JP2021112152A - バクテリオファージ由来エンドライシン - Google Patents
バクテリオファージ由来エンドライシン Download PDFInfo
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- JP2021112152A JP2021112152A JP2020006483A JP2020006483A JP2021112152A JP 2021112152 A JP2021112152 A JP 2021112152A JP 2020006483 A JP2020006483 A JP 2020006483A JP 2020006483 A JP2020006483 A JP 2020006483A JP 2021112152 A JP2021112152 A JP 2021112152A
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Abstract
Description
(1)以下の(a)〜(d)のいずれかに示す、ブドウ球菌に対するエンドライシンタンパク質。
(a) 配列番号1に示すアミノ酸配列からなるタンパク質
(b) 配列番号1に示すアミノ酸配列において、1若しくは数個のアミノ酸が欠失、置換、挿入及び/又は付加されたアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(c) 配列番号1に示すアミノ酸配列と80%以上の配列同一性を有するアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(d) 配列番号1に示すアミノ酸配列の部分配列を含み、かつペプチドグリカン分解活性を有するタンパク質
(2)以下の(e)〜(h)のいずれかに示す、ブドウ球菌に対するエンドライシンタンパク質。
(e) 配列番号2に示すアミノ酸配列からなるタンパク質
(f) 配列番号2に示すアミノ酸配列において、1若しくは数個のアミノ酸が欠失、置換、挿入及び/又は付加されたアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(g) 配列番号2に示すアミノ酸配列と80%以上の配列同一性を有するアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(h) 配列番号2に示すアミノ酸配列の部分配列を含み、かつペプチドグリカン分解活性を有するタンパク質
(3)(1)又は(2)に記載のエンドライシンタンパク質を含有する抗ブドウ球菌剤。
(4)ブドウ球菌感染症の治療及び/又は予防のための、(3)に記載の抗ブドウ球菌剤。
(5)(3)に記載の抗ブドウ球菌剤を含有する医薬品。
(6)(3)に記載の抗ブドウ球菌剤を含有する飲食品又は飼料。
(7)(3)に記載の抗ブドウ球菌剤を含有する抗菌洗浄剤組成物。
(8)(1)又は(2)に記載のエンドライシンタンパク質をコードする遺伝子を含むポリヌクレオチド。
(9)(8)に記載のポリヌクレオチドを含むベクター。
(10)(9)に記載のベクターで形質転換された宿主細胞を培養し、該培養物から(1)
又は(2)に記載のエンドライシンタンパク質を回収することを含む、ブドウ球菌に対するエンドライシンタンパク質の製造方法。
本発明のエンドライシンタンパク質は、未分類かつゲノム配列が明らかとなっていないファージS6から分離した2種のエンドライシンタンパク質である。ファージS6は、殆どのブドウ球菌種に感染可能であることから、そのファージにコードされるエンドライシンは、すべてのブドウ球菌種のペプチドグリカン分解活性を有すると考えられる。
本発明のエンドライシンタンパク質は、上記のとおり、ブドウ球菌に対してペプチドグリカン分解活性を示すことから、これを有効成分とする抗ブドウ球菌剤として提供できる。ここで、「抗ブドウ球菌」には、ブドウ球菌の可逆的な増殖抑制と不可逆的な増殖抑制(すなわち殺菌)の両方が含まれる。
(1)ゲノム配列解読
ファージS6について、次世代シークエンサーを利用してゲノム配列を解読するために、大量培養を行った。黄色ブドウ球菌株SA27をLB培地(1%トリプトン、0.5%酵母エキス、1%塩化ナトリウム、pH7.8)に植菌し、ファージS6を加え、30℃で好気培養を行った。ファージ液をポリエチレングリコールで濃縮し、その濃縮液をCsCl密度勾配超遠心法で精製した。精製したファージ液を超遠心でペレットにし、ファージペレット試料からゲノムDNAを抽出した。
ファージゲノムの系統解析には、VipTreeを使用した。ウイルスゲノムはNCBIからダウンロードした。ダウンロードしたウイルスゲノムのリストを表1−1、表1−2に示す。
まず、ファージS6ゲノムのアノテーションはDfast(https://dfast.nig.ac.jp/dfc/)を使用して行い、ゲノム配列上のORFを推定した。その結果、272個の遺伝子が予想された。
黄色ブドウ球菌のエンドライシンの系統解析には、MEGA X(https://www.megasoftware.net/)を使用した。エンドライシンのタンパク質配列は、NCBIからダウンロードした。エンドライシンS6 ORF93とS6 ORF94の系統解析結果を図2に示す。なお、図2中のA〜Hのエンドライシンのリストを下記表2−1及び表2−2に示す。
(1)人工合成遺伝子の作製
S6 ORF93、S6 ORF94のGC含量はそれぞれ36.09%、34.70%であった。大腸菌で効率よく発現させるため、コドン使用量の補正を行う必要があると考えた。そのため、VecterBuilder (https://www.vectorbuilder.jp/tool/codon-optimization.html)を使用して、コドン使用量を補正した人工合成遺伝子dS6 ORF93 (GC 47.92%)、dS6 ORF94(GC 49.05%)を作製した。配列番号5は、S6 ORF93コード領域を併記したdS6 ORF93の塩基配列、配列番号6は、S6 ORF94コード領域を併記したdS6 ORF94の塩基配列を示す。
