JP2021529180A - Epsを媒介するための組成物および方法 - Google Patents
Epsを媒介するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)(35U.S.C.§119(e))の下、2018年6月29日出願の米国仮出願第62/692,581号の優先権を主張し、当該出願の内容は、その全体がこれにより参照により本明細書に組み込まれる。
したがって、関連付けられる細菌感染症を処置または死滅させ、表面および水系からそれらを取り除くためにバイオフィルムの保護的障壁を切り抜けることへの必要性が存在している。
イタリック体のアミノ酸(アミノ酸88〜164)は、Bボックスドメインを表す。
下線のアミノ酸(アミノ酸186〜215)は、C尾部ドメインを表す。これらは、断片、例えば、Aボックスドメイン、Bボックスドメイン、AおよびBボックスドメイン(ABボックスドメイン)、C尾部ドメインおよびNドメイン(アミノ酸1〜185)の非限定的な例である。一態様では、断片は、C末端ドメイン、またはBボックスドメインを含むポリペプチドから本質的になる。
本開示を行うための様式
I.バイオフィルム構造および疾患
細胞内細菌核様体
細胞外細菌核様体(nucleoi)
慢性および再発性感染症は、細菌バイオフィルムの結果である
eDNA依存性EPSは、普遍的な基礎をなすアーキテクチャの質を有する
DNABIIファミリーのタンパク質は、バイオフィルムeDNA−スキャフォールド化EPSの構造的完全性を維持する要である
ポリアミンは、細胞内外で遍在性であり、バイオフィルムのeDNA−スキャフォールド化EPS構造に必要とされる
B−DNAのZ−DNAへの変換は、eDNA−スキャフォールド化EPSをヌクレアーゼ抵抗性にし、安定な構造材料を作り出すための新規手段であり得る
II.3部構成のアプローチ
A.ポリアミン
ポリアミンはDNABIIタンパク質と共同して機能して、eDNAスキャフォールドのアセンブリーを方向付ける
ポリアミン生合成は、バイオフィルム構造に必要とされる
抗DNABIIは、DNABII−ポリアミン依存性DNA構造を破壊する
カチオン交換体P11によるNTHIバイオフィルム破壊は、外因性DNABII(HU)およびスペルミジン添加によって妨げられ得る
DNアーゼは、成熟病原性細菌バイオフィルムを破壊することができない
DNABIIタンパク質およびポリアミンは、相乗的に相互作用してDNAにヌクレアーゼ抵抗性を与える
B.DNABII、ポリアミンおよびDNAはin vitroでZ−DNAを形成する
細菌バイオフィルム中のEPSはZ−DNAおよびポリアミンを含有する
HU欠損NTHIはネイティブバイオフィルムを形成すること、ポリアミンを組み込むこと、およびB−DNAからZ−DNAへのシフトを誘導することができない
III.診断方法および治療方法
抗体およびその誘導体
抗体による機能解析
組成物
スクリーニングアッセイ
併用療法
キット
実験番号1
ポリアミンは、殆ど全ての生物によって産生および利用される、遍在性で小型の脂肪族ポリカチオンである。Michael et al. (2016) J Biol Chem. 291(29):14896−903;D’Agostino et al. (2005) FEBS J. 272(15):3777−87。ポリアミンは、アミノ酸から得られ、転写、翻訳、転写調節、オートファジーおよびストレス抵抗性を含む、成長および増殖の中心となる数多くの細胞機能において役割を果たす。Miller−Fleming et al. (2015) J Mol Biol 427(21):3389−406。ポリアミン合成のための複数の経路が存在し、代謝レパートリーにおけるその存在は、種間で変動する。Michael et al. (2016) Biochem J. 473(15):2315−29。その静電媒介性相互作用の非特異的性質のため、ポリアミン合成は、転写、翻訳およびタンパク質分解機構の組合せにより密接に調節される。Miller−Fleming et al. (2015) J Mol Biol 427(21):3389−406。
ポリアミンは細菌バイオフィルムの細胞外マトリックスに存在する
ポリアミン合成阻害またはポリアミンアンタゴニズムは細菌バイオフィルムを破壊する
(実施例2)
実験番号2
カチオン交換樹脂は、分類不能Haemophilus influenzae(NTHI)による予め形成されたバイオフィルムおよびバイオフィルム形成に負の効果を有する
DNABII(HU)は、カチオン枯渇された予め形成されたNTHiバイオフィルムを部分的に回復した
