccc aactgcggtc accaatcttt 21840 aacgtgtaac ctgtgtcact catctatcaa caatccctta taatgtgtat cagttattag 21900 acggcggatt cggatccggc tcaggcttcg gagacggcgg aggagttggg ggagtatcag 21960 cttttaaagc cgtcatccac ccccgaccag acaccgcatc acccttctta ttaatctggg 22020 caggatacgc cttcaacgtc acaccatacc cgtacacttc gccattctta cccttaatct 22080 cgtcacgatc aatcaactca acttcgggga agtagtagcg gataacctga tcgccatcaa 22140 taatatccat caacagggca tgaacacccg tcgtggcacc aggagaaata tcgaacgaac 22200 ccgaatcgga tccggcagta accttcgact gccaaaacag ttcgataacc tccttcttcg 22260 actcgatcag ctggaaagag atttcgatag acgactcggt ggccaccgtg cgaacaacat 22320 ccgcattctg ccaagccttc aaatcatccg ttttacgctc aggcttaatc ttaaacccat 22380 catccgacag ataccctaaa gcagtcaacc catcaggaac cgtcttcaca ccatcaatag 22440 tgtcaccagc gtgagcttta ccaatataga cgtcacccgt aacagcagag cgaacattag 22500 acgctttacg tgttgcagcc atcataaccc ccaaaaaaca atatcaaaca aacaaaatga 22560 aacaatcaat tacgttaagc atttactcgg actctacagg cctacatatc agctcaaaca 22620 acgaatacac atcaaaacgt gcaccatcca ccaacaaatc aggaccagtc gatctcttgc 22680 agtgcactac cgggtcaccg tcaacaccat cagccagcac agcctcaaca cgacgtgcca 22740 acgacatagc ccgatcaggc gtatcagaaa acacgttcac ccgcaaaaac acctgctcac 22800 gaacatgcaa ctcggggccg ccatccaacg ccaaccaaat caagtcaccc tcaaaccggt 22860 caggaacagt gccagtacac ggcacatcag acagccaacc atcatcagcc aacacacgct 22920 tcgcccatac tcttgggtca ccgtaaacga tcacgacgca gccccaatcg acctagccaa 22980 cgtgccatgc ttcgcctcaa tacgcttacc acccttatag gtggtaccaa tcctggccac 23040 agcctcaaca cggtgaacct gaacctccga cgacaacccg ccacgatatt gggccttatc 23100 gaaagcatta ccgcccacat tcgccgatgc ggcacgccgc acacgctcgc cacgctcagc 23160 caacatagcc tgcaccccag aagacttcaa cacctcacgg atacccggca aattaagctt 23220 cacattcaca tcctgagcca ctacctatca gcccttctta cgcttcacat gaatctgcgt 23280 accagcatcc cagccagaca tcggatgatg ccacaccaca ggagacccgt cagcctccca 23340 cacaacaccc ctaatacgcc acctacaacg ataatcagcg cccacaacag gctgcttgaa 23400 cagcatcgac caatgctcat aatccgagtc acggcctgcc gcatcatcct cctgcgacaa 23460 cgaagaatag atggccacat gatggaacac agtctcgaca ggcttagacc agtcttccac 23520 cttgtcgcca agatcatcga cacgaacagt tggttgaagc atcacaaccg tctcgccgta 23580 aggaaaacta gtcatatcat atctcccaca aagggccagc gtagccgtta atattcgacc 23640 cgcacgagca gccgccaccc cacacagtgg aacacacctc agaatgattc acgccaccat 23700 tcatggtcgg tgtaatagtg aacgctttac cagccccacc atcaccttca cacaacttct 23760 tcaacgcagc aatctctgaa ggccacaaca agttcgtggg cgtattagac cgtgtagtct 23820 gggagaacgg ccccgccatc tcatactgca cctgcccaga aaccccggta tcattccagc 23880 gcagcaaagc cctacgtagg atcgccttag ccgcatcctt gtacttgaaa tccggtttag 23940 cgatacaggg ggcgacactg atagccacag cctccacatc ggcgatcatc gcctcaagct 24000 tcccctcagg aatatcggcg aaaggcttaa tatcctcagg cttcaaaatg atacccatca 24060 acaccacccc ctgcacatag tacacattcg cttatcttgt atcagttacc agccggagga 24120 ttaggctcag gcttcggggc cggaggagga gtcggtgcag ccttctcctt cacaacagca 24180 aacgaatcaa gcgactcaat agccacatac aggacagcct ctgcacgaac cataacctca 24240 ttatggccct tcaaatcgcg gccagtctga tccggatcgc catactcgat cagctcgatc 24300 gggaagttac gctggaaccc ccaatgaaca cgagagaaat cgccaacaat agccttaaca 24360 ccagaggcag gcgacatctc cggggcacca gaaacagtcg aagaagcacc aacactcaag 24420 ccacgccaat tatccaggcc ggcgaacccg gcggcaggat acatcggctg accggcaagc 24480 ggagacccct tcggatacac ctcagtagac agggaaaacg agaacgccgg atccaaagca 24540 accccgttag gaacctgcaa accagccccc gcaatcaggc cgacagcctt aacaagatcg 24600 gtcgtggcag aatccgtggc atcaaccgtc ttcttcgtct tatccagcga cactttgaca 24660 gcagcagcag gcttacccgt agcaggatca acaccatgga aagcaatcaa atccacggcg 24720 cgaccaatcg aggcacccag ggcaggcgaa atcagatcct gaagcacacc caaacggtag 24780 tcggcgtcag cccacataaa ctcgtccgag acacgctgct gagtcacaac cttgataggc 24840 tgcgcagtaa acgccgaaac accaaccgaa gcggaaggct taacctcacc ctcgccaaca 24900 atcttagcgc gaggaacacc actaaacacg gcacccttca ccgggccgaa aatcgtcggc 24960 tgctccggcg acagtttcgc caaaacacca gaatcgatag cacggtcacg aaccgcacca 25020 atcatagaac caggaagctc aagcttccct gcagaaagaa aatcgtcagc catcagaaat 25080 catctcctag aattattgac aagagcatcc acaaacgcga caccctcacg tcgtttaaca 25140 tcatcaacgg gggcactccc cgcaagacgg cgcacacccg cgccaccact actatggtcg 25200 atcaaaccct tcaaagcctt agcagactcc atcagtgctt cacggtcgct accgtgcaag 25260 aaagcgacag catcacccga caggccacac tcggcagcca cctcgcgctt cacaccctca 25320 agaacaaacc cgttgatcct gtcttcgagt tcctcattct tgcgacgaag ctcatcaata 25380 gtagatccag aatcatcact cgatgtacga agcttctcca actcggcaaa attactttta 25440 gcacgagact cccatttacg ggcctccgcc ttccaatcag tcccagacga cctatcttcg 25500 ccgtcaccct tcgactgacc gtcaaccttt ttgccatcat ccttcactgc gatgtcaaca 25560 acattatctc cctttccggg aacctcttca ccgctgtcaa cattctgttc ttcaacgttt 25620 tgatcggcca tagcctaacc ttacactcct tgcggaaaac aacacaacat tgttgacccc 25680 cgtgcgggag acaacccgtg caccgataac cggcgatgca caaccggaaa ccatttatct 25740 catgtcgcca acagtacgca tagccttcaa aatattgcca ggcgactgct gcaacccgtg 25800 atcatcaacc cactcgcgag ccttctcata aacccgctga tatgcggtgt ccgcagagct 25860 gggctcccaa cgcccaacaa cctcgaccac cgtacacccg caatgatcat gatacttcga 25920 accaaacggg cgcttaccac cacgcttatg acgccgagta tgaccggtag tgagcgcccg 25980 ctctttggtc gtataatccg acctcgtagc caacatggca caaaaagcac acggatcacc 26040 atcagtcacc ctgcgccacg acctaccctg cgcaccagca gaccactcaa ccgtgtcacg 26100 gccagcattc atgacagccc gattaacacc cgcagccatc gcatcaatcg tatcattcac 26160 cctatccggg tcattattca tcatcttcat agtcgaaaac gacctcgcta aagctgccgc 26220 ggcatcaaac tcgtcataca cgatcaaacc aggatcgaca ccgttcaacc ggcgaaaatc 26280 ttgcacgaat ttagcggcca tagccgctga accgtcatgg ccggcacgct ccaactccac 26340 acacaaacgc acatactgtg tatccgacat cttcccagaa cgccacaaac ggccaagctc 26400 agaataatac cccgcatact ttccggcaaa ccttatcgcc tgccgctgat acccggtagc 26460 agccaaccgc gactcaaccc ccgaagccat ctatcaaacc tcattcgtct gccttgatat 26520 agccccagca agcgccgcca acggatcaga cgactcggca cgatgacgca tcacagcctc 26580 aacctgcaca tcatcaagcc ccaacatctc caacactgta cgagaatcag caggcaaaat 26640 accggcaccc acaagcttcg tcacagcatc cgccgtagca gcccgagtcg gcgtcgaagc 26700 atcacgccac ctcaacccaa catcaccaaa aaaagcagcc tcatccacgc