JP2015182982A - 細菌の増殖抑制 - Google Patents
細菌の増殖抑制 Download PDFInfo
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- JP2015182982A JP2015182982A JP2014061575A JP2014061575A JP2015182982A JP 2015182982 A JP2015182982 A JP 2015182982A JP 2014061575 A JP2014061575 A JP 2014061575A JP 2014061575 A JP2014061575 A JP 2014061575A JP 2015182982 A JP2015182982 A JP 2015182982A
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- ion
- atom
- bacterium
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- phthalocyanine
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Abstract
Description
以下の発明は主として上記の成果及び考察に基づく。
[1]標的細菌が鉄欠乏状態で分泌するヘム獲得蛋白質と、非消光性フタロシアニンとの複合体。
[2]前記標的細菌が緑膿菌、セラチア菌、蛍光菌、ペスト菌、黄色ブドウ球菌、結核菌、エルシニア属細菌、プロビデンシア属細菌、アクロモバクター属細菌、歯周病原性細菌、及びインフルエンザ菌からなる群より選択される、ヘム獲得系を持つ細菌である、[1]に記載の複合体。
[3]前記標的細菌が緑膿菌であり、前記ヘム獲得蛋白質が緑膿菌のHasA蛋白質である、[1]又は[2]に記載の複合体。
[4]前記非消光性フタロシアニンが以下のいずれかの化学式で表される、[1]又は[2]に記載の複合体、
[5][1]〜[4]のいずれか一項に記載の複合体を有効成分とする細菌増殖抑制剤。
[6][5]に記載の細菌増殖抑制剤を含有する医薬。
[7]点眼薬である、[6]に記載の医薬。
[8][5]に記載の細菌増殖抑制剤を含有する、消毒、洗浄又は保存剤。
[9][5]に記載の細菌増殖抑制剤を標的細菌の感染組織又は臓器に送達した後、前記非消光性フタロシアニンのQ帯励起光を該感染組織又は臓器に照射するステップを含む、細菌の増殖抑制方法。
[10][5]に記載の細菌増殖抑制剤を添加した培養液で細胞又は組織を培養することを特徴とする、細胞又は組織の培養方法。
本発明の第1の局面は、ヘム獲得システムを持つ標的細菌の増殖抑制に有用な複合体に関する。ヘム獲得システムを持つ細菌では、鉄欠乏状態になるとヘム(鉄ポルフィリン錯体)獲得蛋白質(HasA)を分泌し、鉄源としてのヘムを宿主から獲得する。HasAは菌体外でヘモグロビンなどのヘム蛋白質からヘムを獲得し、緑膿菌外膜の特異的受容体であるHasRにヘムを受け渡す。本発明の典型的な使用方法では、鉄欠乏状態の標的細菌に対して本発明の複合体を作用させるとともに、複合体を構成する非消光性フタロシアニンのQ帯を励起可能な光(Q帯励起光)を照射する。このような操作の結果、HasRによるヘムの獲得が阻害され(HasRの相互作用部位が非消光性フタロシアニンでブロックされる。或いは、HasRに受け渡された非消光性フタロシアニンがHasR内部にとどまり、ヘムの通路を遮断する)、標的細菌の増殖が抑制されるとともに、非消光性フタロシアニンが励起され、励起三重項状態から溶存酸素へのエネルギー移動によって一重項酸素を生成し、標的細菌を傷害する。このような複合的な作用により、効率的且つ効果的に標的細菌の増殖を抑制する。標的細菌の種類や状態、或いは光の照射条件等によって効果は変動するものの、上記のごとき適用によれば、標的細菌(集団の一部又は全部)を死滅させることも可能である。実際、後述の実施例に示す通り、緑膿菌を標的細菌とした実験によって、極めて強い殺菌効果が確認されている。
