JP2020502264A - 抗生物質組成物 - Google Patents
抗生物質組成物 Download PDFInfo
- Publication number
- JP2020502264A JP2020502264A JP2019549665A JP2019549665A JP2020502264A JP 2020502264 A JP2020502264 A JP 2020502264A JP 2019549665 A JP2019549665 A JP 2019549665A JP 2019549665 A JP2019549665 A JP 2019549665A JP 2020502264 A JP2020502264 A JP 2020502264A
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- Prior art keywords
- silver
- antibiotic composition
- examples
- ebselen
- bacteria
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
本出願は、2016年12月5日に出願の米国仮出願番号第62/430,101号の利益を主張し、これは参照によりその全体が本明細書に組み入れられる。
金属含有剤および抗微生物剤の組み合わせを、本明細書において開示する。金属含有剤は、本明細書において開示される金属または金属イオンを含んでよい。金属含有剤は、抗生物質活性を有する金属イオン、例えば、銀、銅、亜鉛、水銀、スズ、鉛、ビスマス、カドミウム、セリウム、クロムおよびタリウムイオンを含んでよい。銀、金、銅および亜鉛の抗微生物金属イオンは、生体内で使用しても安全であり身体中に実質的に吸収されないとみなすことができる。抗微生物剤は、ゲンタマイシン、カナマイシン、ジェネティシン、テトラサイクリンなどの抗生物質、非有機セレン剤もしくは有機セレン剤(例えば、エブセレンまたはその類似体)、または本明細書に記載される任意の抗微生物剤であり得る。いくつかの例では、金属含有剤(例えば、銀)は、細菌のチオレドキシン(Trx)系、グルタチオン(GSH)系、または両方を直接的に標的とすることによって、グラム陰性細菌に対する有機セレン剤(例えば、エブセレン)またはある種の抗生物質の抗菌効果を増強する。いくつかの例では、GSH系を標的とすること/攻撃することは、1種以上の細菌の死滅における抗生物質組成物の有効性を増加させる。いくつかの例では、抗生物質組成物は、本明細書において開示される銀剤および抗生物質を含んでよい。
Rは、H、1〜14個の炭素原子の炭素鎖(所望によりベンズイソセレナゾール−3(2H)−オン−2−イル、ベンズイソチアゾール−3(2H)−オン−2−イル、OH、アルコキシル、SH、NH2、N−アルキルアミノ、N,N−ジアルキルアミノ、COOHで置換される分枝または非分枝である)を有するアルキル、所望によりC1−C5アルキル、OH、アルコキシル、SH、NH2、N−アルキルアミノ、N,N−ジアルキルアミノ、COOH、CHO、NO2、F、Cl、Br、Iで置換されるアリール、および所望によりC1−C5アルキル、OH、アルコキシル、SH、NH2、N−アルキルアミノ、N,N−ジアルキルアミノ、COOH、CHO、NO2、F、Cl、BrおよびIで置換されるヘテロアリールからなる群から選択され、
Aは、飽和、不飽和または多価不飽和の3〜6員の炭素鎖を表し、
Nは所望により、1個以上の炭素と置き換わってよく、当該1個以上の炭素は1個以上のOR、SR、およびアルキルアミノ、C1−C5アルキル、OH、アルコキシル、SH、NH2、N−アルキルアミノ、N,N−ジアルキルアミノ、COOH、CHO、NO2、F、Cl、Br、およびIで所望により置換される]を有する化合物またはその医薬的に許容される塩などの、エブセレンまたはその類似体を含んでよい。
場合によっては、本開示は抗生物質組成物を提供し、ここで、当該抗生物質組成物は銀含有剤および有機セレン剤を含む。いくつかの例では、銀含有剤は、銀イオンを含み得る。いくつかの例では、銀含有剤は、硝酸銀を含み得る。いくつかの例では、銀含有剤は、クエン酸二水素銀を含み得る。いくつかの例では、有機セレン剤は、セレナゾール化合物を含み得る。いくつかの例では、有機セレン剤は、ベンズイソセレナゾール−3(2H)−オン化合物を含み得る。いくつかの例では、有機セレン剤は、エブセレンを含み得る。いくつかの例では、抗生物質組成物は、液体剤形であり得る。いくつかの例では、抗生物質組成物は、溶液または懸濁液の剤形であり得る。いくつかの例では、抗生物質組成物中の銀含有剤の濃度は、約0.5〜50μM、約1〜25μMまたは約1〜10μMであり得る。いくつかの例では、抗生物質組成物中の銀含有剤の濃度は、約5μMであり得る。いくつかの例では、抗生物質組成物中の有機セレン剤の濃度は、約4〜25μM、約30〜200μM、約30〜150μMまたは約30〜100μMであり得る。いくつかの例では、抗生物質組成物中の有機セレン剤の濃度は、約40μMまたは約80μMであり得る。いくつかの例では、銀含有剤および有機セレン剤は、約1:2〜約1:20のモル比であり得る。いくつかの例では、銀含有剤および有機セレン剤は、約1:4、1:8または1:16のモル比であり得る。いくつかの例では、抗生物質組成物は、1種以上のグラム陰性細菌またはグラム陽性細菌に対して約10〜100nMのIC50値を示す。いくつかの例では、抗生物質組成物は、1種以上のグラム陰性細菌またはグラム陽性細菌に対して約50nM以下のIC50値を示す。いくつかの例では、1種以上のグラム陰性細菌は、K.ニューモニエ(K.pneumoniae)、A.バウマンニ(A.baumannii)、緑膿菌(P.aeruginosa)、E.クロアカ(E.cloacae)、大腸菌(E.coli)または任意のこれらの組み合わせを含み得る。いくつかの例では、抗生物質組成物は、AgNO3およびエブセレンを含み得る。いくつかの例では、本明細書において開示される組成物は、液体剤形であり得る。いくつかの例では、抗生物質組成物は、液体剤形で5μMのAgNO3および4μMのエブセレンを含み得る。いくつかの例では、抗生物質組成物は、液体剤形で5μMのAgNO3および20μMのエブセレンを含み得る。いくつかの例では、抗生物質組成物は、液体剤形で5μMのAgNO3および40μMのエブセレンを含み得る。いくつかの例では、抗生物質組成物は、液体剤形で5μMのAgNO3および80μMのエブセレンを含み得る。