gagcatccaa 26760 cgccttggca gccagaaaac caaccgacag ccagccctga ccaaacgacg tttgacgccg 26820 ctcagcccgc ttcacaagcc gagactcctc cgccgccaac gcctcacccg aaggcggatt 26880 agacgtgata aacccaaaat aacgctcagg caccgcagcc tcaccagcag tcaactgggc 26940 taatagccgc atctgatccg aatacggtgt aggactattg accggaaacg accccacatt 27000 cggcgtgtca ccgtcatcat ccttatccac agcccacact gaagccatag acagcaccca 27060 gccaggctgc gaaaactcgt cagccgacac acccgtaacc caacgctgag ggtaggcata 27120 aaaatcacga ttcacagact ggcccaacaa agtgcgcaca gcctcatccg tgtaagccct 27180 aatagacctc gtaatctcgg agcgcccatc aatcctcgaa gtacggcgac gattcacaac 27240 aggcaccaac ggaaccgcac ccaacacatt ctcaatacgg cccgtctcaa cccactcgcg 27300 agacccacgc cgctccacct gaacaatcac atcaggaagc aacaactccg cctcaacaac 27360 ctcaggatca cacgtctgct gcaccacaag gccagcatca agacgagacc catcggcaga 27420 aaacctgccc gtacaattct tcggagactg cggacgaaca gaaacagtgc catcctcttg 27480 ggggataaca gccacaaacg acaaaccaaa aatcagcgca tcaagatgca catcacacga 27540 agccgtagca agcctgttcg cagcatacac accatccaaa ccgtagccgt caccattcgt 27600 ccagccaagc caatccagac gctcctccaa agcatccaca gcgataccag gccacgacac 27660 aaccgtctgc acccgctgca actccggagg aatagcaacc cccaaatcac gcacccggct 27720 agagccctca tagtagccct caatacggca atgccacgaa gacaaccttt ggatacgatc 27780 aaacatgccc tcaatcagat tcagctcatc cgagttcata ccacactcac ccgcttccta 27840 ccagaccgtt cacgccgctt ctgccgagcc gtcttagccc ccaaaaacgc caacgacaca 27900 gcctccaaag gcacctcgga accatcctta aacgaggaac cccaacccca agcagaaccc 27960 ttacgcttct gcacagccga cctcacagca agctccaaca tgtcacggcg agaatcagcg 28020 cgaggatgag acacaacacc cgaacgcaca ccctccaaaa acgactggca cgcctccaca 28080 tagatgccag tatcggcaac cacaacacca cggcccggaa caccacgatc cgtcaacgcc 28140 ttctgcaaca acaccgcacc cgaaccggca accataattt tattagtgtc gccccaacgc 28200 aacgccaacc agtcagcaag ctgccccaca ccatcaacaa tcgtgccaga cagcccatca 28260 ataacctcaa catgaacacc agcaacagtc ctgccagcac ccgctaaagc cacccgatcc 28320 cccgacctgg aaaacgagac accaaacact ttaccgccaa caagctcaac atcatcaacc 28380 gcagactgag cccacttatc agtcggtatc acagacgtag cagactggcc acgatcccac 28440 caaccaagac gctcccgagc aaaaccggca gcagacatcg actcatgctc atccgagact 28500 gtcccaaaat tcaggcgacg acccagcgca ggattagtat cccccgcaag cttccgccac 28560 tgccgcccca catcatccgg aaccgactca tccggaatcg aaaactccgt ccacgcaatc 28620 cgcttaccac cagacaaagc ctgaccgcgc aaacgaagca caaccgaacc atcagccaaa 28680 ggccccggcg gcgtacccaa aaaaatctgc tgcggatcac ccgaaggagc agcgcttact 28740 gtaggaagca aagcctccaa ctgctcatcc gacaactcct gagcctcatc acacaccaag 28800 tcatcaaccg taaacccgcg agcagacccc cggctacgag ccacaaactc caccgaaccc 28860 caacccggac aaccacactt acgctcaaac gtggcacaat ccggatgatg caacacaata 28920 gcctcctgac cattcgtcgc ccgaatcgac ttcaccatac gagacaagtc aggaaactgc 28980 cgctcattct caaaaaacga cctcaaccgc ataaacgcct tacgagccga cttcaactcg 29040 tgagccgtat gcaaaatacg gcgaccctga atcgtcgcct taaacaactc cacaatctca 29100 aggatcgcat tctttccatt ctggcgaggc acaaacaccc cacacacacc cgaggcaagc 29160 ctgccattac cgccaaccgc aagccaatca tccaacacct gctgctgcca cggatcaggc 29220 gacaacccat acgccctacc aagctcacca gcatccccgc cagcagtcac cgaatacgcc 29280 gcagcaacac gatgacgcgg aacctgagaa ccaacaacac cagacaccta atcaggcccc 29340 cctacgcttc ctgtacctgt caatcatcgc caccgcagaa ccattaccgc gaccaccaga 29400 cgccacatca accgaatacc gatccaacat ggccataaac gccttcacat gagcacgaag 29460 cgaagccacc aaatccgccc ggccctcacg ccacaccaca tcatgaatca ccgcagcatc 29520 aagaagaaac agccactcct catcgctcac atattgcgca cgcgaatcct caccccacac 29580 acgccaccac cgacgcgtct ccccacacca atcacgagac tcaggaagct caggctgcac 29640 cacactcacc accaacacac aacaagaaat gtcgacaaaa cgataaaaca acaaaaggga 29700 ggtatttcac taagccgtac gaggtcttgc acgggtgtgc a 29741 <110> Kyungpook National University Industry-Academic Cooperation Foundation <120> A bacteriophage that kills Propionibacterium acnes <130> NP14-0023 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 29741 <212> DNA <213> Artificial Sequence <220> <223> Bacteriophage Pacnes 2012-15 <400> 1 ggtcttgcac gggtgtgcag ggggtggtcc gggtgggggt ttgcgggttt gtcaccatga 60 aactaatgtt tttgtggttt gttgttggaa ttgaatgttt ggttgtgttc tgttgccttt 120 gcttctgttg catgttctgc agatgatttg gccgttgtcg agggtgttga gtcctcccct 180 gctgacgggt gtgatgtggt cggcttcggg gctggttggt agctggtggg tgtcccaggt 240 gatggtggct ccgcagagtg ggcaggcgac ctggccttgt tgtcgggctt gggtgatgag 300 tcgttgccgc cagcggcggt gggcggagga tgcggtgcgg ttggtgtgtg ccatcacgcc 360 tccgctcccc aatagtgcct ctatgggctc tggttgcctc tgtaacggcc tggaatgtgt 420 tgggggtatg aataccttgc ccttgccccg ctgttcgatt ctaggggcct ttttgtgcgt 480 ttgagggggt gttctgtttg tgtcggggtg tttgttttct cttcctaccc ccacggttgt 540 gagaaagatc acattgcccc ccagcggtgt caaaagaaga aaggacacgg aagaaaacgg 600 gggagtgggt gttcgcactt cacggcttag cgcttggcgc ctagcggtgt agaacacagc 660 caaaacgtgt acacccttaa ggtttttaaa gtcttctaca tataatatac actttaagtc 720 ttacctggcg ttaagggttt acgtgtgaca cgccgtacgc cttcagccga acacgccaag 780 gtttgaagga agaacacggg tagagtgagt gtggggagtg tgcgatggga gcttgcgacc 840 aagcacacga gtcacacggt aaaagatcat cggcgctgat ggtaaaggtt cctcttctcc 900 cctgatgaag aaaagaagag aagagagaaa gaaccaaaga gagtagagaa gtaaagaagt 960 taacccctta gctcttctaa aacttttata acttatataa ttatattata ttataatacc 1020 tataagcttt aagacttata ggttataata ttaaagttta agactgatgg ttaactttaa 1080 gtatttaaag ctttaatgtt ttatagttac ttaaagtatt aaagcttata agtatttata 1140 tttactttaa gttttaaagt cttacacact gatgtaaagt ttatatcctt aagtgctaag 1200 cctttaaggt tttatactta acttaggtgt taaggtttaa agttttaaac gtttaactgt 1260 taaggtttta tatttacttt aagacttaaa ggctttaatg tttatttata accttaagtg 1320 ttaagtactt aaggttactt aaagtgttta aagcttataa gtctttaagt attaatattt 1380 actttaagtg tttaaggctt taaggctgat gccgagccct tgaggggctc ggtgctcagc 1440 gttaaggtct taagggctta gcgctaagcc ttgaagcttt aaagtgtttg gtagactgat 1500 gt; ccagcctatc atatgccacc tgggatgagt caaacacggt ggtttggctc tataggcggg 1620 tttgaggggt gtaaacgggt gtttttggta gtaaaggtcc aaaaattaaa cctaaacttt 1680 tccttaaatt ttcttagagt cttgtaacct ttgagggtgg ttaaggctga aacccctagc 1740 cagaacgggt ttcactccca gacagctgtc acactgtacc cctgtgtcct