緑膿菌(Pseudomonas aeruginosa):配列番号1
セラチア菌(Serraia marcescens):配列番号2
蛍光菌(Pseudomonas fluorescens:配列番号3
ペスト菌(Yersinia pestis):配列番号4
ピリドポルフィラジン
本発明の複合体の典型的な用途は、標的細菌の増殖抑制である。そこで本発明の第2の局面は、本発明の複合体を有効成分とする細菌増殖抑制剤及びその利用に関する。本発明の細菌増殖抑制剤は、例えば、床や流し、医療機器ないし器具(例えば、コンタクトレンズ、カテーテル、人工呼吸器、ネブライザー、吸痰チューブ、花瓶、加湿器のタンク)、家具(机、テーブル、収納庫など)、調理器具、食器、OA機器、喀痰、排泄物、吐瀉物など、標的細菌の付着、定着、混入、生育及び/又は増殖等のおそれがある場所や物の消毒(洗浄)に用いることができる。また、蓄尿、花瓶、水槽などに添加することにより、標的細菌の増殖ないし繁殖を防止することもできる。更には、コンタクトレンズ(視力補正用コンタクトレンズ、治療法コンタクトレンズ、検査用コンタクトレンズ)の洗浄や保存、手/指先の消毒(洗浄)にも本発明の細菌増殖抑制剤を用いることができる。以上のように、細菌増殖抑制剤は、消毒剤、洗浄剤、保存剤等に利用可能である。
緑濃菌を選択的に殺菌し得る新規な方法を開発すべく、フタロシアニンの特性に注目して以下の実験を行った。
1.ガリウムフタロシアニンを捕捉したヘム鉄獲得蛋白質(HasA)の調製
(1)HasAの調製
緑膿菌(Pseudomonas aeruginosa)PAO1株のHasAはC末端の21アミノ酸が欠損した状態で分泌される。そこで、本実験においても欠損型の(truncated)HasAを用いることにした。既報の方法(非特許文献1)に従い、当該欠損型のHasA(アミノ酸配列を配列番号5に示す)を調製した。概要を説明すると、全長HasA(配列番号1)をコードする遺伝子をPCRで合成し、クローニングベクターに挿入した。ベクターに保持された全長遺伝子(配列番号6)から欠損型HasAをコードする領域を切り出し、サブクローニングした。得られた組換えプラスミドで大腸菌M15[pREP4](QIAGEN)を形質転換した。形質転換後の大腸菌をLB培地で培養し、IPTGを添加して発現を誘導した。引き続き培養した後、集菌し、-80℃で保存した。次に、菌体をHバッファー(20mM リン酸ナトリウム, 15mM 2-メルカプトエタノール, 20mM イミダゾール, 0.5M NaCl, pH7.4))に懸濁した後、超音波処理により菌体を破砕した。遠心分離後の上清をNiアフィニティーカラムで精製した。Hisタグを除去するためにトロンビンで処理した後、リン酸緩衝生理食塩水(PBS)で透析した。再度、Niアフィニティーカラムでの精製及び透析を行った。最終的に得られたサンプルを液体窒素で凍結し、使用直前まで-80℃で保存した。
ガラス製ビーカーに0.2 (w/v)塩酸アセトン溶液15mLとスターラーバーを入れ、穏やかに撹拌しながらHasAのPBS溶液(140 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM KH2PO4, pH 7.3)をパスツールピペットを使って一滴ずつ滴下するとアポHasA沈殿が生成する。遠心分離(5000rpm 10分間後)により、アポHasAを底に集め、上澄みを丁寧に取り除いた。7Mの尿素溶液(トリス塩酸緩衝溶液pH7.5)15mLを沈殿に加え、HasAを溶解させ、溶液を透析膜に移してPBSで透析した。透析後、不溶蛋白をフィルターで除去した。アポHasAの濃度は、可視紫外光吸収スペクトル測定により算出した(アポHasAの280nmのモル吸光係数:28.6mM-1cm-1)。
アポHasAのPBS溶液10mLに、5等量のガリウムフタロシアニン(図2)のジメチルスルホキシド溶液10mLを撹拌下に滴下し、4℃で1時間撹拌した(ジメチルスルホキシドの最終濃度は50%)。透析によりジメチルスルホキシドを除き、不溶蛋白質をフィルターで除去した。ゲル濾過カラムPD10とSephacryl S-200 HR(GEヘルスケア社)にて精製した。ガリウムフタロシアニン捕捉HasAの濃度は、ビシンコニン酸法(BCA法)により算出した。