いくつかの例では、本明細書において開示される抗生物質組成物は、1種以上の賦形剤、例えば、異なる物質、またはサイズが異なる以外は同一の物質を更に含み得る。いくつかの例では賦形剤は、担体、例えば、水不溶性多糖類またはオリゴ糖類を含み得る。いくつかの例では、担体は、酢酸セルロース、酢酸酪酸セルロース、酢酸プロピオン酸セルロース、酢酸フタル酸セルロース、キトサン、β−シクロデキストリン、エチルセルロース、フタル酸ヒドロキシプロピルメチルセルロース(HPMCP)、微結晶性セルロース、デンプン、およびこれらの任意の組み合わせからなる群から選択できる。いくつかの例では賦形剤は、増粘剤、例えば水溶性多糖類を含み得る。いくつかの例では、増粘剤は、ヒドロキシプロピルメチルセルロース(HPMC)、アカシア、アルギン酸、コロイド状二酸化珪素、カルボキシメチルセルロースカルシウム、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシルプロピルセルロース(ヒプロメロース)、メチルセルロース、スクロース、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、およびこれらの任意の組み合わせからなる群から選択できる。いくつかの例では、賦形剤は、第1の賦形剤(本明細書において開示される任意の賦形剤)および第2の賦形剤(本明細書において開示される任意の賦形剤)を含み得る。いくつかの例では、賦形剤は、担体(例えば、微結晶性セルロース)および増粘剤(例えば、HPMC)を含み得る。
いくつかの例では、本明細書において開示される活性薬剤は、錠剤、カプセル、ゲル、ロリポップ、非経口注入 、脊髄内注入、吸入、スプレー、エアロゾル、経皮パッチ、イオントフォレーゼ輸送、吸収ゲル、液体、液体タンニン酸塩、坐薬、注入、静脈内点滴の剤形、または対象を処理するためのこれらの組み合わせとして製剤化される。いくつかの例では、薬剤は、錠剤、カプセル、カシェ剤、軟ゼラチンカプセル剤、硬ゼラチンカプセル剤、徐放性カプセル、タンニン酸錠剤、口腔崩壊錠剤、多層錠剤、発泡錠剤、ビーズ、液体、経口懸濁液、咀嚼錠剤、経口液剤、舐剤、ロリポップ、経口シロップ、薬学的に許容される賦形剤を含む無菌包装粉末、他の経口剤形などの単一の経口剤形またはそれらの組み合わせとして製剤化される。いくつかの例では、本明細書の開示の組成物は、本明細書において更に開示される1種以上の異なる剤形を使用して投与できる。例えば、複数の活性薬剤を含む組成物は、固体形態、半固体形態、マイクロエマルジョン形態、ゲル形態、パッチ形態または液体形態で投与できる。このような剤形は、本明細書において更に開示される。いくつかの例では、本明細書の開示は、必要とする対象への経口送達のための方法および経口送達のために製剤化される組成物に関する。いくつかの例では、口腔または食道の粘膜層を通して対象に1種以上の薬学的活性薬剤を送達するように組成物を製剤化できる。いくつかの例では、胃および/または腸管の粘膜層を通して対象に1種以上の薬学的活性薬剤を送達するために組成物を製剤化できる。
いくつかの態様では、本明細書において開示される液状組成物は、貯蔵安定性があり、例えば、当該液状組成物は、貯蔵中に分離しない(浮遊および沈殿の両方)かまたは、激しい振盪(それは投与の一貫性に大きく影響を及ぼす)を必要としない。いくつかの例では、本明細書において開示される液状組成物中の1種以上の活性薬剤は、調節放出、例えば、徐放、即時放出、または混合でのように提供される。いくつかの例では、本明細書において開示される液状組成物中の1種以上の活性薬剤は、調節放出のために製剤化されるマトリックス中に、充血除去剤、去痰剤、去痰剤または鎮痛剤を含んでよい。例示的な去痰剤は、塩化アンモニウム、N−アセチルシステイン、アンブロキソール、グアイフェネシン(例えば、グリセロール、グアヤコール酸塩)、テルピン水和物、グリセリルグアヤコール塩、ヨウ化カリウム、クエン酸カリウム、グアイヤコールスルホン酸カリウム、オレガノ葉抽出物25〜500mg(液状抽出物であり得る)、レッドクローバー25〜500mg、クロウメモドキ根25〜500mg、コロハ25〜500mgまたは任意のこれらの混合物を含む。本発明の活性物質のための担体の例は、分解性、部分分解性または非分解性でかつ一般的に生体適合性の任意のポリマー、例えば、液体、マトリックスまたはビーズの形態のポリスチレクス、ポリプロピレン、ポリエチレン、ポラクリレックス、ポリ乳酸(PLA)、ポリグリコール酸(PGA)および/またはポリ乳酸ポリグリコール酸(PGLA)を含む。
一態様では、本明細書において開示される液状組成物を調製するための方法は、1種以上の活性薬剤を有する1種上のビーズを、泡形成を減少させる条件下で、当該1種以上のビーズの密度またはそれとほぼ同じであり得る密度および、チキソトロープ剤、水および1種以上の防腐剤を有する高密度チキソトロピー溶液と混合することを含む。別の態様では、液状組成物を調製するための方法は、低キャビテーション型プロペラを用いて混合することにより1種以上の活性薬剤を含む1種以上のビーズ、増粘剤および界面活性剤を含む混合物を混ぜること、および泡形成を最小限にするように当該混合物の表面下で当該混合物を再循環させることを含む。別の態様では、液状組成物を調製するための方法は、空気の導入を最小限にする条件下で、担体上またはその周囲の1種以上の活性薬剤および増粘剤を含む混合物を混ぜることを含む。空気および/または気泡の導入を最小限にする、減少させるおよび/またはなくす条件は、単独で、組合わされてかつ/または任意の順序で使用される以下の工程の1つ以上を含む:ダイアフラムポンプを使用して、例えば、水およびチキソトロープ剤ならびに1種以上の防腐剤、着色剤および風味剤を混合する工程;液体表面下に再循環チューブを配置する工程;液体を保持する容器の側面に沿って液体を加える工程;液体表面上にビーズ(例えば、1種以上の活性薬剤を含む1種以上のビーズ)を散らす工程;容器をこする1種以上のパドルがない状態で溶液を混合する工程;プロペラミキサーで溶液を混合する工程;溶液を、キャビテーションを減少させるかまたは最小限にする速度にてプロペラミキサーで混ぜ合わせる工程、および二つ以上のこれらの工程の組み合わせ。別の態様では、液状組成物を調製するための方法は、気泡の導入を最小限にする条件下で、低イオン濃度およびチキソトロープ剤を有する溶液中で1種以上の徐放性ビーズの混合物と担体上の1種以上の活性薬剤を混ぜ合わせることを含む。
場合によっては、本開示は、本明細書において開示される抗生物質組成物を1種以上の細菌と接触させることを含む、1種以上の細菌を阻害するかまたは死滅させる方法を提供する。場合によっては、本開示は、本明細書において開示される抗生物質組成物を細菌感染と接触させることを含む、細菌感染を処置する方法を提供する。いくつかの例では、1種以上の細菌は、1種以上のグラム陰性細菌を含む。いくつかの例では、1種以上の細菌は、1種以上の多剤耐性グラム陰性細菌を含む。いくつかの例では、1種以上の細菌は、K.ニューモニエ(K.pneumoniae)、A.バウマンニ(A.baumannii)、緑膿菌(P.aeruginosa)、E.クロアカ(E.cloacae)、大腸菌(E.coli)または任意のこれらの組み合わせを含み得る。いくつかの例では、細菌感染または1種以上の細菌は、表面に存在し得る。いくつかの例では、細菌感染または1種以上の細菌は、哺乳動物に存在し得る。いくつかの例では、細菌感染または1種以上の細菌は、ヒトに存在し得る。いくつかの例では、上記接触は注射、例えば静脈内注射または皮下注射によるものであり得る。いくつかの例では、上記接触は、局所適用によるものであり得る。いくつかの例では、上記接触は、経口であり得る。いくつかの例では、上記接触は、少なくとも約1分間、2分間、3分間、4分間、5分間、10分間、20分間、30分間、40分間、50分間、1時間、2時間、3時間、4時間、5時間、6時間、7時間、8時間、9時間、10時間、11時間、12時間、18時間、1日間、2日間、3日間、4日間、5日間、6日間、1週間または1ヵ月の間持続する。いくつかの例では、上記接触は、1時間につきまたは毎日、1、2、3、4、5、6、7または8回発生する。いくつかの例では、上記接触は、毎日約3、4、5、6、7、8、9、10、11または12分または時間毎に発生する。いくつかの例では、抗生物質組成物は、単一単位用量であり得る。いくつかの例では、細菌感染または1種以上の細菌と接触される有機セレン剤の量は、用量あたり約10〜100mg、約10〜50mgまたは約20〜30mg、例えば約25mgであり得る。いくつかの例では、細菌感染または1種以上の細菌と接触される銀の量は、用量あたり約1〜20mg、約1〜10mgまたは約5〜7mg、例えば約6mgであり得る。