ttccggacac 1800 gctaggtgtt cagtgctgat gggtgttccc tcaggctttc gagtactcgt cgctaaggct 1860 cctcgtactc tcaagccttc cctgatggcg tgtacccctt tcagggctgt gcctcatcgg 1920 ctgagcctgt tcgggctgat gccgagccct tgaggggctc ggtgctaagt gctcaacccc 1980 tcagtgctaa gaccttaaag cttgaaggtg tgaaggctga tgctccccct tctttcttgt 2040 accgtgtcct tcttcccccc acagtatccc acactgtcca catagttgag gcttagctaa 2100 ccaagatagg tactcatggt ctatgccgag accgctcatc tcatacaagc ctcctgtagg 2160 cgtctagaat cgatcagaat gtgctggggg tataaatacc tagcccccac ccggcaaggc 2220 gctcctaggc gccatgcaga ggctttaaac agcatttctg ggctacactc tctacgctag 2280 atcggcagag tagcctcgag ggtgcacacc aagccaggag gatgtgatac atctcacaca 2340 gtatgagggt gtagattcca tgcccagatg gggtaccccc acttttgcga tgcagacctg 2400 catcagcctg tcaatccatc taccgaacct gctatcaccc agacataccc ctgggacgcc 2460 ctagaagtgg cctagaatcg atcagcaggg tcaaccctat ataatcctac ccccagaaga 2520 tttgaggcgc ttagaggagc aataaaggct taagtgatat acgccacacc ctatgccaca 2580 tccacatgaa acgctcacaa ccgttgagcg tagccttgac cttgatgccc cacctcaacc 2640 atcatgggat cctgtcggca caaccacaca ccccgatgaa aggacaacac gatggcctac 2700 acgctcatca cccccagctt caccaccctc tacaggcaaa ccgaaatcga tccactcaac 2760 ctccacaaca ccatcggaga ctacagtgac aacatcgatc tcgacatggt gcagcgcctc 2820 taccacgccc aagtagaaca atccatacgc ctcatccgcc cacactggat agtcaccctc 2880 gacggagccg tatacgggcc acccgactgg cagtcactca ccgagaaaga agccgaagag 2940 ttgcacgaca tcatcgacat gatcgatctt gactccatca tcgccgcatc aacccgataa 3000 accaacaca aacccgcaac aaccaacaca agagtaaagg acatgatcat gcagaagatc 3060 gccaaccact tcacccagct ctacaccccc acccaggact gccctgagcc tttcgacctg 3120 acacgcctcg aaaacctcca ctgcgaccac atggattttg agggcctcgc cgaagcctac 3180 cggcagcgcg tagagattga actccacaag ctacgccccc acacattcat cgcatccgac 3240 ggcaccgtgt tcagctacga cgagtggaag ccactgacac agacagaggc gacacaactc 3300 tactggaatg tgacacgcat caacatcgga agcctgctcg ccctgttcac ccgataaaac 3360 cccaaccaca cacaacgagc ctagaatcgc ctagaaatac ctgacctata taatcctacc 3420 cccaagggct gaaaggccct aaattagcat taccgccaac cgtataatcg aaaataggag 3480 cacatatgca atggcaatgt cgcaaatgcg ataccacaat catcggatac aagccagaac 3540 actgcacagt ctgccacgag acattcacta gtaccacctc aggcgatatg caccgtgtag 3600 gtgatcacgg ggttaaggaa ggcaccaatc gccgcagatg cctcacggtg gacgagatgc 3660 tcaccaaggg catgcagcgt aacaaactcg gctactggac cagcggcggt acctcatact 3720 gggtgaaaga agcataaccc caagccacac accaaacgct cactgggtat gagcgcacac 3780 ttgacatggg gaaccatcca cgccatgatt aatcatgtca acaacgaaca aaccccagaa 3840 aggggacaac agtcatgaac aagaaaaacg gctacaccat cgcaggcatc acagccgcca 3900 tcatcgcagc cgcctccttc ctcccagccc cagacgacaa cccgccactc acctcacagc 3960 ccgcaccaca ggtaaccaca gccaacaccg aatggacacc tgaaaccgcc cagcagcgca 4020 aggctgagaa gaaagcacgg caagccgcag cagtccactc cctacaagca gaacagcagc 4080 gcgcccaccg gcaagcccaa gccaggggtg aagaaacctc cacaggtctc accatgctca 4140 ccgccgcaca cgcctgcaac cagaaagtca cccagcaagc cgccacacaa ggcgtcaaat 4200 ggaacggcaa cccggacatc gacctcttcc tccacaaagt gatcggcagc aaaaaagaca 4260 ccttctcgat cgcctacggg gctacggcac gccaacccgg cgcctccaag acgcaggtga 4320 aagtcttctg ccaagtctcc ggcacagaag acaacccaca ggtagatgac ctgtccatca 4380 acccagcacg ctaaggacgt ccaatgtctc tcatgtcaga ctacacagcc aaagtcggcc 4440 tctccgatat cggccacatc atccacggcg ccgaactctc actccaaaca gccactgaca 4500 tcgcttccag aatcgacacc ctcaagcaag aaatcaacct cacaaacgaa ataaacacac 4560 tactggaaat cgaagcacaa ctgtacaaca tttataaaac aatcaacacg aaaacaaggg 4620 aatacaatga acaatcacac caaaacaacc ggtgaactcc acagctacga aaccttcttc 4680 accagcctcg cctggatcca aggcgccctc atcacatgga tgtacgcaac cggcaccagc 4740 cacaaagccg ccctcgccat caccgccgcc tgcgccctcg ccaccctgct cggcgcatca 4800 accctcacct accagcccaa agaccacaca tgattacaac acccatactg atcgcagaaa 4860 ccctcgccat cattattctc gccgccgcac tcgcccacaa caacaaccag taacccacgc 4920 ttaaggagca cacacctcat ggatgagccc acccgcatat acaccaaccc caacaccggt 4980 gcccgaaaag aactcaaact gtgcaggctc tccctcatcg accccgcatc cctccacgcc 5040 ctcggcgagg ttgcaggcta cggtgccacc aaatacggcg acaataactg gaccggagga 5100 tacccctggt gtcacagtgt cgacgccctc taccgccatg tgcttgcctg gcagcaagga 5160 aacaacctcg accacgaatc acatctgccg catctggccc acgccgcctg gcactgcctc 5220 gcactcctcg cctaccagca acacgatgcc ggccaagaca cccgcaaccc atggaacaca 5280 cacaaaggcg accagtaatg cccctagcac aaaaacccgc tatcatcgac ctacccgacc 5340 acatctcatt ctcaagcctg acacagtggg tagaatgcgg cgaaaaatgg cgactcatgc 5400 acggctacca cgccacagcc cacacctggt atgccaccat agccggaagc gtcatccacg 5460 ccatcactga aacctgggat aaaaaccttt accaccaaac cgatgcggac atcccaccct 5520 ttggcgacct gttcaccgaa gagatcatcc gccaagtcgg tgatggcgaa gacattcgac 5580 cctcaggacg cacctgcaaa accgtctgcg aaagtggagg accccataag aaagactatg 5640 attggtggat gcactacggg cccatctacg tggaaaggtg gacaacctgg aggaagaggc 5700 acaccgagta tgagatcgcc accatcgacg gccagcccgg catcgaatac cccgtcgaag 5760 ccaccctcga caatgacacc cgggtagtag gatacattga caggatcctc cacaacccca 5820 ccaccggcga atacaccatc ctcgacctca aaaccggggc cataccgcaa ggaaacctgc 5880 aactctacac ctaccggcac ctactccatc tcaaagatga tatacagccg gcgtatggca 5940 tgttttggac acccagccac aaaacaacct ccggcgacac caacaccgga tacgacaccg 6000 ggcccatccc gctagacacc gaggctgcac gccacatcgg ggtcatgtat actagcgcca 6060 tgcaaggaat cgcccacaac gtgttcgtgc cccacgtcac cccgatgtgt aaaggctgcc 6120 ccgtccgaga ctcatgctgg gcctacgggg gcgcgcaagc ctaccggtac cccaccaaaa 6180 ccatcaccca gccacgcaac aacaaggagg ataactgagc atgcaagaca acacagacga 6240 cgaccgattc acgatcaccc tcaaatacgg tggagactac gccgcaccct ggaccgtcat 6300 ccgcggagac accgccgacc aggtaaagaa agccatcatc gacctgttag gcggactcaa 6360 aaacagctcc gcggcaagga actgggacct ggcaaccctg atcgccacag catccatcat 6420 cctccaagac cgatacaacc aggccgccaa agactacgta gacaacatcg catcagaagg 6480 aaacaacacc atcatcgaca aaattaacaa tgccacaagc aaggcacagc tagcagacct 6540 tctgaaacag tacaagaaga ccatcactag taacagtgac gtgtcagagg cgttccgcag 6600 caaacgaaac agcctcaccc gataaaaacc gacacaaacc aacaaaacag taaaggaaac 6660 aacaatggga ctcgccaact accgaaacaa cagcaacagc accttcttca acccgtcccg 6720 aaaccaggac gccaccgcca tcgccttcaa agtccacgat gtggaacaca acactgaagg 6780 atacggcgga caaaccgcag