二価金属は、カチオン枯渇された予め形成されたNTHIバイオフィルムを部分的に回復する
スペルミジンは、カチオン枯渇された予め形成されたNTHIバイオフィルムを部分的に回復する
P11ホスホセルロースのカチオン枯渇効果は、バイオフィルムとの直接的接触を要求しない
スペルミジンの外因性添加は、トランスウェルシステムにおけるP11ホスホセルロースのカチオン枯渇効果を補償する
スペルミジンおよびDNABIIは、相乗的に作用して、非接触媒介性P11ホスホセルロースによりカチオン枯渇されたバイオフィルムを回復させる。
カチオン交換樹脂でコーティングされた非生物的表面は、用量依存性様式でバイオフィルム形成を予防する
(実施例3)
実験番号3
細菌バイオフィルムは、Z−DNAが蓄積するにつれて、ヌクレアーゼ破壊に対して抵抗性になる
ポリアミンおよびDNABIIタンパク質は協同して、バイオフィルムマトリックスにおけるZ−DNA構造を安定化する
Z−DNAからB−DNAへの復帰は、ヌクレアーゼ感受性を回復する
(実施例4)
実験番号4
(実施例5)
実験番号5
TEDSの形成に寄与するUPECポリアミン合成遺伝子を同定する
TEDSの形成に寄与するUPECポリアミン搬出遺伝子を同定する
馴化培地におけるポリアミンを定量する
TEDSにおけるポリアミンの定常状態レベルの役割を確立する
表1.バイオフィルム形成を予防するヌクレアーゼおよびそのスペルミジン感受性
細菌バイオフィルムにおけるDNA、DNABIIおよびポリアミンの定常状態レベルの割合の頑強性の検査
TEDSに好まれるポリアミンが存在するかどうかを決定する
成果および代替
3部構成eDNA依存性スキャフォールドの発達におけるZ−DNAの役割を決定する
単一種バイオフィルムにおけるZ−DNAの存在量を明らかにし、Z−DNAが、ポリアミンおよび/またはDNABIIタンパク質と共局在するかどうかを決定する
二重種バイオフィルムにおけるZ−DNAの存在量を決定し、Z−DNAが、ポリアミンおよび/またはDNABIIタンパク質と共局在するかどうかを決定する
一方のパートナーが、eDNA、ポリアミンおよびHUに寄与することができない場合の、二重種バイオフィルムにおけるZ−DNAの程度、ならびにZ−DNAが、ポリアミンおよび/またはDNABIIタンパク質と共局在するかについて確立する
ヒト試料におけるZ−DNAの検出
TEDSの発達におけるZ−DNAの機能を調査する
Z−DNAに特異的なヌクレアーゼを使用してTEDSをプローブする
B形態へのDNAの駆動がTEDSに影響を与えるかを決定する
Z形態へのDNAの駆動がTEDSに影響を与えるかを決定する
IHFおよびHUがポリアミン誘導性Z−DNAの存在下でDNAに結合するかを決定する
IHFおよびHUがZ−DNAに結合するかを決定する
細菌バイオフィルム破壊におけるEPS成分および構造を標的とする作用物質の有効性を決定する
EPS eDNAスキャフォールドの以前に発見された成分を標的とする作用物質(抗DNABII抗体およびヌクレアーゼ)が、新たに発見されたTEDS成分/構造を標的とする作用物質(すなわち、ポリアミンおよびZ−DNA)と相乗的であるかどうかを決定する
ポリアミン、DNABIIタンパク質および/またはB形態eDNAの標的化
Z−DNA、DNABIIタンパク質および/またはB形態eDNAの標的化
ポリアミン、Z−DNA、DNABIIタンパク質およびB形態eDNAの標的化
TEDSに対する処置および抗微生物薬の相乗作用を決定する
抗微生物薬とTEDSの標的化との相乗作用
(実施例6)
実験番号6
(実施例7)
実験番号7
等価物
Claims (55)
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の作用物質と接触させることを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 対象においてバイオフィルムを処置するための方法であって、バイオフィルムに感染した前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- バイオフィルムを発生しやすい対象においてバイオフィルムの形成を予防するための方法であって、前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の作用物質を投与することを含み、必要に応じて、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- それを必要とする対象において、バイオフィルムを産生する細菌によって引き起こされる感染を処置するための方法であって、前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の作用物質と、前記生物の複製を阻害する作用物質とを投与することを含み、必要に応じて、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の1種または複数種の作用物質と接触させることを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 