1.1 結果
銀とエブセレンの組み合わせは細菌に対する選択的で相乗作用的な毒性を示した
グラム陰性モデル細菌である大腸菌(E.coli)の増殖に対するエブセレンとの組み合わせでの硝酸銀の効果をマイクロプレートにおいて調べた。DHB4株の一晩培養物をルリア・ベルターニ(LB)培地で1000倍希釈し、硝酸塩(AgNO3)としてイオン性銀(Ag+)で16時間処理した。Ag+単独は16時間の処理後に42μMの最小発育阻止濃度(MIC)で大腸菌(E.coli)の増殖を阻害し、一方で2μMのエブセレン追加はAg+のMICを4.2μMへと劇的に減少させた(p=0.000028<0.001)(図1A)。一方、組み合わせた5μMのAg+および2.5μMのエブセレンは、ヒトHeLa細胞に対する相乗作用的な毒性を示さなかった(p=0.98>0.05)(図1B)。加えて、細菌細胞および哺乳動物細胞に対するエブセレン自体(2、4、8μM)の毒性は、同程度であり(図1Aおよび1B)、細菌増殖に対する効果を有しなかった(図1C)。これらの結果は、エブセレンと組み合わせたAg+による処置は、哺乳動物細胞より細菌に対する有意な選択的で相乗作用的な毒性を示すことを示唆し、エブセレンの存在下での細菌に対する銀のMICの劇的な減少は、銀の全身での医学的利用を可能にする。
臨床において最も処置が困難な以下の5種のMDRグラム陰性病原体種が存在し、それらは典型的なGSH陽性の細菌でもある:クレブシェラ肺炎桿菌(Klebsiella pneumonia)、アシネトバクター・バウマンニ(Acinetobacter baumannii)、緑膿菌(Pseudomonas aeruginosa)、エンテロバクター・クロアカ(Enterobacter cloacae)および大腸菌(Escherichia coli)。各々の種から2株を単離し、一晩培養物をLB培地で1000倍希釈し、連続的濃度のエブセレンと組み合わせたAg+で16時間処理した。試験された10株全てに対するエブセレンと組み合わせたAg+の相乗作用的な殺菌効果が観察された(表1)。これらの5つの種の中で、A.バウマンニおよびE.クロアカは非常に容易に形成される薬剤耐性株であり、それらは臨床において、イミペネム、セフェピムおよびセホタキシムなどを含む第四世代セファロスポリンによって処置される必要がある。単離されたイミペネム、セフェピムおよびセホタキシム耐性のA.バウマンニ(AB−1/2)およびE.クロアカ(ECL−1)株が同定され(表2および3)、それらはエブセレンと組み合わせたAg+に感受性であった(表1)。これらの結果は、既存の耐性を有する広範な細菌に対して活性である、エブセレンと組み合わせたAg+が『救命への一縷の望み』であるかもしれないことを示し、このことは、従来の抗生物質に耐性がある感染に対してさえ、正しい経験的治療の的確な機会を増加させるであろう。
Ag+およびエブセレンは一般にチオールを標的とする薬剤であると考えられているため、細胞における細菌のTrxRまたはTrxの活性を、エブセレンと組み合わせたAg+で処理した(図3Aおよび3B)。細胞抽出物中のTrxRおよびTrx活性は、Ag+またはエブセレン単独のいずれによっても影響を受けなかったが、組み合わせた5μMのAg+および20μMのエブセレンは、TrxR(p=0.00018<0.001)およびTrx(p=0.0036<0.01)活性の劇的な消失をもたらした(図3Aおよび3B)。この観察と一致して、レドックスウエスタンブロット(Redox Western Blot)で測定されたTrx1の酸化還元状態も、エブセレンと組み合わせたAg+の処置によって影響を受けた。Trx1は未処理の細菌においては主に還元型であり、組み合わせた薬剤による処理によって酸化された(図3C)。Trxの酸化還元状態に対する上記処理の効果を調べるために、Trx2抗体を本実験で使用して酸化型Trx2を検出した。還元型Trx2は、おそらく認識部位の遮断のために、この抗体により検出できなかった。酸化型Trx2は、上記処理で観察されなかったが、陽性対照であるジアミドにより酸化されたTrx2は検出された(図3D)。これらの結果は、Trx2がTrx1と比較して上記処理に対してそれほど感受性でないことを示した。加えて、Trx1および2のタンパク質レベルは、Ag+およびエブセレンの組み合わせによる10分の処理により影響を受けなかった(図3Cおよび3D)。
細胞内TrxRおよびTrx1酵素活性は減少した一方で対応するタンパク質のレベルはエブセレンと組み合わせたAg+による処理によって変化せず、TrxRおよびTrxが阻害されたことを示唆した。エブセレンは細菌TrxRの既知の可逆的競合阻害剤であるため、大腸菌のTrxRおよびTrx活性に対するAg+の効果を調べた。事前にNADPHとインキュベートした100nMの大腸菌TrxRをAg+とインキュベートした場合、IC50は、金化合物であるオーラノフィンと同程度の約50nMであった(図4A)。大腸菌TrxRがAg+によって特異的に阻害され得るかどうかを検出するために、還元型大腸菌Trx1の存在下でこの酵素をAg+とインキュベートした。するとTrxRに対する阻害効率が減少した(図4A)。これは、TrxがAg+とも反応し、TrxRに対し保護的役割を果たすことを示唆した。蛍光分光学法は、Ag+が還元型Trx1と相互作用しその蛍光スペクトルを変化させることを更に確認した(図4B)。1〜10μMのAg+とのインキュベーションは、10μMのTrx1のトリプトファン蛍光強度を増加させた。一方、10μMのTrx1の蛍光強度は、20〜100μMのAg+で処理した場合減少した(図4B)。これに一致して、Trx活性は、Ag+濃度の増加と共に減少した(図4C)。Trx1活性は脱塩後に回復しなかったため、Ag+によるTrx1の阻害は不可逆的であった(p=0.00021<0.001)(図4D)。このことは、Ag+が還元型の大腸菌Trx1のスルフヒドリル基と堅固な複合体を形成することを示唆した。これら全ての結果は、銀が細菌のTrxおよびTrxR活性を不可逆的に阻害することを示す。