accgcatcta cgctgatgtc accatcttcc acaccctaga 6840 cgacctcaac aacggcaccc cagaaaccat ccccaacgcc atcatcgaaa aagtgcgagg 6900 caacaacgac cggccacact ccatgatccg cgatttagag gcatatcttg gcgaggagca 6960 ggccttcaaa ctagccaccg tgcgcaccaa aaacggcttc aacgcggtcg tactcaaacc 7020 attagacgac gctatctacg acaaggtggc cgaatatgtg gacaaacgcg ataacggcca 7080 gctagacgac accacagcct ctactgacat cgatatcgac tccatctgac catccacaac 7140 caaccgatag acagatagat taaggtcccg atgctctctc tacaacgatc cttcgagaga 7200 gcctcccaaa cagccgccga gctgccccgc ataccacaac tcgcacccct atacgataac 7260 caagacttgc acatccacaa aggggacctg gtgatgattg cggggcgctc aggcagccaa 7320 aaatcagggc tagccatgtt catcacagca atgctcaacc agcccaccct ctacatatca 7380 ggggacatga caccctggga ggcctccaca cgaatcatct cactcaacac ccaacacacc 7440 accacacaga tacaacaaaa catcgacgac tacgggccag aatactatcg agacaccatc 7500 cggcacggcg aacgcatcac attctcattc cagtcaccca tcacctggac agacatcacc 7560 atggagctac aagcctacat ggaaatgtgg aaccgtttcc ccgacatcat cgtcatcgac 7620 aacctgatgg acatccaaga ctgcgagagt gactatcagg cccagcagga agccatgcaa 7680 tggatcacag ccctcggccg cgacacagga tccaccatca tcgtcaccca ccacgcaacc 7740 gacaaaacag gaaccgacat cgaacacccc ccggcacgcc gcgaaatcaa aaacggcctc 7800 tccgaaaaac cacaactcat cctcggagtc tcactctacg gtggcgaaga caacggcaac 7860 gggctcacca tacccgccga agcccgcatc gcagtgttga aacagcgcac cggcaaatcc 7920 agcccagacg gcacccgata cgaaagacta cgagcctacc ccgaatacac attcttcgga 7980 ccactggtag aaaaacagcc atggaacatg accccaacac acaaaggact atcatgtcga 8040 cilgcaatc acgcaaccgc cgggccggag ccgaatggga aacccgactc ctccaccagc 8100 tacgagacac cggccatgat atagagcgcc tccacctcaa cggcagagaa gatgagggag 8160 acctgattct caaaaccggc aacaaaacct atataatcga agcgaaagcc ggccagcagc 8220 atttggccca attcgtgaaa gaagccacaa ccgaggcacg caactatgag caacaccgca 8280 accgagaaaa ccagtccacc ataggactcg ccgtcatgaa acaacgcaac aagccatgga 8340 gcgaagccta tgtggtatca accctcaacg agctcctccc acacctctga cacctgccgc 8400 ctcctcgaca tctaccggat acgctacaac ccgtccaaaa acgagcagca catcctgtgc 8460 ccgttccacg acgaccacca gccctccatg agcatcaacc tcgacaaggg cgtctggtac 8520 tgccacacat gcggtgtcgg aggcggactc gcccaactga aacaacgatt agaagaagaa 8580 aacccgaatg tacgacagca tacgcccata caacattgtg gaacgccgcc gaattcagaa 8640 agcctcggcc ctctacgaaa cccacctcga aaacattctc gacctgctct cagcaagagg 8700 catcagcgaa gaaacagcac gctaccacca ccttggatac atcgacaatg accccatccc 8760 aggccacgaa aactacaacc agtgcatcac catcccctac atgtaccccg tttggggcgg 8820 cccagccgaa atacgaaaaa tgcgtttccg ctgctcactc ccgcacgact gcaaaaccca 8880 caaccacccc aaatacctaa ccccagccgg ggacacaggc tccatctaca acatggccgc 8940 catggccaac ctggcagccg aaatgcacat ttgcgaaggc gaattcgact ccatgatcct 9000 agaacaatgc ggatggccag cagtagccat ccccggcgcc acctcgtggc aaaacttctg 9060 gaccaaattc ttcgaaggct acgaccacat ctacatctgg tccgacccag acaaagcggg 9120 agaccagatg gcccaaaccc tccagacggc actcccccaa gccactcatg tgcccctcac 9180 catcggcgat gtgacagaca cctacctaaa aaccggcaaa acagggttga cacaagccct 9240 caacacagtg ctacaataaa accacaccaa cagcccaaac aaagaaaggt acactaaaac 9300 atcatggatc ccctcgacac gtgccccatc cccaaccggc gcaacattag ccaagcagcc 9360 aggaggcgta tccgcctcgc catctgtgca gaaaaatggg ctgatggtga agaccccacc 9420 tacatcatgc acacctgggg caccacctat gatgggatgc gatccatgat ccgcgccaac 9480 cccgacatta aactacccga cgacatggcc aaacgtttac acaaagtatg ccgggaagcc 9540 taccccaaaa accagccaaa caggcaccga agcggatggg acgcctacga gaaaaactac 9600 tacacccacg aaatactctt cctcgactcg tttaacgtgc cagccctcga aatcctcaac 9660 cggctcgacg tgtcatgggc catgtggaaa caaatcctcg cagagcagca cctgacccgg 9720 ctccagcagg agaccgacaa cgcctgccag tgggcaaacc tgcgaaagca gcaccccgat 9780 aagactgatc aagaaatcac tcagatgatg tatagtaacc aggtgacgtt tagcaaggtg 9840 atgaaaacca tacccgcata aacactcatg acacctgcat agtatttgca cactctttca 9900 caaataggag acatgatggt cgccaaaacc caacacttga tcgacatgca cggggacaac 9960 aacaacgata agtttcccga gcacctacgt gacgtcatgt gcggccgtgc catcatccac 10020 gatgccggcg aagtctcatg gtgcacccgc aaaccaggac acgacggcga ctgccgcaca 10080 ggatggcagc ccaccacaca accgttagga caccatggca accaaaactg aaacactcat 10140 ccaacgatac ggggccaaag ccgccgacgt cctcgccgac aaaaccatcc ccgcctcatg 10200 gctcgcaaaa cagctcaccc aagccggata ccccatctcc gccaccgtca tcaaagacca 10260 cagacgcaaa ctcaaccacc agaaaggaga cacacaatga tcgacaacat tgacaggctc 10320 ctcgcacagc tagcccaaca caacaccgaa gcagacacca tccacgatga tctcgccaac 10380 ggcaccgtac gacgaacacg catctccgaa tggacactcc ccaacggaga aaccggccga 10440 tcaatccaaa aaatcatcga ccaccagcca gaaacagacc catacccggt cgacgaactc 10500 gtagctaagc tagccgaatg gacaccaccc aaaccagaaa ccaacaccca aagcagtgac 10560 gagaccgcgt ttgtcatagg ggcgggcgac ttccaaatcg gcaaaggcat cccccagggt 10620 gaaaccgcac acttcgcaga cgactatctt cgatccctca cagccgccac acactactgg 10680 caacaggcag gcaaacccga acgagtccac atcgcattcc tcggcgacat gatcgaagga 10740 tacgtgtcac aaggaggcaa caacgcctgg cgcacacaaa cacccttgac ggaacaaatc 10800 aggctcaccc gcatggccat gatgcaactc atccaccaat tcgaccactg cgccaacgtg 10860 acggtcacat ccatccccgg aaaccacgga gaagccgtgc gcttcggtaa aggcgtcacc 10920 acctacgacg acagttttga tgtggactgc tgccgcgcca tcgcagaagc ctaccaactc 10980 accaacaact accctaacct ccacttttat ttcccccacc gggacgaaat gaccaccacc 11040 gtcaacgtag ccggggccac catcctgcac gcccacggac accaatggcg caacaaccaa 11100 cactacgaat ggtggcgcgg ccaagaattc cacaacggca ccgtatccca tatactcatg 11160 gcaggacacc gacaccacct ccacatatct gagcaaggac aacgcacctt catccaatgc 11220 ccatccatgg aaggagaatc cgtctggtac cgacacaaga cgggcaccac cggcaacccc 11280 ggactcgtgt gctacactat ccaccataaa acaccaaaca actaccagat agcccgataa 11340 aagagatgcc atgagcagac gaccaaccaa agtccaacaa gccacaaccg ccaactgggg 11400 gtgggcaacc ccccaccacc aacaccagct acacaaagcc tgcaccaaca ttgcgcgcca 11460 ctacccggcc gtcaaccccg acgacctcta ccaagacgca ctcctctaca tagccgtacg 11520 caaccaatac caccaactca caggcaacca gtggacccaa atgtgctacc gtgtagccca 11580 acggctagca aacaaaacag tccaacacct cgacctaccc aaacccgtac acgaaatcac 11640 agccatagcc gacagccaaa ccagcaacta aggagaaccc cccatggtta tcaccatcct 11700 cgacgacgga acccaaacca ccaggctaca aacagtaggc tccaccacca ccgccatcat 11760 caccaacaca gaaacacccg