緑膿菌PAO1株(独立行政法人 理化学研究所 バイオリソースセンター 微生物材料開発室より入手)の単一コロニーを3mLのM9培地をベースとする最小培地で24時間37℃、180rpmで培養し、この菌体溶液10μLを、40mMのEDTAを鉄イオン捕捉剤として加えた同じM9培地をベースとする最小培地(1.2% (w/v) Na2HPO4・12H2O, 0.6% (w/v) KH2PO4, 0.1% (w/v) NaCl, 0.2% (w/v) NH4Cl, 0.2% (w/v) カザミノ酸, 22 mM ブドウ糖, 0.0002% (w/v) ビタミンB1)で培養した。終濃度が1.0μMとなるようにガリウムフタロシアニンHasA溶液を添加して、ハロゲンランプの590nm以下の光をカットオフフィルターでカットした可視光を2時間30分照射した。光照射後の菌体溶液をLB培地(1% トリプトン、0.5% 酵母エキス、1% 塩化ナトリウム)プレートにプレーティングして12時間37℃でインキュベートし、形成されたコロニー数を光照射有と無で比較した。光照射をしなかったサンプルでは、100個以上のコロニーが観測されたのに対して、光照射を行った場合には、コロニーが観測されず、緑膿菌が増殖能力を失っていた(図3)。
鉄欠乏状態で培養した緑膿菌の培養液に、非消光性のガリウムフタロシアニンとHasAの複合体を添加し、可視光を照射することによって、緑膿菌を殺菌できた。ガリウムフタロシアニンが可視光照射により励起され、励起三重項状態から溶存酸素へのエネルギー移動によって一重項酸素を生成し、細菌を死に陥らせたと考えられる。ヘム等のポルフィリン誘導体とは対照的に、フタロシアニンは生体由来組織への影響が最も少ない650nm〜700nmに非常に強い吸収を持つ。従って、理想的な光増感剤であり、肺がん、食道がん、子宮頸がんを治療する光線力学療法における第二世代の光増感剤としてその利用が検討されている。以上の実験結果は、緑膿菌の増殖抑制ないし殺菌という、フタロシアニンの新たな用途を示すものである。可視光照射しない場合には、「HasA−ガリウムフタロシアニン」による緑濃菌の生育阻害は観測されたが、殺菌には至らなかった。また、ヘム獲得システムを持たない大腸菌は殺菌されず生育阻害も観測されなかったことから、緑濃菌のヘム獲得システム選択的な殺菌機構と考えられる。さらに、低濃度(1μM)の「HasA−ガリウムフタロシアニン」で光殺菌が進行していることから、可視光照射によってHasRの存在する菌体外膜周辺に致命的な損傷を与えていると考えられる。
Claims (10)
- 標的細菌が鉄欠乏状態で分泌するヘム獲得蛋白質と、非消光性フタロシアニンとの複合体。
- 前記標的細菌が緑膿菌、セラチア菌、蛍光菌、ペスト菌、黄色ブドウ球菌、結核菌、エルシニア属細菌、プロビデンシア属細菌、アクロモバクター属細菌、歯周病原性細菌、及びインフルエンザ菌からなる群より選択される、ヘム獲得系を持つ細菌である、請求項1に記載の複合体。
- 前記標的細菌が緑膿菌であり、前記ヘム獲得蛋白質が緑膿菌のHasA蛋白質である、請求項1又は2に記載の複合体。
- 前記非消光性フタロシアニンが以下のいずれかの化学式で表される、請求項1又は2に記載の複合体、
- 請求項1〜4のいずれか一項に記載の複合体を有効成分とする細菌増殖抑制剤。
- 請求項5に記載の細菌増殖抑制剤を含有する医薬。
- 点眼薬である、請求項6に記載の医薬。
- 請求項5に記載の細菌増殖抑制剤を含有する、消毒、洗浄又は保存剤。
- 請求項5に記載の細菌増殖抑制剤を標的細菌の感染組織又は臓器に送達した後、前記非消光性フタロシアニンのQ帯励起光を該感染組織又は臓器に照射するステップを含む、細菌の増殖抑制方法。
- 請求項5に記載の細菌増殖抑制剤を添加した培養液で細胞又は組織を培養することを特徴とする、細胞又は組織の培養方法。
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