GSH系およびTrx系の1つの主な機能は、ROSを除去して細胞内酸化還元バランスを保ち酸化ストレスから守ることである。Trx系の阻害およびGSHの欠乏が、ROS増加の原因である可能性がある。ROSレベルの増加が殺菌効果を説明するかどうか決定するために、ROSレベルをAg+およびエブセレンで処理した細胞で測定した。5μMのAg+または20μMのエブセレン単独による処理は、ROS濃度を変化させなかった一方で、5μMのAg+および20μMのエブセレンの組み合わせはROSレベルの増加をもたらした(p=0.00012<0.001)。更に、組み合わせた5μMのAg+および20μMのエブセレンによる処理によって引き起こされたH2O2レベルの増大が、アンプレックスレッド法によっても確認された(p=0.00057<0.0001)(図5C)。さらに、H2O2による傷害からの大腸菌デヒドラターゼクラスターを障害するOxyRコンポーネントを欠く大腸菌変異体(OxyR−)は、野生型(WT)と比較してAg+およびエブセレンによる処理に対してより感受性であった(表4〜6)。全ての結果は、細菌に対するAg+とエブセレンの致死性はROS生成を伴うことを示した。
菌株
全ての試験管内実験は、大腸菌(Escherichia coli、E.coli)のDHB4株およびそれに由来する酸化還元表現型株(表6)および臨床的に単離された多剤耐性(MDR)グラム陰性菌(表2、3、7)を用いて実施した。全ての生体内実験は、中国湖北省の三峡大学附属第一医院(First Affiliated Hospital of Three Gorges University)において臨床患者の尿から単離された大腸菌ZY−1株(表7)を、三峡大学附属第一医院の倫理委員会からの研究の承認および当該患者のインフォームドコンセントを得たうえで使用して実施した。当該株を完全に同定し、保存した。他の臨床分離MDRグラム陰性菌(表2、3)は、中国湖北省の三峡大学の人民医院(Renmin Hospital of Three Gorges University in Hubei Province,PRC)において、全ての承認およびインフォームドコンセントを得て臨床患者から得られた。
全ての実験は、ルリア・ベルターニ(LB)培地(EMD millipore)で実施された。特に明記しない限り、大腸菌株および臨床病原体の抗菌実験について以下の濃度が使用された:0、1、2、4、5、20、40、80μMの2−フェニル−1,2−ベンズイソセレナゾール−3(2H)−オン(エブセレン)(Daiichi)、および0、0.625、1.25、2.5、5、10、20、40、80μMの硝酸銀(Sigma-Aldrich)。4−アセタミド−4 '−マレイミジルスチルベン−2,2'−二スルホン酸(AMS)(Invitrogen)、プロテアーゼ阻害剤カクテル(Roche)、DCTM protein assay(Bio−RAD)、ヨウ化プロピジウム(PI)(BD Biosciences)、大腸菌DHB4株のTrxR、ヒツジ抗大腸菌Trx1抗体およびラビット抗大腸菌Trx2抗体はIMCO社(ストックホルム市、スウェーデン国)から購入、ヤギ抗ラビットIgG−HRP(Santa Cruz、ロット番号:H1015)、ラビット抗ヤギIgG−HRP(Southern Biotech、ロット番号:12011−PG56)、グルタチオン−タンパク質複合体に対するIgG2aマウスモノクローナル抗体(VIROGEN、ロット番号:101−A、クローン番号:D8)、4−12%のBolt Bis-Trisゲル(VWR)、全ての他の試薬は、シグマアルドリッチから購入した。
大腸菌DHB4株細胞の一晩培養物を、ルリア・ベルターニ(LB)培地で1000倍に希釈し、連続的濃度のAgNO3および/またはエブセレンで16時間処理した。細胞生存率を、600nmで吸光度を測定することによって決定した。0.8%(v/v)のDMSOで処理した培養物を、対照として使用した。
HeLa細胞をATCCから購入し、マイコプラズマ検出およびSTR分析(ATCC、アメリカ合衆国)によるヒト細胞株認証を行った。HeLa細胞を、5%CO2インキュベーターで37℃にて10%のFCS、100単位/mlのペニシリンおよび100g/mlのストレプトマイシンを補充したDMEM培地中で培養した。当該細胞を、96マイクロウェルプレートに播種し、70〜80%の培養密度まで増殖させた。当該細胞を、エブセレンおよびAgNO3の連続的組み合わせで24時間処理した。細胞毒性を、MTTアッセイによって検出した。
10の臨床分離MDRグラム陰性(GSH陽性)株を0.4のOD600nmに増殖させ、96マイクロウェルプレート中の100μlのLB培地に100倍希釈した。100μlのエブセレンおよびAgNO3の系列希釈物を、個々のウェルに加えた。最小阻止濃度(MIC)を、37℃での16時間培養の後測定した。0.8%(v/v)のDMSOで処理した培養物を、対照として使用した。
大腸菌DHB4株細胞を0.4のOD600nmに15ml試験管中で増殖させ、組合みわせでの5μMのAgNO3および連続的濃度のエブセレン(0、20、40、80μM)で処理した。未処理の大腸菌の生存を、OD600nmの測定およびコロニーの計数によって、抗生物質処理した細胞と比較した。コロニー形成能アッセイのために、細胞を6,000rpmで5分間遠心分離することによって10分、1時間、2時間および4時間の時点で収集し、PBSで3回完全に洗浄した。当該細胞をPBSで連続希釈し、100μl培養物をLBプレートに蒔いた。コロニーを終夜培養後に計数し、CFU/mlを以下の公式を使用して算出した:[(コロニー数)*(希釈倍率)]/(蒔いた量)。
大腸菌DHB4株細胞を0.4のOD600nmにLB培地で増殖させ、当該細菌細胞を異なる希釈度のエブセレンおよびAgNO3で10分間処理した。細胞を、6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、次いで細胞を、プロテアーゼ阻害剤カクテルを含有する溶解緩衝液(25mMのTris・HCl(pH7.5)、100mMのNaCl、2.5mMのEDTA、2.5mMのEGTA、20mMのNaF、1mMのNa3VO4、20mMのβ−グリセロリン酸ナトリウム、10mMのピロリン酸ナトリウム、0.5%のTriton X−100)中に再懸濁し、超音波破砕によって溶解した。細胞可溶化物を、13,000rpmで20分間遠心分離することによって得て、タンパク質濃度を、ローリータンパク質分析(Bio-Rad DCTM)によって測定した。
大腸菌DHB4株細胞を0.4のOD600nmにLB培地で増殖させ、当該細菌細胞を異なる希釈度のエブセレンおよびAgNO3で10分間処理した。ウエスタンブロット法を、エブセレンおよびAgNO3で処理された大腸菌細胞のTrx1およびTrx2の酸化還元状態を検出するために実行した。上記細胞を6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、1.0ml中の5%TCAを用いてタンパク質を沈殿させた。沈殿物を1mlの事前に氷冷したアセトンで3回洗浄し、15mMのAMSを含有する0.5%のSDSを加えた50mMのTris・HCl(pH 8.5)中で37℃にて2時間溶解した。タンパク質を、13,000rpmで20分間遠心分離してペレットを除去することにより得て、タンパク質濃度を、ローリータンパク質分析(Bio-Rad DCTM)により測定した。Trx1およびTrx2の酸化還元状態を、ヒツジ抗大腸菌Trx1抗体(ウサギ抗大腸菌Trx2抗体)を1000倍希釈で用いて検出し、続いてChemiluminescence Reagent Plusの検出を行った。