aaaccatcac cgccaaatac accatcgcaa aagatggcac 11820 agccacctac agcatcagcg gaaacaccta cctcggcgac caccaacaca tcatcaaact 11880 catgtacgac tactgccact gcgtaggacg attcgacacc accaacacca gcaacccaga 11940 caacttcgac aacctgttca gggggtgacc agtgaaccga acctacacca cagccgacat 12000 catccaagcc gcccaatgga tctggaacgg cggcccatgg aaaccatcag tcgagccagg 12060 catgccaccc ccaccaaccg cgccacaaca ccacggaaac aacatcgtct ccatgatcga 12120 cctgcagctc gccatcgacg actacaccct cacctgccag ccatccaagc agcggaaacg 12180 gctagcacgg ttggcagcct tccgggaagt atacgggtac gaccaaacat atgcgtcggc 12240 cgcccaacga ttgggtgtca cccggcaaac cgtgaaacag tgggcagacc aaacactgat 12300 gacactcacc gaatacgcaa acagcacata ctacatgcca gacgataacg aaggaatggc 12360 ataacacgat gaacaacaca cacaatatcc cctacaccgc cctcaaaaca gcggtacacc 12420 gcatcgtcca acaacagccc accaacatgc agcagctgga aaacattgtt gacggtgtcg 12480 aaaaccagta ccatgtaccc atctccctcg acaacgtgaa cctcaccatc aaagaagtca 12540 gcctcgacaa ccttgctatc gaccaggaca cgctagacga gtgcagcgaa atcctgtggg 12600 actgcgacag tgcaggacac cccacaaaca accagcagcc gaaggcaagc caggaagcca 12660 gccgacgata tcatgcggtc catcctctgc caccgcgaca accacaaaaa tgttatcggc caggatgttc 12780 tgcaccaggc caacgaaact atctcagcct gcctccacct ggaccagctc atcgaagaca 12840 ccctagacga caacctgtaa aacccctgca gacacaaaaa gagtgcccca gcagcagcca 12900 ccacacaaac atggcagcac cgctggggca ctcttttatc aatattcact tatcacacaa 12960 caggcgattc tatcgtgcaa acctccgact cggctgcacg cctcggcaca tagcccgcaa 13020 caccagtatc gtccatcggc tcgatcatgc caggatccga cacatcaacc aggtgagact 13080 ccactattcc cggatcgtcg ggtggaacaa gcccggcatc aacaaccgta gtcttcggct 13140 tgccagccac aaacgaaggg ttaccaaacg aagtagccac cgacaggaca gcagcaaccg 13200 tggccgtgat cagggcagac tcccacggca aaccgcgaaa cgactccgcc gtataggtga 13260 cacccgccgt cacacccaac acagcaacaa acgtttgaat aaaagttttc agggcacgct 13320 ccaacaggcc caaccaaaac tgtttaccca tcacacatca ccatcacttt ttcaaccggt 13380 taacgtccgc ctcaagccgg gcaagacggc tgcgacactc caacacgtaa taccagacac 13440 tccacagggc atccttagta cgccacagct tccccgtcac cggattcttc acccacgaca 13500 aagcctccac acggcgcgct agatcaccat tctgaacctg aaccacaccc acatcgtgat 13560 gcagcttatt caccgactgg gccacctgcc cagacaactg tttaatctga tcatgtaacg 13620 ccttcacatc agccatactc aactctccac tctctccact gccgccgttg acgacggcca 13680 taaacctgtc ccacggaaac catggccccg gatcgtcatg atccgactga tgccacgcat 13740 ccgtcacatc cacatgcccg cacacgccac gcctgccagc cttcaaatcg gccacagaca 13800 gtttcctctt cggaacacca tgcttgtcac acaactgccg gcacagcaca gcagccttct 13860 ccaccgcagg ccacacccga gggtcaagcc actgctcccg agtataagca tgccccggca 13920 ccctaaacga ggcgtgcgaa cccccatcag cacaaatctc tatacccaaa gaatgcggat 13980 taggtggggc atgccaacca atcgtagact cagacaagca ctgcaccgtc tcagagacat 14040 cgcacacata gtgtgcagaa ccccccgaag aaggactcgc aaaatagttt gctgtagaca 14100 ccgcccgccc tttacgggaa gcggacggaa accccacatc cgggcatgtc gcatgaatca 14160 caaccctatt caccggatga ttagagccgg ccgagtgatg cgccgcagga atgtatctca 14220 ccgcatgtca ccaccaaaca ccactatcaa catcagtaac acccttccac tatcattcat 14280 ttgcgggatg acacggtaac cacaggtgat ggtttcacat cctggcaggc tgcagaaccc 14340 gctatggtag aggccgtacc gtcatcatat ttgacgatca ggcggccccc ggaacagtac 14400 acggacacca cagagcggcc atcacgccca tctttgccat ccttaccgtc cttaccattc 14460 acaccgtcta caccggcaga accctgcaga ccctgaggcc caacagggcc acgctcaccc 14520 tgtgcacctt gcggaccggc agggccacgg ccaccatcag ccccatcagc gccatcccta 14580 cctggcacac catctttgcc atcagcgccg tcaacacctg cacgtcccgg aacaccatca 14640 cggccatcct taccgtcact gccgggcagc ccgtcaggac ctttcacacc attcaaaccc 14700 ggggaaccct gcggaccaac agggccaacc agcccagcag aaccatcaac accattacgg 14760 ccatcaacac cggcaacacc tgcagggcct tgcggtcccc gtacaccggc cgggccaggc 14820 acaccctgca cgctacgctc aacacgttga gcatccacac acaagccaga ctggtgaagc 14880 cgcaccgact cccggccacc agaggcacac gcctgccgca cacggctagc caacccttta 14940 gccgccgtac cattcgactg ggctcgagcc tgctccgaat ccctttgcga agccacagcc 15000 ccgaaacgta aagcaccccc ggcaaccacc gccaacagta caagcgacag gaacaacaac 15060 accatggaag ccttctcaaa cgagcggcgc tgccgcttct cctcctccaa ctccctcaca 15120 attcaccccc caccgctatc aacagtatcc ttcaaaaact cgggcaaatc aggcatcttc 15180 acaggctcaa cattatccgg cagattcgcg ttataacggt gaacaatatg gcgaatattc 15240 cacgtgtatt cttccatagc atcaacctgc gcagacaact gcctcagcct cttcttcgac 15300 ctgtacgtaa ccgcctgaat cgaaccaaga acagtagcga tagcggtaca aagagaggct 15360 acgagtgtgg gtgtaaacca tgacactaca gccccctacc actacaacca ccacaacacg 15420 tcacataccc gcaagccgcg cattacacgc cgacagcaat ccaattagcc accgcaggaa 15480 caccagacgg cttcgaacca tcattcgtaa taaacgccaa accaaaatcc ttggtagtga 15540 tattgtaggc tttcacatca atttgggtgg tacccccagc agccgtggcc atagacgcca 15600 ccaccaccgg cggggtagca aactggcgat caaacggaac agtataggca tacacattcg 15660 aaccgccaaa cttgatagac ttagtgccag tctcaatcct cggggacaac aacatccact 15720 tgtcggcatg gttagcccac acagcccccg aaggcaccat cacccggtca ccctccacag 15780 gggtagggtc acaggcggca gactccccaa acgccaccct agccgctata gcacgcctat 15840 ccagctgctg ctgcaacccg tcagacgaca acaccaaagt cgccaacagc tgctgatgaa 15900 acacgccagg ctcggcacgc aacacgtcac gggcacgctc cgaagagccg ccaggaacaa 15960 tctccaacct ggcagtattc tcctgccaat ccctggacag gacaacatag tcgtaccttg 16020 gcttccccgg acccggaagc tgctccgtca ccgtctcaac actattcgac gtacacatca 16080 ccccgtgagc ccacgcctgc cccggcagga cctcacacaa caccgtggca ccctgaaccg 16140 tagtgccaac cctgaaatcg tcagggccct tcacagacgg catattaccc atcagaccag 16200 acatttgagc ccaatcatac tcggtcaaca caccatcaaa acccttacac acaataccca 16260 caacacaccc ctcacaatta gaacttttgc aaatcccgca cacccgcagc caaaccagcc 16320 acacgccgcg ccaacagggc cgacggatta tcctcataat caccggcaac cggtgtcact 16380 ttcgtccacc cgtcacccgg cgatacacac tccacatcaa tctgccgaac aatctccgcg 16440 atagggccag aacccacatc aacataaatc aaatccccag gcatcagatt gccgggccca 16500 aaacgcaaca catccgactc agccaactcg atcttaaaac cagacgtggc ctgtgattcc 16560 gacaacacct gctcagcctc atcgtaaaga gacaccttct ctgaatccgt gttacgggca 16620 tccttaaaca cctcgacacg atcaaaccag cccccctcgg ccatcgaatc aacatcctca 16680 caaaacagcc gatcccgacc ctcgccgcgc cccccaacaa ccaccgatgt ggccttcggg 16740 gcgtcacgca catactccca cgacacaatc