対象においてバイオフィルムを処置するための方法であって、バイオフィルムに感染した前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の1種または複数種の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- バイオフィルムを発生しやすい対象においてバイオフィルムの形成を予防するための方法であって、前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の1種または複数種の作用物質を投与することを含み、必要に応じて、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- それを必要とする対象において、バイオフィルムを産生する細菌によって引き起こされる感染を処置するための方法であって、前記対象に、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の1種または複数種の作用物質と、前記生物の複製を阻害する作用物質とを投与することを含み、必要に応じて、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 前記接触させることが、in vitroまたはin vivoである、請求項1または5に記載の方法。
- ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する前記作用物質が、tRNAである、請求項1、5または9のいずれか一項に記載の方法。
- 前記作用物質が、ポリアミン合成の阻害剤、または前記ポリアミンの前記DNAへの結合を阻害する作用物質であり、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、いずれかの前記請求項に記載の方法。
- 前記ポリアミンが、プトレシン、スペルミン、カダベリン、1,3−ジアミノプロパンまたはスペルミジンの群から選択される、いずれかの前記請求項に記載の方法。
- 前記作用物質が、ポリアミンアナログであるジフルオロメチルオルニチン、トランス−4−メチルシクロヘキシルアミン、サルドモジド、メチルグリオキサール−ビス[グアニルヒドラゾン](MGBG)、1−アミノオキシ−3−アミノプロパン、オキサリプラチン、シスプラチン、ジシクロヘキシルアミン、任意のその誘導体、またはその塩を含む、請求項11に記載の方法。
- 前記作用物質が、前記バイオフィルムからカチオンを枯渇させる作用物質、必要に応じて、カチオン交換樹脂、アミノポリカルボン酸、クラウンエーテル、アザクラウンまたはクリプタンドを含む、請求項1〜9のいずれか一項に記載の方法。
- 前記バイオフィルムからカチオンを枯渇させる前記作用物質が、スルホネート、スルホプロピル、ホスホセルロース、P11ホスホセルロース、ヘパリン硫酸またはその誘導体もしくはアナログの群からの作用物質である、請求項14に記載の方法。
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する作用物質とin vitroで接触させることを含み、前記接触させることが、表面を、カチオンを枯渇させる有効量の作用物質でコーティングすることを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する有効量の作用物質とin vitroで接触させることを含み、前記接触させることが、表面を、カチオンを枯渇させる有効量の1種または複数種の作用物質でコーティングすることを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 前記作用物質が、前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する、請求項1〜9または16もしくは17のいずれか一項に記載の方法。
- 前記作用物質が、抗B−DNA抗体またはその断片もしくは誘導体を含む、請求項16〜18のいずれか一項に記載の方法。