AgNO3との組み合わせでのエブセレンにより処理された大腸菌細胞のS−グルタチオン付加タンパク質の総量を、ウエスタンブロット法によって検出した。細胞を上記の通り培養および洗浄し、30mMのIAMを含有する溶解緩衝液(25mMのTris・HCl(pH7.5)、100mMのNaCl、2.5mMのEDTA、2.5mMのEGTA、20mMのNaF、1mMのNa3VO4、20mMのβ−グリセロリン酸ナトリウム、10mMのピロリン酸ナトリウム、0.5%のTriton X−100、プロテアーゼ阻害剤カクテル)中に再懸濁した。超音波破砕による溶解後、細胞可溶化物を、13,000rpmで20分間遠心分離することによって得た。タンパク質濃度をローリータンパク質分析(Bio-Rad DCTM)によって測定した。試料を90℃にて10分間SDSローディングバッファーとインキュベートし、次いで、MESランニングバッファーを用いて4〜12%Bolt Bis−Trisゲル上で分離した(150V、40分)。ウエスタンブロットアッセイを、グルタチオン−タンパク質複合体に対するIgG2aマウスモノクローナル抗体(VIROGEN、101−A/D8)を用いて実行した。
11の大腸菌DHB4酸化還元表現型株を、0.4のOD600nmに増殖させ、96マイクロウェルプレート中の100μlのLB培地に100倍希釈した。エブセレンおよびAgNO3の系列希釈物を、個々のウェルに加えた。最小阻止濃度(MIC)を、37℃での24時間培養後に測定した。0.8%(v/v)のDMSOで処理した培養物を対照として使用した。
銀による組換え型細菌TrxRの阻害を、大腸菌酵素を使用して実行した。実験は、5μMの大腸菌Trx存在下で、50mMのTris・HCl(pH7.5)、200μMのNADPH、1mMのEDTA、1mMのDTNBを含有する溶液中で、96マイクロウェルプレートを用いて実行した。412nmでの吸光度を、VERSAマイクロウェルプレートリーダーを用いて5分間測定し、最初の2分の傾斜を、TrxR活性を表現するために使用した。Trx活性を、反応混合物中の5μMの大腸菌Trxの代わりに100nMの大腸菌TrxRを組み合わせたこの方法により検出した。
銀を有する還元型大腸菌Trxの蛍光スペクトルを、280nmでの励起を使用するPerkinElmer Enspire Multilabel Readerで10μMにおいて記録した。
大腸菌DHB4株細胞を0.4のOD600nmでの吸光度にLB培地で増殖させ、当該細菌細胞を異なる組み合わせのエブセレンおよびAgNO3で10分間処理した。細菌におけるROS生成量を分析するために、細胞を6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、5μMのH2DCF−DAで20分間染色した。インキュベーション後に、細胞を遠心沈殿しPBSに再懸濁し、ROS生成をフローサイトメトリー(CyAn ADP、Beckman coulter)によって定量化した。
大腸菌DHB4株細胞を0.4のOD600nmでの吸光度にLB培地で増殖させ、当該細菌細胞を20μMのエブセレンおよび5μMのAgNO3で10分間処理した。細胞を、6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、10秒間超音波処理した。50mMのリン酸ナトリウム緩衝液(pH7.4)中の50μMのAmplex(商標) Red試薬(Molecular Probes社、オレゴン州ユージーン)、0.1U/mLのHRPの存在下で、50μlの試料を光から保護して室温にて30分間インキュベートし、560nmでの吸光度で検出した。
大腸菌DHB4株細胞を0.4のOD600nmに増殖させ、エブセレンの系列希釈物(0、2、4、8μM)で16時間処理した。細胞生存率を、600nmで吸光度を測定することによって決定された。0.8%(v/v)のDMSOで処理した培養物を、対照として使用した。
直接生存率アッセイを実施して、エブセレンおよびAgNO3で処理した大腸菌DHB4株の健康なマウスの血液中での生存能力を評価した。リン酸緩衝食塩水(PBS、pH7.6)で処理した細胞を陽性対照として使用し、この実験を二度繰り返して実施した。要約すると、血液を3匹のマウスから抽出し、ヘパリンで凝血防止されたチューブに採取した。約100個の大腸菌DHB4細胞を対数増殖期中に収集し、殺菌したPBSで洗浄し、100μlの血液に加えた。37℃にて6時間のインキュベーション後に、各々の血液試料からの二連の100μlアリコートをLB寒天上に広げ、生存しているコロニーを終夜培養後に数えた。結果は、エブセレンおよびAgNO3は自然免疫が大腸菌を除去するのを促進できることを示した。
本実験は、10nM大腸菌TrxRの存在下で、50mMのTris・HCl(pH 7.5)、250μMのNADPH、1mMのEDTA、1mMのDTNBを含有する溶液中で、96マイクロウェルプレートを用いて実施した。412nmでの吸光度を、VERSAマイクロウェルプレートリーダーを用いて5分間測定し、最初の2分の傾斜を、TrxR活性を表現するために使用した。
平均値、標準偏差(SD)およびt検定(両側、対応なし)による有意性を、GraphPad Prismソフトウエアで算出した。*:p=0.05、**:p=0.01、***:p=0.001。
実施例2 生体内実験
2.1 結果
2.2 材料および方法
軽度腹膜炎マウスモデルによるアッセイ
本実験は乱塊法および単盲検試験で設計され、40匹のマウスを4つの群、10匹のマウス/群に分けた。接種を、26ゲージのシリンジを使用して100μlの6.0×106CFU/mlの大腸菌ZY−1株接種物を腹注することにより実施した。接種物を、無菌生理食塩水中8%(w/v)のムチンを含む懸濁液で送達した。接種物の導入の1時間後に、群あたり10匹のマウスを抗菌処置し、当該マウスを7日間観察して全生存率を評価した。実験を二度繰り返して実施した。
群あたり5匹のマウスに6mgのAgNO3/kg体重および連続的濃度のエブセレン(10、15、20、25mgのAgNO3/kg体重)を腹腔内投与した。マウスを7日間観察して全生存率を算出した。
群あたり3匹のマウスを、PBS、6mgのAgNO3/kg体重と組み合わされた25mgのエブセレン/kg体重および媒体を非経口投与することによって処置した。当該動物を2日間観察し、後眼窩血液試料の採取を処置の6、24および48時間後に実施した。血液をヘパリンで凝血防止された全血試験管に採取し、血液化学分析装置(SYSMEX XE5000)により更に分析した。
平均値、標準偏差(SD)およびt検定(両側、対応なし)による有意性を、GrapPad Prismソフトウエアで算出した。*:p=0.05、**:p=0.01、***:p=0.001。
実施例3 従来の抗生物質との比較
3.1.大腸菌に対する結果