gaacccgact cggacgtcaa cacatgttta 16800 cgcgtcaccg cgggcacaca atcaaacacc aaaccccgct gatcaaactt cgcatcctca 16860 aactggttca ccgaaacagt catatgagcc cacgacaaca ccggcaacaa tttatcggca 16920 aacacgtgaa accgcacctg aaaatcctta atatagcgtc cacgacgctc atcatcgttc 16980 ataaacaaat ccggaggaaa acgccacgca ttatccccca acacctgctt agccaccgac 17040 tccgccgcac ccgaatagtg agcataatca cggtccgcac gccactccga accaaccaaa 17100 ccggggcgat aattcacagg ccacatcaac atacgccaca acagccgaat atcatcctca 17160 cacgtgatag tcacacgcga agaacgccaa ggacccacac catgcaccct acgcacaggc 17220 ccagaaaaaa tctggccacc accataatca acaaccaggc gtgcaccagg cttcgtcaac 17280 ccgtcaagcc ttgaatgatc cccagacacc accaactcca gcgtcgacaa accattccac 17340 ttcaacgaca acttgagcga ctcaaaaaaa ttgataggcg ccacccgatg atagtctggc 17400 gtaaacaatg ttatctgcgg gacaagacca gccacaatat attcaccaag ccctcaaaaa 17460 cctgtactgc accgacacaa caatggcacc caaaccaacc atctcaatat tcacactctt 17520 agaaccgcca ggcgggatag gcgcaaactc ccactccttc aaacgatcca tcacatcctc 17580 aaacccgttc aacaatgcag actgtttgcg aggatccgta tcaatagtaa tccaatcaaa 17640 ctcctcgaca ggatagtctg atgacacacg caaaccatca atctgcacag accacgaatc 17700 caacggaccc tcaacacgaa tcacaggcca cgcaggcaca tcacccctgt tagacaagtt 17760 atcccagcca gaccccacac ccggtgtcaa caccacagga aacgcggtac catccttgcc 17820 gacagggccg ccacccaacc aatcctgcaa cttcgcgtta ctaaaacgaa acctctgctc 17880 atccccatac caaaacggat cataagccgt caaatgcaac agataacgcg catagccgcg 17940 gttcaccgga tcagttgtga acgtgtcatc agccgaatca aaccggcagt gtagcacacg 18000 ctctttgccg gcaggagtct tcaccgacag ttccccctcc tccccaggag gaaaagcaga 18060 ccacaactcg tcataggctt tcaaaaaacc gtcacgaaac ccgcccgccg gatcctcgtc 18120 gacacccgac accagcaccg gcagcgtcac ctcccggggc ttcacattaa acccgcgcca 18180 ctccgagccg tgcacaccaa catgagtttg agaaaactgc tccacctcag gcatacccag 18240 gccgcgcaac gaatcattca acaacatgac aggagacgac cccgtataat ccgtcaaatg 18300 aagcacacgc tccggagcat tacccaccaa cggaaacatc gtccaatcca cagtcaaacc 18360 ggcacgatca gaagggtcag gaataaacat gcacaacacc ccctcaatca catgtaagcc 18420 aacgcgttca acgcgtcacg ctgctgccgc tcaatccgct tagcaaactc ggcaggatca 18480 ccatacgtcg ggccgttcac attcaccaca acactcttat cattcgcacg ctgatacctg 18540 ccatacgggg taaacgagcc caccgatgat cgcacaccaa accgggcatc aaccgcatca 18600 ggcagacttc cagccacacc agacatagca tccaacgcca aacccgcatt acctgttatc 18660 ccctcagcca aaccggcaac aacctgacgg ccaacctcgt cacgaaacac ccgagacggg 18720 gaatgaatac ccagagcaga cttcgccgcg ttcgcaatct gggaacccat gttacgcaca 18780 gtatccaaca agccactcaa agcactctta ataccgttac ccaaaccaga caccacgtca 18840 cggccagcag acaccaacaa ggaccccata ctacccaagg cacccctaat attgctgggc 18900 agattccgga aaaaacctat cacactatgc acaccgctag acacagccga acccatagca 18960 tgcatagcag aagaagccgc accacgagcc gcgttaaacc cactagaggc tgcgctacga 19020 accctagacg ccatagagcc aaagaacgag cccaccgcgg acgccaccga agacaccaca 19080 ctacgtatcc cgttcatcgc agccgaaaca gcgccacggg ccgcgttaaa ccccgacctc 19140 acatgggagg caaccgacaa accaagccgc gtaaaaaacc ccacaacagc ggcaacgccg 19200 ccagaaatga tcgacttaaa accgcccata aacgccgacg taaacgccct aatacgattc 19260 cagccattca gtatagccga acccatatgc gccacaccag acaccaaatg gcccacaacc 19320 catgagatga cacgggcaac agcagcaatc acacgggcca cagcagacac gacagcacca 19380 acaatacggg caacaaaccc caccacagca gccaccatcg gagccacaac agcaagaata 19440 cgggccacca cctgtatcac aaccgcaaca acctgaacca ccacacgcat aaccgccgca 19500 atcacaggca tcaacgaccg gatcaaacca ataataggtg gcagcacaga catgaccgca 19560 cccaaaatct gctgaatcac aggcatcaac accggcacca actgcatgac cacgccaaca 19620 acctgccgta tcacagccac aacagcctgc aacaccggca tcaacgtagg cagcaacatg 19680 gccgcaacct gcgtcaccat gccaataatc tgcgtgatca caggaaccag acgggccacc 19740 agcataccaa tcacaggcat caactgggca gccaacccgg caaccatacc aataatctgg 19800 gcaaacactg gcgccaacct ggcaaccagc cccgcaacaa tcccgaacag cggctgcaag 19860 gcggccataa tctgccccag ggcctggcca accacagcca caagctgcat cacagcggca 19920 cggaactggg cgttcgtcgc aaacattgcc gcaaacaagc cgatcacaac accgacaggg 19980 ccacccaagg cacggaacac gccgccaagc cccccggcgg cacccttcaa agcaccaaac 20040 gatggtagca gattcttcaa cgacaccgcc aacggggcaa accctgcaac cagttttccc 20100 acacccgcag caacaatacc aaacacggcg gtgccgccag caaacatggc agccaaattc 20160 accttcggaa ccggcaaatg cagcctcgca aaaatgccct tcaactgctc cgccttggcg 20220 cgcatctgtg cattcattcg agtgatcata gcgggcatcc ggttaatcca cgccaaaata 20280 gacggcatca cccgctgaat accctgatca acagaagcaa acaaaggctt cacagaatcc 20340 gtgacagact tgataaccgg attcaacgca acaaaaatct gccgcaaccc gttaagaaac 20400 ggcgccatag ccgtagcacc aagataaccc agggcaccct taacattctt catagcgccc 20460 tcaaacgtct gaccagacgc ctgcgcagca ccacccatac caagcttcat cgcagccgca 20520 aacgtggcaa aatcaatctg ccccttcgac accatctgcg acacctcagc cgacgtttta 20580 cccgtctgcc tggcaagcaa agacaggaca ggcacacccg ccatagtaag ctgcaacatg 20640 tcatcgccct gcaacttacc gcgagccata accgacgtga aaatagcgcc cgtatcctga 20700 aacgacttac ccgaaatata cgacacatcg gcgacagtct tcaacacgtc agtcatctgc 20760 ccgccagact tcacaccaga agcagacaac gcggcagccg tagaagccgc atcccccaga 20820 gcatacgacg tgccagtcac agcctcaata gccgaattca taatcgaaga cgtgtcagaa 20880 gacgtatgac ccaaaccagt cagtttagcc tgcgcctcat cgatagccat agccctagca 20940 ataccgccac caatagtcac atcatagata gacttgaggc ccttcttagc aacattgatg 21000 gcacccatca ttgcggcgcc acccaaagcc aacttcatcc cggaagcaaa aagactaccc 21060 gaacgctgac cctcagccgg cataacaccc gacaactgtt taccaacatc agccttcaaa 21120 ccgggcatct tcgtatacaa cgacacatat gcggaagcaa tctcaccaga catacactat 21180 tcaccccaac acatcaatct cgcgagacac cccgccaccg gcacgaacac gcgccaaaat 21240 atcgtccacc tgcccagacg taaaccttgc cctacgctca tccgtcggcc tcgccacagg 21300 ctccggctgc ccctcactat tagcagacct gtaatgatcc aacacgtcca acaccgccca 21360 ctcgcaccac tcaaacgggc gctgccaacc attgagatgg gccgccaact ggctagacgt 21420 atcagtacac aacacgccag ccagccggac agcctcaccc caacacatta cagggccacc 21480 aacatcataa acagagcaac cgaaccgggt cctccaatca tattcgatgg ccccacgata 21540 atcatcaatc aggccgtgga gccaaactat tcccccaaag aggcaccctt accgtcaggc 21600 ttgtattcca tccactcacg gaaaatctcg gcaacacgaa ccataggaag cccctccaaa 21660 gcctccacag catccgctgg ggcggcagcc tccaacatag