JP5866298B2 - 抗菌剤およびその使用法 - Google Patents
抗菌剤およびその使用法 Download PDFInfo
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- JP5866298B2 JP5866298B2 JP2012550177A JP2012550177A JP5866298B2 JP 5866298 B2 JP5866298 B2 JP 5866298B2 JP 2012550177 A JP2012550177 A JP 2012550177A JP 2012550177 A JP2012550177 A JP 2012550177A JP 5866298 B2 JP5866298 B2 JP 5866298B2
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Description
多くの種類の表面におけるバイオフィルムの形成は、深刻な、ますます満たされない医療問題である。バイオフィルムは、ほんの数例を上げれば、カテーテルおよびポート、移植された人工器具などの金属表面、深い傷外傷領域などの生きている組織、ならびに歯、歯肉組織および骨などの口腔組織を含む多くの表面上で形成することができる。
バイオフィルムの理解の中で最も重要な進歩の中にクオラムセンシング(QS)の発見があり、この手段は、バイオフィルム形成細菌の数が特定の閾値に達した時に、それら自体の存在を伝え、バイオフィルム形成のプロセスを開始するというものである。分子レベルでの伝達「トリガー」の探索により、グラム陰性細菌の主要なクオラムセンシング伝達分子としてアシルホモセリンラクトン(AHL)のファミリーが同定された。グラム陽性菌のクオラムセンシングでは、少なくとも3つのステップのカスケードが関与するが、少なくともいくつかの種において、重要なものの1つはAHLである。グラム陰性細菌およびグラム陽性細菌の両方で、QSシグナルの検出は遺伝子発現を介すると現在理解されている。AHLが、センシング分子の結合部位を占有することができる時に、AHLは、バイオフィルムの菌体外多糖「スライム」の産生をもたらす反応のカスケードを開始する。
式1:LuX 1 イニシエータ+AHL⇔LuX 1−AHL
KAHL=[LuX 1−AHL]/[AHL]
式2:LuX 1 インデューサー+Fur⇔LuX 1−Fur
KFur=[LuX 1−Fur]/[Fur] (式中、Kfurは約1である。)
AHL+H2O<=>HO−(CH2)2−CH−(CONH−R)−COOH
AHL+EtOH<=>HO−(CH2)2−CH−(CONH−R)−COOEt
AHL+H2O<=>3−アミノテトラヒドロフラン−2−オン+HOOC−R(一般に、脂肪酸)
本出願の抗菌剤には、アルコール、過酸化物または過酸化物生成剤およびキレート剤が含まれ、残りのバランスは水で構成されている。本出願の抗菌剤の特有の設計特性および個々の成分の組み合わせに由来する相乗効果は、単一の成分治療の落とし穴を避ける効果のスペクトルを提供する。
本出願の抗菌剤は、微生物成長の阻害または軽減のために提供することができる。本出願の抗菌剤は、微生物成長を阻害するかまたは軽減するためにも提供することができる。
バイオフィルム研究が増え、ヒトおよび動物の病因におけるそれらの重要性が広く認識されるにつれて、脆弱性の他の点が知られるようになる。多くの場合、これらの研究は生物に固有のものであり、したがって、一般的な医療への応用のための潜在能力はいまだ知られていない。一方、いくつかは、狭い範囲の適用できる種でさえ、医学的に重要な治療に方法(window)を提供するとても重要な病原体を含む。例えば、Mukherjeeらは、酵素アルコールデヒドロゲナーゼ(Adh1p)が、アルコールベース機構を介してカテーテル表面にバイオフィルムを形成するカンジダ・アルビカンスの能力を制限することを示している。興味深いことに、Adh1p酵素はバイオフィルムの形成に必要であるが、ひとたびバイオフィルムが浮遊カンジダ・アルビカンス細胞によって産生されると、Adh1pの生産は浮遊量に対して著しく減少する。同様に興味深いことに、浮遊カンジダ・アルビカンスとバイオフィルムカンジダ・アルビカンスとの間で比較を行った時、アセトアルデヒドをエタノールに変換するAdh1pの化学的活性において著しい変化が見られる。浮遊形態において、この酵素は大量のエタノールを産生するが、バイオフィルムにおいて、アセトアルデヒド量が著しく上昇する。この知見は、バイオフィルムに結合したAdh1pは、アセトアルデヒドをエタノールに処理することができないことを意味しているようだが、この現象のメカニズムを説明していない。しかし、発明者らは、バイオフィルム中のエタノールの量を制限することによって、このカンジダ・アルビカンスはAdh1p活性を下方制御し、次に、追加のバイオフィルム成長を促進すると推測することができる。本出願の抗菌剤は高レベルのエタノールで設計され、これは、単独で、Mukherjee効果のバイオフィルム形成の減少を介してカンジダ・アルビカンスに対する有意な活性を提供する。さらに、発明者らの成分の組み合わせは、浮遊カンジダ・アルビカンスに対して迅速な活性があることがすでに示されている(未発表データ)。高レベルの浮遊細胞の死滅とわずかに残っている生存細胞によるバイオフィルム形成の予防を支援する能力のこの組み合わせは、カテーテルおよび他の移植装置のカンジダ感染に対して非常に十分な保護を患者に提供することが期待される。