グラム陰性細菌モデルである大腸菌の増殖に対する硝酸銀(AgNO3)および5つの異なる機能的分類(βラクタム系、アミノグリコシド系、合成、テトラサイクリンおよびマクロライド系)を代表する9種の抗生物質の抗菌効果を96ウェルマイクロプレートで調べた。大腸菌DHB4株の一晩培養物をルリア・ベルターニ(LB)培地で1000倍希釈し、組み合わせた硝酸塩としてのイオン性銀(Ag+)の系列希釈物および9種の抗生物質でそれぞれ24時間処理した。エブセレンを陽性対照として使用し、それはグラム陰性細菌に対して銀と共に相乗作用的に作用した。ここで結果は、9種の抗生物質のうちの4種(ゲンタマイシン、カナマイシン、ジェネティシン、テトラサイクリン)が大腸菌DHB4株の増殖に対して相乗作用的な活性を有することを示した(表9)。さらに、Blissモデルを使用して組み合わせた銀および抗生物質によって示された治療効果の性質を決定した。相乗効果の程度を、組み合わせたAg+および4種の抗生物質(ゲンタマイシン、カナマイシン、ジェネティシンおよびテトラサイクリン)の間で1および4時間の時点で定量化し、結果は、Ag+および4種の抗生物質が大腸菌に対する相乗作用的な組み合わせを実際に有することを示した(図7)。全ての結果は、銀がグラム陰性細菌に対するある種の抗生物質の抗菌効果を増強できることを指摘した。
組み合わせでのAg+およびエブセレンは、高レベルのROSを生じさせることができ、組み合わせでのAg+および抗生物質の効果は、更なる研究を必要とする。したがって、本発明者らは、組み合わせたAg+および4種の抗生物質で処理した細胞におけるROSレベルを測定し、組み合わせたAg+およびエブセレンを陽性対照として使用した。結果は、組み合わせた5μMのAg+および80μMの抗生物質による処置がROSレベルの増加をもたらすことを示した(p<0.0001)(図8A)。更に、組み合わせた5μMのAg+および80μMの抗生物質による処置によって引き起こされるH2O2レベルの増大は、アンプレックスレッド法によっても確認された(p<0.0001)(図8B)。結果は、ROSが大腸菌に対する組み合わせたAg+および抗生物質の相乗作用的な殺菌効果の決定因子の1つであることを実証した。
チオール依存性抗酸化系の1つの主な機能は、ROSを除去して細胞内酸化還元バランスを保ち酸化ストレスから守ることである。Trx系の阻害およびGSHの欠乏が、ROS増加の原因である可能性がある。組み合わせでのAg+およびエブセレンは、細菌のTrxおよびGSH系を標的とすることが証明されているが、組み合わせでのAg+および抗生物質の効果は、更なる研究を必要とする。0.4のOD600nmに増殖させた大腸菌DHB4株を、組み合わせた5μMのAg+および80μMの抗生物質で処理し、組み合わせたAg+およびエブセレンを陽性対照として使用した。ここで結果は、処置の10分後に、組み合わせたAg+および抗生物質によって処理された細胞抽出物におけるTrx活性は、抗生物質または対照群と比較して劇的に阻害され(図9A、p<0.001)、同時に、組み合わせたAg+および抗生物質によって処理された細胞抽出物中のTrxR活性も抗生物質または対照群と比較した場合に統計学的に低下した(図9B、p<0.05)ことを示した。同一の結果が、処理時間を60分まで延長した場合に得られた。
全ての結果は、組み合わせた銀および抗生物質がTrx系に対する直接的な影響を有することを示した。
組み合わせでの5μMのAg+および80μMのエブセレンは、10分の処理後にGSHを減少させることも証明された。その実験において、組み合わせた5μMのAg+および80μMのゲンタマイシンまたはカナマイシンのみが、抗生物質それ自体と比較した場合に細胞抽出物中の総GSH量をわずかに減少させることができ(p<0.05)(図10A)、一方、他の組み合わせは、差を示さなかった(図10B)(p>0.05)。同一の結果が、処理時間を60分まで延長した場合に得られた(図11Aおよび11B)。更に、タンパク質のS−グルタチオン付加は、組み合わせたAg+およびエブセレンにより処理された細菌において減少したが、10分(図10B)または60分(図11B)の処理について組み合わせた5μMのAg+および抗生物質とインキュベートされた細菌では減少しなかった。
3.1において同定された4種の従来の抗生物質を、銀と組み合わせたエブセレンと比較して更に研究した。臨床的に単離された株であるK.ニューモニエ(K.pneumoniae)、A.バウマンニ(A.baumannii)、緑膿菌(P.aeruginosa)、E.クロアカ(E.cloacae)および大腸菌(E.coli)を使用すると、5種の抗生物質のうちの4μMのエブセレンのみが、銀のMICを劇的に低下させた。
5つの臨床的に最も処置が困難なMDRグラム陰性病原体種が存在する:クレブシェラ肺炎桿菌(Klebsiella pneumonia)、アシネトバクター・バウマンニ(Acinetobacter baumannii)、緑膿菌(Pseudomonas aeruginosa)、エンテロバクター・クロアカ(Enterobacter cloacae)および大腸菌(Escherichia coli)。各々の種から1株を単離し、一晩培養物をLB培地で1000倍希釈し、組み合わせた連続的濃度のAg+および抗生物質により24時間処理した(表10)。結果は、組み合わせたAg+および抗生物質がこれらのMDRグラム陰性細菌に対する弱い抗菌効果を示し、同時に、組み合わせたAg+およびエブセレンが、広範な耐性菌に対する唯一有効な抗生物質であるかもしれないことを示した。本結果は、組み合わせた銀および抗生物質はTrx系およびGSH系の両方ではなくTrx系を直接的に破壊できるのみであるという事実によって説明される可能性がある。
菌株
全ての試験管内実験は、大腸菌(Escherichia coli、E.coli)DHB4株および下記に示す臨床的に単離された多剤耐性(MDR)グラム陰性菌を用いて実施した。臨床分離MDRグラム陰性菌は、中国湖北省の三峡大学の人民医院(Renmin Hospital of Three Gorges University in Hubei Province,PRC)において、全ての承認およびインフォームドコンセントを得て臨床患者から得られた。
全ての実験は、ルリア・ベルターニ(LB)培地(EMD millipore)で実施した。2−フェニル−1,2−ベンズイソセレナゾール−3(2H)−オン(エブセレン)(Daiichi)、9種の抗生物質:アンピシリン、カルベニシリン、ゲンタマイシン、ストレプトマイシン、ジェネティシン、カナマイシン、クロラムフェニコール、テトラサイクリン、エリスロマイシン、硝酸銀(Sigma-Aldrich)、メトキシポリエチレングリコールマレイミド(MeO−PEG−Mal)(Sigma-Aldrich)、ヨードアセトアミド(IAM)(Sigma-Aldrich)、プロテアーゼ阻害剤カクテル(Roche)、N−アセチルシステイン(NAC)(Sigma-Aldrich)、DCTMタンパク質アッセイ(Bio-RAD)、大腸菌DHB4株TrxR、ヒツジ抗大腸菌Trx1抗体はIMCO社(スウェーデン国ストックホルム市;http://www.imcocorp.se)から購入、ウサギ抗ヒツジIgG−HRP(Santa Cruz)、グルタチオン−タンパク質複合体に対するマウスIgG2aモノクローナル抗体(VIROGEN)、4〜12%のBolt Bis−Trisゲル(VWR)。他の全ての試薬はSigma-Aldrichから購入した。