- 前記作用物質が、リボフラビン、エチジウムブロマイド、ビス(メチジウム)スペルミン、ダウノルビシン、TMPyP4、第四級ベンゾ[c]フェナントリジンアルカロイド、キナクリン、9−アミノアクリジンまたはその誘導体を含む、請求項16〜18のいずれか一項に記載の方法。
- 前記作用物質が、クロロキンまたはその誘導体を含む、請求項16〜18のいずれか一項に記載の方法。
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、有効量のHMGB1タンパク質またはその生物活性断片および抗B−DNA抗体またはその断片もしくは誘導体とin vitroで接触させることを含み、前記接触させることが、表面を、有効量のHMGB1タンパク質またはその生物活性断片および抗B−DNA抗体またはその断片もしくは誘導体でコーティングすることを含む、方法。
- バイオフィルムの安定性を阻害するための方法であって、前記バイオフィルムを、有効量のクロロキンおよび抗B−DNA抗体またはその断片もしくは誘導体とin vitroで接触させることを含み、前記接触させることが、表面を、有効量のクロロキンおよび抗B−DNA抗体またはその断片もしくは誘導体でコーティングすることを含む、方法。
- 全身性エリテマトーデス(SLE)および/または嚢胞性線維症(CF)を患う患者においてバイオフィルムを処置するための方法であって、前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する有効量の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 全身性エリテマトーデス(SLE)および/または嚢胞性線維症(CF)を患う患者においてバイオフィルムを処置するための方法であって、前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する有効量の1種または複数種の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 前記作用物質が、クロロキンまたはその誘導体を含む、請求項22または25に記載の方法。
- 前記作用物質が、抗B−DNA抗体またはその断片もしくは誘導体を含む、請求項22または25に記載の方法。
- 前記作用物質が、リボフラビン、エチジウムブロマイド、ビス(メチジウム)スペルミン、ダウノルビシン、TMPyP4、第四級ベンゾ[c]フェナントリジンアルカロイド、キナクリン、9−アミノアクリジンまたはその誘導体を含む、請求項22または25に記載の方法。
- 全身性エリテマトーデス(SLE)および/または嚢胞性線維症(CF)を患う患者においてバイオフィルムを処置するための方法であって、有効量のHMGB1タンパク質またはその生物活性断片および抗B−DNA抗体またはその断片もしくは誘導体を投与することを含む方法。
- 全身性エリテマトーデス(SLE)および/または嚢胞性線維症(CF)を患う患者においてバイオフィルムを処置するための方法であって、有効量のクロロキンおよび抗B−DNA抗体またはその断片もしくは誘導体を投与することを含む方法。
- プラチナベースの化学療法を受けているか、または受けた患者において前記化学療法の投与に付随するバイオフィルム産生感染を処置するための方法であって、前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する有効量の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- プラチナベースの化学療法を受けているか、または受けた患者において前記化学療法の投与に付随するバイオフィルム産生感染を処置するための方法であって、前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する有効量の1種または複数種の作用物質を投与することを含み、前記作用物質が、HMGB1タンパク質でも、その断片でも、その各々の等価物でもない、方法。
- 前記作用物質が、クロロキンまたはその誘導体を含む、請求項31または32に記載の方法。
- 前記作用物質が、抗B−DNA抗体またはその断片もしくは誘導体を含む、請求項31または32に記載の方法。
- 前記作用物質が、リボフラビン、エチジウムブロマイド、ビス(メチジウム)スペルミン、ダウノルビシン、TMPyP4、第四級ベンゾ[c]フェナントリジンアルカロイド、キナクリン、9−アミノアクリジンまたはその誘導体を含む、請求項31または32に記載の方法。