aaaacatcac ctcaacctgg 21720 gcgaaatcag ccgactcccc cgactgggca atcttggcgg cacggcgaaa aacacgggca 21780 ggaacagcct gcgccgtctc ctccgcatca gccaacaccc aactgcggtc accaatcttt 21840 aacgtgtaac ctgtgtcact catctatcaa caatccctta taatgtgtat cagttattag 21900 acggcggatt cggatccggc tcaggcttcg gagacggcgg aggagttggg ggagtatcag 21960 cttttaaagc cgtcatccac ccccgaccag acaccgcatc acccttctta ttaatctggg 22020 caggatacgc cttcaacgtc acaccatacc cgtacacttc gccattctta cccttaatct 22080 cgtcacgatc aatcaactca acttcgggga agtagtagcg gataacctga tcgccatcaa 22140 taatatccat caacagggca tgaacacccg tcgtggcacc aggagaaata tcgaacgaac 22200 ccgaatcgga tccggcagta accttcgact gccaaaacag ttcgataacc tccttcttcg 22260 actcgatcag ctggaaagag atttcgatag acgactcggt ggccaccgtg cgaacaacat 22320 ccgcattctg ccaagccttc aaatcatccg ttttacgctc aggcttaatc ttaaacccat 22380 catccgacag ataccctaaa gcagtcaacc catcaggaac cgtcttcaca ccatcaatag 22440 tgtcaccagc gtgagcttta ccaatataga cgtcacccgt aacagcagag cgaacattag 22500 acgctttacg tgttgcagcc atcataaccc ccaaaaaaca atatcaaaca aacaaaatga 22560 aacaatcaat tacgttaagc atttactcgg actctacagg cctacatatc agctcaaaca 22620 acgaatacac atcaaaacgt gcaccatcca ccaacaaatc aggaccagtc gatctcttgc 22680 agtgcactac cgggtcaccg tcaacaccat cagccagcac agcctcaaca cgacgtgcca 22740 acgacatagc ccgatcaggc gtatcagaaa acacgttcac ccgcaaaaac acctgctcac 22800 gaacatgcaa ctcggggccg ccatccaacg ccaaccaaat caagtcaccc tcaaaccggt 22860 caggaacagt gccagtacac ggcacatcag acagccaacc atcatcagcc aacacacgct 22920 tcgcccatac tcttgggtca ccgtaaacga tcacgacgca gccccaatcg acctagccaa 22980 cgtgccatgc ttcgcctcaa tacgcttacc acccttatag gtggtaccaa tcctggccac 23040 agcctcaaca cggtgaacct gaacctccga cgacaacccg ccacgatatt gggccttatc 23100 gaaagcatta ccgcccacat tcgccgatgc ggcacgccgc acacgctcgc cacgctcagc 23160 caacatagcc tgcaccccag aagacttcaa cacctcacgg atacccggca aattaagctt 23220 cacattcaca tcctgagcca ctacctatca gcccttctta cgcttcacat gaatctgcgt 23280 accagcatcc cagccagaca tcggatgatg ccacaccaca ggagacccgt cagcctccca 23340 cacaacaccc ctaatacgcc acctacaacg ataatcagcg cccacaacag gctgcttgaa 23400 cagcatcgac caatgctcat aatccgagtc acggcctgcc gcatcatcct cctgcgacaa 23460 cgaagaatag atggccacat gatggaacac agtctcgaca ggcttagacc agtcttccac 23520 cttgtcgcca agatcatcga cacgaacagt tggttgaagc atcacaaccg tctcgccgta 23580 aggaaaacta gtcatatcat atctcccaca aagggccagc gtagccgtta atattcgacc 23640 cgcacgagca gccgccaccc cacacagtgg aacacacctc agaatgattc acgccaccat 23700 tcatggtcgg tgtaatagtg aacgctttac cagccccacc atcaccttca cacaacttct 23760 tcaacgcagc aatctctgaa ggccacaaca agttcgtggg cgtattagac cgtgtagtct 23820 gggagaacgg ccccgccatc tcatactgca cctgcccaga aaccccggta tcattccagc 23880 gcagcaaagc cctacgtagg atcgccttag ccgcatcctt gtacttgaaa tccggtttag 23940 cgatacaggg ggcgacactg atagccacag cctccacatc ggcgatcatc gcctcaagct 24000 tcccctcagg aatatcggcg aaaggcttaa tatcctcagg cttcaaaatg atacccatca 24060 acaccacccc ctgcacatag tacacattcg cttatcttgt atcagttacc agccggagga 24120 ttaggctcag gcttcggggc cggaggagga gtcggtgcag ccttctcctt cacaagca 24180 aacgaatcaa gcgactcaat agccacatac aggacagcct ctgcacgaac cataacctca 24240 ttatggccct tcaaatcgcg gccagtctga tccggatcgc catactcgat cagctcgatc 24300 gggaagttac gctggaaccc ccaatgaaca cgagagaaat cgccaacaat agccttaaca 24360 ccagaggcag gcgacatctc cggggcacca gaaacagtcg aagaagcacc aacactcaag 24420 ccacgccaat tatccaggcc ggcgaacccg gcggcaggat acatcggctg accggcaagc 24480 ggagacccct tcggatacac ctcagtagac agggaaaacg agaacgccgg atccaaagca 24540 accccgttag gaacctgcaa accagccccc gcaatcaggc cgacagcctt aacaagatcg 24600 gtcgtggcag aatccgtggc atcaaccgtc ttcttcgtct tatccagcga cactttgaca 24660 gcagcagcag gcttacccgt agcaggatca acaccatgga aagcaatcaa atccacggcg 24720 cgaccaatcg aggcacccag ggcaggcgaa atcagatcct gaagcacacc caaacggtag 24780 tcggcgtcag cccacataaa ctcgtccgag acacgctgct gagtcacaac cttgataggc 24840 tgcgcagtaa acgccgaaac accaaccgaa gcggaaggct taacctcacc ctcgccaaca 24900 atcttagcgc gaggaacacc actaaacacg gcacccttca ccgggccgaa aatcgtcggc 24960 tgctccggcg acagtttcgc caaaacacca gaatcgatag cacggtcacg aaccgcacca 25020 atcatagaac caggaagctc aagcttccct gcagaaagaa aatcgtcagc catcagaaat 25080 catctcctag aattattgac aagagcatcc acaaacgcga caccctcacg tcgtttaaca 25140 tcatcaacgg gggcactccc cgcaagacgg cgcacacccg cgccaccact actatggtcg 25200 atcaaaccct tcaaagcctt agcagactcc atcagtgctt cacggtcgct accgtgcaag 25260 aaagcgacag catcacccga caggccacac tcggcagcca cctcgcgctt cacaccctca 25320 agaacaaacc cgttgatcct gtcttcgagt tcctcattct tgcgacgaag ctcatcaata 25380 gtagatccag aatcatcact cgatgtacga agcttctcca actcggcaaa attactttta 25440 gcacgagact cccatttacg ggcctccgcc ttccaatcag tcccagacga cctatcttcg 25500 ccgtcaccct tcgactgacc gtcaaccttt ttgccatcat ccttcactgc gatgtcaaca 25560 acattatctc cctttccggg aacctcttca ccgctgtcaa cattctgttc ttcaacgttt 25620 tgatcggcca tagcctaacc ttacactcct tgcggaaaac aacacaacat tgttgacccc 25680 cgtgcgggag acaacccgtg caccgataac cggcgatgca caaccggaaa ccatttatct 25740 catgtcgcca acagtacgca tagccttcaa aatattgcca ggcgactgct gcaacccgtg 25800 atcatcaacc cactcgcgag ccttctcata aacccgctga tatgcggtgt ccgcagagct 25860 gggctcccaa cgcccaacaa cctcgaccac cgtacacccg caatgatcat gatacttcga 25920 accaaacggg cgcttaccac cacgcttatg acgccgagta tgaccggtag tgagcgcccg 25980 ctctttggtc gtataatccg acctcgtagc caacatggca caaaaagcac acggatcacc 26040 atcagtcacc ctgcgccacg acctaccctg cgcaccagca gaccactcaa ccgtgtcacg 26100 gccagcattc atgacagccc gattaacacc cgcagccatc gcatcaatcg tatcattcac 26160 cctatccggg tcattattca tcatcttcat agtcgaaaac gacctcgcta aagctgccgc 26220 ggcatcaaac tcgtcataca cgatcaaacc aggatcgaca ccgttcaacc ggcgaaaatc 26280 ttgcacgaat ttagcggcca tagccgctga accgtcatgg ccggcacgct ccaactccac 26340 acacaaacgc acatactgtg tatccgacat cttcccagaa cgccacaaac ggccaagctc 26400 cccgcatact agccaaccgc gactcaaccc ccgaagccat ctatcaaacc tcattcgtct gccttgatat 26520 agccccagca agcgccgcca acggatcaga cgactcggca cgatgacgca tcacagcctc 26580 aacctgcaca tcatcaagcc ccaacatctc caacactgta cgagaatcag caggcaaaat 26640 accggcaccc acaagcttcg tcacagcatc cgccgtagca gcccgagtcg