凍結保存からの大腸菌DHB4株を、37℃、400rpmにて一晩増殖させた。一晩培養物を、15mlチューブにて5mlのLB培地で100倍希釈し、400rpm、37℃でインキュベートした。細胞を0.4のOD600nmに増殖させ、抗生物質処理に使用した。要約すると、細胞を、96マイクロウェルプレート中の100μlのLB培地に1000倍希釈した。抗生物質100μl(0、1、2、4μM)および硝酸銀(AgNO3、0、1.25、2.5、5、10、20、40、80μM)の系列希釈物を個々のウェルに加えた。最小阻害濃度(MIC)を、37℃での24時間培養後の未処理の細胞と比較して増殖の90%を阻害した薬剤の最も低い濃度として決定した。100μlのエブセレンおよび硝酸銀の同じ系列希釈物で処理した培養物を、陽性対照として使用した。
薬剤相乗作用を、Bliss独立性モデルを使用して決定し、それは以下の公式:S=(fX0/f00)(f0Y/f00)−(fXY/f00)[式中、fXYは、一方の薬剤について濃度X、かつ他方の薬剤について濃度Yで組み合わせた薬剤の存在下での野生型増殖速度を指す;fX0およびf0Yは、それぞれXおよびYの濃度での個々の薬剤の存在下での野生型増殖速度を指す;f00は、薬剤の非存在下での野生型増殖速度を指す;およびSは、正の値についての相乗作用的な相互作用及び負の値についての拮抗的な相互作用を決定するパラメータである、相乗効果の程度に相当する]を使用して相乗効果の程度を算出する。異なる時点での増殖速度を、分析されている増殖曲線または死滅曲線の傾きを算出することによって決定する。
大腸菌DHB4株細胞を0.4のOD600nmでの吸光度にLB培地で増殖させ、当該細菌細胞を組み合わせでの銀および抗生物質で10分間処理した。細菌におけるROS生成量を分析するために、細胞を6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、5μMのH2DCF−DAで20分間染色した。インキュベーション後に、細胞を遠心沈殿し、PBSに再懸濁し、ROS生成をフローサイトメトリー(CyAn ADP、Beckman coulter)によって定量化した。
大腸菌DHB4株細胞を0.4のOD600nmでの吸光度にLB培地で増殖させ、当該細菌細胞を組み合わせでの銀および抗生物質で10分間処理した。細胞を、6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、10秒間超音波処理した。50mMのリン酸ナトリウム緩衝液(pH7.4)中の50μMのAmplex(商標) Red試薬、0.1U/mLのHRPの存在下で、50μlの試料を、光から保護して室温にて30分間インキュベートし、560nmでの吸光度で検出した(Molecular Probes社、オレゴン州ユージーン)。
大腸菌DHB4株細胞を、LB培地で0.4のOD600nmでの吸光度に増殖させ、当該細菌細胞を80μMの抗生物質および5μMのAgNO3でそれぞれ10および60分間処理した。80μMのエブセレンおよび5μMのAgNO3で処理した培養物を、陽性対照として使用した。細胞を、6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、次いで細胞を、プロテアーゼ阻害剤カクテルを含有する溶解緩衝液(25mMのTris・HCl(pH7.5)、100mMのNaCl、2.5mMのEDTA、2.5mMのEGTA、20mMのNaF、1mMのNa3VO4、20mMのβ−グリセロリン酸ナトリウム、10mMのピロリン酸ナトリウム、0.5%のTriton X−100)中に再懸濁し、超音波破砕によって溶解した。細胞可溶化物を、13,000rpmで20分間遠心分離することによって得て、タンパク質濃度を、ローリータンパク質分析によって測定した。
大腸菌DHB4株細胞を、LB培地で0.4のOD600nmでの吸光度に増殖させ、当該細菌細胞を80μMの抗生物質および5μMのAgNO3でそれぞれ10および60分間処理した。80μMのエブセレンおよび5μMのAgNO3で処理した培養物を、陽性対照として使用した。ウエスタンブロット法を、処理された大腸菌細胞のTrx1の酸化還元状態を検出するために実施した。細胞を6,000rpmで5分間遠心分離することによって収集し、PBSで3回完全に洗浄し、1.0ml中の5%TCAでタンパク質を沈殿させた。沈殿物を1mlの事前に氷冷したアセトンで3回洗浄し、15mMのMeO−PEG−Malを含有する0.5%のSDSを加えた50mMのTris・HCl(pH 8.5)中で37℃にて2時間溶解した。タンパク質を、13,000rpmで20分間遠心分離してペレットを除去することによって得て、タンパク質濃度をローリータンパク質分析により測定した。タンパク質を90℃にて10分間SDSローディングバッファーとインキュベートし、次いで、MESランニングバッファーを用いる4〜12%Bolt Bis−Trisゲル上で分離した(150V、40分)。Trx1の酸化還元状態を、ヒツジ抗大腸菌Trx1抗体を1000倍希釈で用いて検出し、続いてChemiluminescence Reagent Plusの検出を行った。
組み合わせでの抗生物質およびAgNO3により処理された大腸菌細胞のS−グルタチオン付加タンパク質の総量も、ウエスタンブロット法によって検出した。大腸菌DHB4株細胞を、LB培地で0.4のOD600nmでの吸光度に増殖させ、当該細菌細胞を80μMの抗生物質および5μMのAgNO3でそれぞれ10および60分間処理した。80μMのエブセレンおよび5μMのAgNO3で処理した培養物を、陽性対照として使用した。細胞を3回洗浄し、50mMのIAMを含有する溶解緩衝液(25mMのTris・HCl(pH7.5)、100mMのNaCl、2.5mMのEDTA、2.5mMのEGTA、20mMのNaF、1mMのNa3VO4、20mMのβ−グリセロリン酸ナトリウム、10mMのピロリン酸ナトリウム、0.5%のTriton X−100、プロテアーゼ阻害剤カクテル)中に再懸濁した。超音波破砕によって溶解した後に、細胞可溶化物を、13,000rpmで20分間遠心分離することによって得た。
タンパク質濃度をローリータンパク質分析により測定し、ウエスタンブロットアッセイを、S−グルタチオン−タンパク質複合体に対するマウスIgG2aモノクローナル抗体(VIROGEN、101−A/D8)を用いて上記の通り実施した。
5株の臨床分離MDRグラム陰性菌を、0.4のOD600nmに増殖させ、96マイクロウェルプレート中の100μlのLB培地に1000倍希釈した。組み合わせた100μlの抗生物質(0、1、2、4μM)およびAgNO3(0、1.25、2.5、5、10、20、40、80、160μM)の系列希釈物を、個々のウェルに加えた。MICを、37℃での16時間培養の後に測定した。100μlのエブセレンおよび硝酸銀の同じ系列希釈物で処理した培養物を、陽性対照として使用した。