- プラチナベースの化学療法を受けているか、または受けた患者において前記化学療法の投与に付随するバイオフィルム産生感染を処置するための方法であって、有効量のHMGB1タンパク質またはその生物活性断片および抗B−DNA抗体またはその断片もしくは誘導体を投与することを含む方法。
- プラチナベースの化学療法を受けているか、または受けた患者において前記化学療法の投与に付随するバイオフィルム産生感染を処置するための方法であって、有効量のクロロキンおよび抗B−DNA抗体またはその断片もしくは誘導体を投与することを含む方法。
- 前記バイオフィルムを、eDNAのDNA結合タンパク質への結合に干渉する有効量の作用物質および/または抗菌剤と接触させることをさらに含む、請求項1または5に記載の方法。
- 前記eDNAの前記DNA結合タンパク質への結合に干渉する前記作用物質が、抗DNABII抗体、抗IHF抗体および/もしくは抗HU抗体またはその各々の断片のうちの1つまたは複数を含む、請求項38に記載の方法。
- 前記対象に、前記eDNAのDNA結合タンパク質への結合に干渉する有効量の作用物質および/または抗菌剤を投与することをさらに含む、請求項2〜39のいずれかに記載の方法。
- 前記eDNAの前記DNA結合タンパク質への結合に干渉する前記作用物質が、抗DNABII抗体、抗IHF抗体および/もしくは抗HU抗体またはその各々の断片のうちの1つまたは複数を含む、請求項40に記載の方法。
- 前記バイオフィルムからカチオンを枯渇させる前記作用物質が、正味の負電荷を有する、請求項14または15に記載の方法。
- 前記バイオフィルムからカチオンを枯渇させる前記作用物質が、正味の中性電荷を有する、請求項14または15に記載の方法。
- 前記eDNAのDNA結合タンパク質への結合に干渉する前記作用物質が、正味の負電荷を有する、請求項38に記載の方法。
- 前記eDNAのDNA結合タンパク質への結合に干渉する前記作用物質が、正味の中性電荷を有する、請求項38に記載の方法。
- 前記eDNAのDNA結合タンパク質への結合に干渉する前記作用物質が、正味の正電荷を有する、請求項38に記載の方法。
- 前記方法が、DNアーゼ酵素の投与の非存在下で行われる、請求項1〜46のいずれか一項に記載の方法。
- ポリアミンのバイオフィルム中のDNAへの結合に干渉する作用物質、バイオフィルムからカチオンを枯渇させる作用物質、バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する作用物質、eDNAのDNA結合タンパク質への結合に干渉する作用物質および/または抗菌剤のうちの1、2もしくは3つまたはそれよりも多くを含む組成物。
- 薬学的に許容される担体をさらに含む、請求項48に記載の組成物。
- ポリアミンの前記バイオフィルム中のDNAへの結合に干渉する前記作用物質が、ポリアミンアナログであるジフルオロメチルオルニチン、トランス−4−メチルシクロヘキシルアミン、サルドモジド、メチルグリオキサール−ビス[グアニルヒドラゾン](MGBG)、1−アミノオキシ−3−アミノプロパン、オキサリプラチン、シスプラチンおよび/もしくはジシクロヘキシルアミン、任意のその誘導体、またはその塩のうちの1つまたは複数を含む、請求項48または49に記載の組成物。
- 前記バイオフィルムからカチオンを枯渇させる前記作用物質が、カチオン交換樹脂、アミノポリカルボン酸、クラウンエーテル、アザクラウンまたはクリプタンド、スルホネート、スルホプロピル、ホスホセルロース、P11ホスホセルロースおよび/もしくはヘパリン硫酸またはその誘導体もしくはアナログのうちの1つまたは複数を含む、請求項48または49に記載の組成物。
- 前記バイオフィルムまたはその局所環境においてB−DNAのZ−DNAへの変換に干渉する前記作用物質が、HMGB1タンパク質、その断片もしくはその各々の等価物、抗B−DNA抗体またはその断片もしくは誘導体、および/またはクロロキン、または任意のその誘導体のうちの1つまたは複数を含む、請求項48または49に記載の組成物。
- 前記eDNAのDNA結合タンパク質への結合に干渉する前記作用物質が、抗DNABII抗体、抗IHF抗体および/もしくは抗HU抗体またはその各々の断片のうちの1つまたは複数を含む、請求項48または49に記載の組成物。
- 請求項48〜53のいずれか一項に記載の組成物と使用のための指示とを含むキットであって、必要に応じて、前記作用物質が、組み合わせられているか、または別々に包装されている、キット。
- 使用のための前記指示が、請求項1〜47のいずれか一項に記載の方法を行うための使用法を提供する、請求項54に記載のキット。
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