作製したdS6 ORF93とdS6 ORF94の人工合成遺伝子のクローニングをpColdII(Takara Bio;N末端に6×His を付加できるタンパク質発現用ベクター)とpColdV(pCold IIIを改変;C末端に6×Hisが付加できるタンパク質発現用ベクター)を用いて行った。タンパク質発現のために、NiCo21 Competent E.coli (New England BioLabs)を使用して形質転換を行い、形質転換大腸菌NiCo21 [pColdII S6 orf93]、NiCo21 [pColdII S6 orf94]、NiCo21 [pColdV S6 orf93]、NiCo21 [pColdV S6 orf94]を得た。形質転換大腸菌の培養をするための培地には、アンピシリン(100 μg/mL)添加LB培地を使用した。
37℃で培養した黄色ブドウ球菌株SA27に4%SDSを加え、オートクレーブした。PBSで5回洗浄し、ペプチドグリカンの調製を行った。ペプチドグリカンはPBSで懸濁した。実施例2で調製した組換えエンドライシンS6 ORF93 pColdII、S6 ORF94 pColdII、S6 ORF93 pColdV各10μL(0.2mg/mL)に、上記のペプチドグリカン90μLを96穴プレート内で混和したサンプルについて経時的に濁度(OD595)を測定した。ネガティブコントロールとしてPBSを使用した。ペプチドグリカン分解活性測定結果を図4に示す。図4に示されるように、組換えエンドライシンとペプチドグリカンを混和したサンプルはいずれも濁度が減少していることから、S6 ORF93はS6 ORF94はペプチドグリカン分解能を有することが確認できた。
Claims (10)
- 以下の(a)〜(d)のいずれかに示す、ブドウ球菌に対するエンドライシンタンパク質。
(a) 配列番号1に示すアミノ酸配列からなるタンパク質
(b) 配列番号1に示すアミノ酸配列において、1若しくは数個のアミノ酸が欠失、置換、挿入及び/又は付加されたアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(c) 配列番号1に示すアミノ酸配列と80%以上の配列同一性を有するアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(d) 配列番号1に示すアミノ酸配列の部分配列を含み、かつペプチドグリカン分解活性を有するタンパク質 - 以下の(e)〜(h)のいずれかに示す、ブドウ球菌に対するエンドライシンタンパク質。
(e) 配列番号2に示すアミノ酸配列からなるタンパク質
(f) 配列番号2に示すアミノ酸配列において、1若しくは数個のアミノ酸が欠失、置換、挿入及び/又は付加されたアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(g) 配列番号2に示すアミノ酸配列と80%以上の配列同一性を有するアミノ酸配列からなり、かつペプチドグリカン分解活性を有するタンパク質
(h) 配列番号2に示すアミノ酸配列の部分配列を含み、かつペプチドグリカン分解活性を有するタンパク質 - 請求項1又は2に記載のエンドライシンタンパク質を含有する抗ブドウ球菌剤。
- ブドウ球菌感染症の治療及び/又は予防のための、請求項3に記載の抗ブドウ球菌剤。
- 請求項3に記載の抗ブドウ球菌剤を含有する医薬品。
- 請求項3に記載の抗ブドウ球菌剤を含有する飲食品又は飼料。
- 請求項3に記載の抗ブドウ球菌剤を含有する抗菌洗浄剤組成物。
- 請求項1又は2に記載のエンドライシンタンパク質をコードする遺伝子を含むポリヌクレオチド。
- 請求項8に記載のポリヌクレオチドを含むベクター。
- 請求項9に記載のベクターで形質転換された宿主細胞を培養し、該培養物から請求項1又は2に記載のエンドライシンタンパク質を回収することを含む、ブドウ球菌に対するエンドライシンタンパク質の製造方法。
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Citations (4)
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JP2010536354A (ja) * | 2007-08-22 | 2010-12-02 | ヒグロス インベスト ゲーエムベーハー | ヒトおよび動物のブドウ球菌(Staphylococcus)感染症において使用するための新しいタンパク質 |
JP2014519815A (ja) * | 2011-05-04 | 2014-08-21 | マイクレオス ヒューマン ヘルス ビー.ブイ. | ポリペプチド |
JP2018527933A (ja) * | 2015-09-15 | 2018-09-27 | マイクレオス ヒューマン ヘルス ビー.ブイ.Micreos Human Health B.V. | 新規なエンドリシンポリペプチド |
JP2019535258A (ja) * | 2016-11-18 | 2019-12-12 | ライサンド アーゲー | 黄色ブドウ球菌に対する新規抗微生物剤 |
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JP2010536354A (ja) * | 2007-08-22 | 2010-12-02 | ヒグロス インベスト ゲーエムベーハー | ヒトおよび動物のブドウ球菌(Staphylococcus)感染症において使用するための新しいタンパク質 |
JP2014519815A (ja) * | 2011-05-04 | 2014-08-21 | マイクレオス ヒューマン ヘルス ビー.ブイ. | ポリペプチド |
JP2018527933A (ja) * | 2015-09-15 | 2018-09-27 | マイクレオス ヒューマン ヘルス ビー.ブイ.Micreos Human Health B.V. | 新規なエンドリシンポリペプチド |
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