gcgtcgaagc 26700 atcacgccac ctcaacccaa catcaccaaa aaaagcagcc tcatccacgc gagcatccaa 26760 cgccttggca gccagaaaac caaccgacaga ccagccctga ccaaacgacg tttgacgccg 26820 ctcagcccgc ttcacaagcc gagactcctc cgccgccaac gcctcacccg aaggcggatt 26880 agacgtgata aacccaaaat aacgctcagg caccgcagcc tcaccagcag tcaactgggc 26940 taatagccgc atctgatccg aatacggtgt aggactattg accggaaacg accccacatt 27000 cggcgtgtca ccgtcatcat ccttatccac agcccacact gaagccatag acagcaccca 27060 gccaggctgc gaaaactcgt cagccgacac acccgtaacc caacgctgag ggtaggcata 27120 aaaatcacga ttcacagact ggcccaacaa agtgcgcaca gcctcatccg tgtaagccct 27180 aatagacctc gtaatctcgg agcgcccatc aatcctcgaa gtacggcgac gattcacaac 27240 aggcaccaac ggaaccgcac ccaacacatt ctcaatacgg cccgtctcaa cccactcgcg 27300 agacccacgc cgctccacct gaacaatcac atcaggaagc aacaactccg cctcaacaac 27360 ctcaggatca cacgtctgct gcaccacaag gccagcatca agacgagacc catcggcaga 27420 aaacctgccc gtacaattct tcggagactg cggacgaaca gaaacagtgc catcctcttg 27480 ggggataaca gccacaaacg acaaaccaaa aatcagcgca tcaagatgca catcacacga 27540 agccgtagca agcctgttcg cagcatacac accatccaaa ccgtagccgt caccattcgt 27600 ccagccaagc caatccagac gctcctccaa agcatccaca gcgataccag gccacgacac 27660 aaccgtctgc acccgctgca actccggagg aatagcaacc cccaaatcac gcacccggct 27720 agagccctca tagtagccct caatacggca atgccacgaa gacaaccttt ggatacgatc 27780 aaacatgccc tcaatcagat tcagctcatc cgagttcata ccacactcac ccgcttccta 27840 ccagaccgtt cacgccgctt ctgccgagcc gtcttagccc ccaaaaacgc caacgacaca 27900 gcctccaaag gcacctcgga accatcctta aacgaggaac cccaacccca agcagaaccc 27960 ttacgcttct gcacagccga cctcacagca agctccaaca tgtcacggcg agaatcagcg 28020 cgaggatgag acacaacacc cgaacgcaca ccctccaaaa acgactggca cgcctccaca 28080 tagatgccag tatcggcaac cacaacacca cggcccggaa caccacgatc cgtcaacgcc 28140 ttctgcaaca acaccgcacc cgaaccggca accataattt tattagtgtc gccccaacgc 28200 aacgccaacc agtcagcaag ctgccccaca ccatcaacaa tcgtgccaga cagcccatca 28260 ataacctcaa catgaacacc agcaacagtc ctgccagcac ccgctaaagc cacccgatcc 28320 cccgacctgg aaaacgagac accaaacact ttaccgccaa caagctcaac atcatcaacc 28380 gcagactgag cccacttatc agtcggtatc acagacgtag cagactggcc acgatcccac 28440 caaccaagac gctcccgagc aaaaccggca gcagacatcg actcatgctc atccgagact 28500 gtcccaaaat tcaggcgacg acccagcgca ggattagtat cccccgcaag cttccgccac 28560 tgccgcccca catcatccgg aaccgactca tccggaatcg aaaactccgt ccacgcaatc 28620 cgcttaccac cagacaaagc ctgaccgcgc aaacgaagca caaccgaacc atcagccaaa 28680 ggccccggcg gcgtacccaa aaaaatctgc tgcggatcac ccgaaggagc agcgcttact 28740 gtaggaagca aagcctccaa ctgctcatcc gacaactcct gagcctcatc acacaccaag 28800 tcatcaaccg taaacccgcg agcagacccc cggctacgag ccacaaactc caccgaaccc 28860 caacccggac aaccacactt acgctcaaac gtggcacaat ccggatgatg caacacaata 28920 gcctcctgac cattcgtcgc ccgaatcgac ttcaccatac gagacaagtc aggaaactgc 28980 cgctcattct caaaaaacga cctcaaccgc ataaacgcct tacgagccga cttcaactcg 29040 tgagccgtat gcaaaatacg gcgaccctga atcgtcgcct taaacaactc cacaatctca 29100 aggatcgcat tctttccatt ctggcgaggc acaaacaccc cacacacacc cgaggcaagc 29160 ctgccattac cgccaaccgc aagccaatca tccaacacct gctgctgcca cggatcaggc 29220 gacaacccat acgccctacc aagctcacca gcatccccgc cagcagtcac cgaatacgcc 29280 gcagcaacac gatgacgcgg aacctgagaa ccaacaacac cagacaccta atcaggcccc 29340 cctacgcttc ctgtacctgt caatcatcgc caccgcagaa ccattaccgc gaccaccaga 29400 cgccacatca accgaatacc gatccaacat ggccataaac gccttcacat gagcacgaag 29460 cgaagccacc aaatccgccc ggccctcacg ccacaccaca tcatgaatca ccgcagcatc 29520 aagaagaaac agccactcct catcgctcac atattgcgca cgcgaatcct caccccacac 29580 acgccaccac cgacgcgtct ccccacacca atcacgagac tcaggaagct caggctgcac 29640 cacactcacc accaacacac aacaagaaat gtcgacaaaa cgataaaaca acaaaaggga 29700 ggtatttcac taagccgtac gaggtcttgc acgggtgtgc a 29741

Claims (9)

여드름균(Propionibacterium acnes)에 대한 특이적 사멸능을 갖는 시포비리대 과(Siphoviridae)의 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP).
Acne bacteria ( Propionibacterium Pacnes 2012-15 (Accession No .: KCTC 12569BP) of the Siphoviridae bacteriophage having a specific killing activity against the acnes .
제 1항에 있어서, 상기 박테리오파지는 서열번호 1로 표시되는 전장 유전체를 갖는 것을 특징으로 하는 박테리오파지 Pacnes 2012-15(기탁번호:KCTC 12569BP).
The bacteriophage Pacnes 2012-15 (Accession No .: KCTC 12569BP) according to claim 1, wherein said bacteriophage has a full-length dielectric represented by SEQ ID NO: 1.
제 1항 또는 제 2항의 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택된 질환의 예방 및 치료용 약학적 조성물.
Pharmaceuticals for the prophylaxis and treatment of diseases selected from the group consisting of inflammation, acne, cottonseed, papules, rashes, erythema blisters, nodules, cysts and false cysts containing the bacteriophage Pacnes 2012-15 of claim 1 or 2 as an active ingredient Composition.
삭제delete 제 1항 또는 제 2항의 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택된 피부 트러블 개선용 화장료 조성물.
A cosmetic composition for improving skin troubles selected from the group consisting of inflammation, acne, cottonseed, papule, rash, erythema blister, nodule, cyst and false pouch containing the bacteriophage Pacnes 2012-15 of claim 1 or 2 as an active ingredient.
삭제delete 제 1항 또는 제 2항의 박테리오파지 Pacnes 2012-15를 유효성분으로 포함하는 염증, 여드름, 면포, 구진, 발진, 고름물집, 결절, 낭종 및 거짓낭으로 이루어진 군에서 선택된 피부 트러블 개선용 의약외품.
A quasi-drug for improving skin troubles selected from the group consisting of inflammation, acne, cottonseed, papules, rash, erythema blisters, nodules, cysts and false cysts containing the bacteriophage Pacnes 2012-15 as an active ingredient of claim 1 or 2.
삭제delete 삭제delete
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US20090047254A1 (en) 2005-07-12 2009-02-19 The University Of Leeds Bacteriophage and their uses

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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090047254A1 (en) 2005-07-12 2009-02-19 The University Of Leeds Bacteriophage and their uses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Lood R. et al, BMC Microbiology 8:pp.139-148 (2008. 8.15.)*

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