Claims (48)
- 銀含有剤および有機セレン剤を含む、抗生物質組成物。
- 前記銀含有剤が銀イオンを含む、請求項1に記載の抗生物質組成物。
- 前記銀含有剤が硝酸銀を含む、請求項1に記載の抗生物質組成物。
- 前記銀含有剤がクエン酸二水素銀を含む、請求項1に記載の抗生物質組成物。
- 前記有機セレン剤がセレナゾール化合物を含む、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記有機セレン剤がベンゾイソセレナゾール−3(2H)−オン化合物を含む、請求項5に記載の抗生物質組成物。
- 前記有機セレン剤がエブセレンを含む、請求項6に記載の抗生物質組成物。
- 前記抗生物質組成物が液体剤形である、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記抗生物質組成物が溶液または懸濁液の剤形である、請求項8に記載の抗生物質組成物。
- 前記抗生物質組成物中の前記銀含有剤の濃度が約0.5〜50μM、約1〜25μM、または約1〜10μMである、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記抗生物質組成物中の前記銀含有剤の濃度が5μMである、請求項10に記載の抗生物質組成物。
- 前記抗生物質組成物中の前記有機セレン剤の濃度が約4〜25μM、約30〜200μM、約30〜150μM、または約30〜100μMである、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記抗生物質組成物中の前記有機セレン剤の濃度が約40μMまたは約80μMである、請求項12に記載の抗生物質組成物。
- 前記銀含有剤および前記有機セレン剤が約1:2〜約1:20のモル比である、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記銀含有剤および前記有機セレン剤が約1:4、1:8、または1:16のモル比である、請求項14に記載の抗生物質組成物。
- 前記抗生物質組成物が1種以上のグラム陰性細菌に対して約10〜100nMのIC50値を示す、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記抗生物質組成物が1種以上のグラム陰性細菌に対して約50nM以下のIC50値を示す、請求項16に記載の抗生物質組成物。
- 前記1種以上のグラム陰性細菌がK.ニューモニエ(K.pneumoniae)、A.バウマンニ(A.baumannii)、緑膿菌(P.aeruginosa)、E.クロアカ(E.cloacae)、大腸菌(E.coli)、またはこれらの任意の組み合わせを含む、請求項16または17に記載の抗生物質組成物。
- 前記抗生物質組成物がAgNO3およびエブセレンを含む、先行請求項のいずれか一項に記載の抗生物質組成物。
- 前記抗生物質組成物が液体剤形で5μMのAgNO3および4μMのエブセレンを含む、請求項1に記載の抗生物質組成物。
- 前記抗生物質組成物が液体剤形で5μMのAgNO3および20μMのエブセレンを含む、請求項1に記載の抗生物質組成物。
- 前記抗生物質組成物が液体剤形で5μMのAgNO3および40μMのエブセレンを含む、請求項1に記載の抗生物質組成物。
- 前記抗生物質組成物が液体剤形で5μMのAgNO3および80μMのエブセレンを含む、請求項1に記載の抗生物質組成物。
- 先行請求項のいずれか一項に記載の抗生物質組成物を含む医薬製剤。
- 先行請求項のいずれか一項に記載の抗生物質組成物を1種以上の細菌と接触させることを含む、1種以上の細菌を阻害するかまたは死滅させる方法。
- 先行請求項のいずれか一項に記載の抗生物質組成物を細菌感染と接触させることを含む、細菌感染を処置する方法。
- 前記1種以上の細菌が1種以上のグラム陰性細菌を含む、請求項25または26に記載の方法。
- 前記1種以上の細菌が1種以上の多剤耐性グラム陰性細菌を含む、請求項27に記載の方法。
- 前記1種以上の細菌がK.ニューモニエ(K.pneumoniae)、A.バウマンニ(A.baumannii)、緑膿菌(P.aeruginosa)、E.クロアカ(E.cloacae)、大腸菌(E.coli)、または任意のこれらの組み合わせを含む、請求項28に記載の方法。
- 前記細菌感染または1種以上の細菌が表面上である、請求項25〜29のいずれか一項に記載の方法。
- 前記細菌感染または1種以上の細菌が哺乳動物に存在する、請求項25〜30のいずれか一項に記載の方法。
- 前記細菌感染または1種以上の細菌がヒトに存在する、請求項31に記載の方法。
- 前記接触が注射による、請求項25〜32のいずれか一項に記載の方法。
- 前記接触させることが静脈内注射または皮下注射による、請求項33に記載の方法。
- 前記接触させることが局所適用による、請求項25〜32のいずれか一項に記載の方法。
- 前記接触させることが経口投与による、請求項25〜32のいずれか一項に記載の方法。
- 前記接触させることが少なくとも約1分間、2分間、3分間、4分間、5分間、10分間、20分間、30分間、40分間、50分間、1時間、2時間、3時間、4時間、5時間、6時間、7時間、8時間、9時間、10時間、11時間、12時間、18時間、1日間、2日間、3日間、4日間、5日間、6日間、1週間、または1ヵ月間持続する、請求項25〜36のいずれか一項に記載の方法。
- 前記接触させることが毎時間または毎日1、2、3、4、5、6、7、または8回発生する、請求項25〜37のいずれか一項に記載の方法。
- 前記接触させることが毎日約3、4、5、6、7、8、9、10、11または12分または時間毎に発生する、請求項25〜38のいずれか一項に記載の方法。
- 前記抗生物質組成物が単一単位用量である、請求項25〜39のいずれか一項に記載の方法。
- 前記細菌感染または前記1種以上の細菌と接触される前記有機セレン剤の量が用量あたり約10〜100mg、約10〜50mg、または約20〜30mgである、請求項25〜40のいずれか一項に記載の方法。
- 前記細菌感染または前記1種以上の細菌と接触される前記有機セレン剤の量が用量あたり約25mgである、請求項41に記載の方法。
- 前記細菌感染または前記1種以上の細菌と接触される前記銀の量が用量あたり約1〜20mg、約1〜10mg、または約5〜7mgである、請求項25〜42のいずれか一項に記載の方法。
- 前記細菌感染または前記1種以上の細菌と接触される前記銀の量が用量あたり約6mgである、請求項43に記載の方法。
- 銀含有剤および有機セレン剤を混合することを含む、抗生物質組成物を製造する方法。
- 前記混合することが液体中で実施される、請求項45に記載の方法。
- 前記混合することが前記有機セレン剤を含む液体に前記銀含有剤を加えることを含む、請求項45または46に記載の方法。
- 前記混合することが前記銀含有剤を含む液体に前記有機セレン剤を加えることを含む、請求項45または46に記載の方法。
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