最近多くの医学的配慮を受けており、バイオフィルムの防止または軽減に潜在的に別の方法を提供する別の種が黄色ブドウ球菌である。特に、MRSA、すなわち、メチシリン耐性黄色ブドウ球菌が、特に厄介ものであり、危険である。CaiazzaとO’Tooleは、α−溶血素とも呼ばれる細胞間相互作用プロモーターのα−毒素がバイオフィルム形成に必要であることを示している。自己溶菌酵素、テイコ酸および表面タンパク質などの他の物質は、バイオフィルムコロニー形成の早期形成に不可欠であるが、α−毒素が必須である。このα−毒素は、多糖類の細胞接着(polysaccharide intracellular adhesion)(PIA)の合成に必要であると思われる。α−毒素はしばらくの間知られており(例えば、Bhakdi S,Tranum−Jensen J参照)、MW=34kDの親水性タンパク質と特徴づけられ、生物の表面膜のポア形成者であると示されている。
リピドAと呼ばれることも多いリポ多糖は、膜脂質の生合成に必要な制御因子であることが知られるエンドトキシンである。リピドAは、いくつかの細菌細胞の死の際に放出される非常に有毒な成分の一つであり、場合によっては、毒素ショックを引き起こす。リピドAの構造は知られている(例えば、Jia et al.参照)。一般的なコア構造は基本的に不変であるが、多数の種に依存する変更が知られている。1つの高度に疎水性である部分は、糖環に結合したOHもしくは糖環に結合したNHのいずれかの一連の脂肪酸アシルエステルまたはアミド(通常は4つの鎖)から形成される。これらの4つの鎖は3’位に水酸基を有し、これらはアシル化もされる場合があり、通常2つの追加の鎖で分子内に疎水性の大きいゾーンを生成する。Jiaらは、水酸基の1つが、3’水酸化物にてパルミトイルエステルを形成することによって、細菌の外膜(OM)を渡る脂質輸送に関与していると報告している。このパルミトイルエステルの形成は、宿主免疫系の攻撃を防ぐため、およびエンドトキシン形成を制御するために、保護機能を提供する。
本出願の抗菌剤を、エタノールなどの低分子量のアルコール、過酸化水素などの過酸化物または過酸化物生成剤、およびEDTAなどのキレート剤を様々な濃度で混合することにより調製した。
本出願の抗菌剤の有効性を説明するために、3つの代表的な病原微生物を実験用に選択した。カンジダ・アルビカンスは真菌種であり、メチシリン耐性黄色ブドウ球菌(MRSA)はグラム陽性細菌種であり、緑膿菌はグラム陰性細菌種である。
感染時に存在する炎症環境が、ガン(および前ガン)の発達および/もしくは進行を活性化するか、またはガン(および前ガン)の発達および/もしくは進行と関連するのかどうかを試験するために、慢性歯周炎にかかり、口腔内に白板症病変を示した被験者を調べた。
本出願の抗菌剤の抗ウイルス活性も、口唇ヘルペスを発症した2人の被験者で試験した。
Claims (7)
- 抗菌剤溶液であって、
(a)水;
(b)20〜60容積%の、エタノール;
(c)0.5〜7.5容積%の、過酸化水素;および
(d)5〜40mg/mLの、エチレンジアミン四酢酸(EDTA)、その酸、その塩、またはそれらの組み合わせ;
を含み、
微生物成長、微生物感染、炎症性疾患、ウイルス性疾患、あるいは微生物成長もしくは感染に起因するかまたは関連する状態の軽減、阻害、または処置に用いられる、
抗菌剤溶液。 - 前記エタノールの濃度が50容積%である、請求項1記載の溶液。
- 前記EDTAが10mg/mLの濃度で存在する、請求項1記載の溶液。
- 前記EDTA、その酸、その塩、またはそれらの組み合わせが10mg/mLの濃度で存在する、請求項1記載の溶液。
- 前記過酸化水素が1.5容積%の濃度で存在する、請求項1記載の溶液。
- 粘度増加剤をさらに含む、請求項1記載の溶液。
- 前記粘度増加剤が、ヒドロキシプロピルメチルセルロース(HPMC)を含む、請求項6記載の溶液。
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WO2011091322A2 (en) | 2011-07-28 |
KR101785130B1 (ko) | 2017-10-12 |
CA2786880C (en) | 2018-04-24 |
JP2016056186A (ja) | 2016-04-21 |
US8846009B2 (en) | 2014-09-30 |
WO2011091322A3 (en) | 2011-09-29 |
CN103108643B (zh) | 2016-10-26 |
JP6118918B2 (ja) | 2017-04-19 |
US8846008B2 (en) | 2014-09-30 |
US20130287860A1 (en) | 2013-10-31 |
MX2012008482A (es) | 2012-11-29 |
BR112012018170B8 (pt) | 2021-05-25 |
KR20120117837A (ko) | 2012-10-24 |
RU2570387C2 (ru) | 2015-12-10 |
BR112012018170A2 (pt) | 2018-11-06 |
CA2786880A1 (en) | 2011-07-28 |
BR112012018170B1 (pt) | 2021-04-06 |
RU2012136147A (ru) | 2014-02-27 |
AU2011207398A1 (en) | 2012-07-26 |
CN103108643A (zh) | 2013-05-15 |
AU2011207398B2 (en) | 2014-11-20 |
US20130287861A1 (en) | 2013-10-31 |
EP2525803A2 (en) | 2012-11-28 |
US9253987B2 (en) | 2016-02-09 |
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