JP6985150B2 - 新規抗感染症化合物 - Google Patents
新規抗感染症化合物 Download PDFInfo
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- JP6985150B2 JP6985150B2 JP2017549649A JP2017549649A JP6985150B2 JP 6985150 B2 JP6985150 B2 JP 6985150B2 JP 2017549649 A JP2017549649 A JP 2017549649A JP 2017549649 A JP2017549649 A JP 2017549649A JP 6985150 B2 JP6985150 B2 JP 6985150B2
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Images
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- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
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Description
−Yは、O、H、OH、SおよびNからなる群から選択され、
------------は、結合なし、単結合または二重結合を示し、
------------は、単結合または二重結合を示し;
−mは、0と3との間の整数であり;
−nは、0と4との間の整数である)の化合物、その塩、その溶媒和物ならびにその塩の溶媒和物の提供により達成される。
1.Staphylococcus lugdunensis菌種の細菌を提供する工程、および
2.前記細菌から本発明の化合物を精製する工程
を含む方法である。
1.生体系においてStaphylococcus lugdunensis菌種の非リボソームペプチド合成酵素系II(NRPS−II)を発現させる工程、
2.発現させたNRPS−IIを、本発明の化合物の合成が可能な条件下でインキュベートする工程、および
3.前記化合物を精製する工程
を含む方法である。
lugA:6007〜13131
lugB:13121〜17341
lugC:17359〜26172
lugD:26893〜28632
GntRファミリー転写制御因子:427〜936
ABCトランスポーター(GdmF型の多剤輸送システム):1253〜2143
ABC−2型輸送システムの透過酵素タンパク質:2140〜2904
ABCトランスポーター:2917〜3630
仮定上の膜蛋白質:3623〜5164
TetR/AcrRファミリー制御因子:5409〜5981
チオエステラーゼファミリータンパク質:26169〜26855
4’−ホスホパンテテイニルトランスフェラーゼ:28640〜29293
(バチルス属菌の)sigYの推定上の負の制御因子:1027〜1266
A.方法
1.菌株および増殖条件
以下の実験において、Staphylococcus属菌株として、S.aureus USA300 LAC、S.aureus USA300 NRS384、S.aureus Mu50、S.aureus RN4220、S.aureus SA113、S.aureus Newman、S.aureus PS187、S.lugdunensis IVK28、S.lugdunensis IVK28 ΔlugD、S.lugdunensis IVK28 ΔlugD::pRB474/lugDおよびS.lugdunensis IVK28−Xylを使用した。MIC測定には、Enterococcus faecium BK463、E.faecalis VRE366、Listeria monocytogenes ATCC19118、Streptococcus pneumoniae ATCC49619、Pseudomonas aeruginosa PAO1およびEscherichia coli DH5αも使用した。また、クローニング用の宿主としてEscherichia coli DC10Bを使用した。さらに、以下に記載のコロニー形成試験の過程で診断用のサンプルからS.aureus60株およびS.lugdunensis17株を単離した。
2.生物活性試験
3.トランスポゾン突然変異誘発およびルグドゥニン遺伝子群の解明
4.S.lugdunensis IVK28−Xylの作製
5.ルグドゥニンの製造および精製
6.ルグドゥニンおよびルグドゥニンの誘導体の化学合成
7.MICアッセイおよび活性スペクトル
8.殺菌アッセイ
9.ヒト好中性顆粒球に対する細胞傷害性
10.耐性発現試験
11.統計分析
12.動物モデルおよび倫理的配慮
13.C57BL/6マウスにおける皮膚感染
14.S.lugdunensis ΔlugDの作製および補完
15.競争アッセイ
16.コットンラットの鼻腔内における共コロニー形成
17.ヒトにおけるコロニー形成実験
B.結果
1.Staphylococcus lugdunensisは、S.aureusに対して強い活性を有する極めて強力な抗菌性の環状NRPSペプチドを産生する
2.S.lugdunensis IVK28 NRPSオペロンの遺伝子構成
3.NRPS−II生合成産物の同定
4.S.lugdunensis IVK28は、S.aureus USA300との共培養実験において、USA300を排除することができる
5.NRPS−IIペプチドの過剰産生および精製
6.新規化合物は殺菌作用を有し、主として主要なヒト病原体に対する活性を有する
7.ルグドゥニンによる局所治療はin vivoマウスモデルにおいて有効である
8.ルグドゥニンの産生によりS.aureusとの競争に勝つ
9.ヒトの鼻腔内にS.lugdunensisが存在することは、S.aureusが存在しないことに関係している可能性が極めて高い
10.ルグドゥニン誘導体の生物活性
9.まとめ
Claims (33)
- 疾患の治療用および/または予防用の請求項1〜6のいずれか1項に記載の化合物。
- 感染症の治療用および/または予防用の請求項1〜7のいずれか1項に記載の化合物。
- 細菌性疾患の治療用および/または予防用の請求項1〜8のいずれか1項に記載の化合物。
- グラム陽性細菌による感染症の治療用および/または予防用の請求項1〜9のいずれか1項に記載の化合物。
- メチシリン耐性Staphylococcus aureus(MRSA)およびバンコマイシン耐性Staphylococcus aureus(VRSA)を含むStaphylococcus aureusによる感染症の治療用および/または予防用の請求項1〜10のいずれか1項に記載の化合物。
- 疾患の治療用および/または予防用の医薬組成物の製造のための、請求項1〜11のいずれか1項に記載の化合物の使用。
- 感染症の治療用および/または予防用の医薬組成物の製造のための、請求項1〜11のいずれか1項に記載の化合物の使用。
- 細菌性疾患の治療用および/または予防用の医薬組成物の製造のための、請求項1〜11のいずれか1項に記載の化合物の使用。
- グラム陽性細菌による感染症の治療用および/または予防用の医薬組成物の製造のための、請求項1〜11のいずれか1項に記載の化合物の使用。
- メチシリン耐性Staphylococcus aureus(MRSA)およびバンコマイシン耐性Staphylococcus aureus(VRSA)を含むStaphylococcus aureusによる感染症の治療用および/または予防用の医薬組成物の製造のための、請求項1〜11のいずれか1項に記載の化合物の使用。
- 請求項1〜11のいずれか1項に記載の化合物および医薬的に許容される担体を含む医薬組成物。
- 疾患の治療用および/または予防用の請求項17に記載の医薬組成物。
- 感染症の治療用および/または予防用の請求項18に記載の医薬組成物。
- 細菌性疾患の治療用および/または予防用の請求項19に記載の医薬組成物。
- グラム陽性細菌による感染症の治療用および/または予防用の請求項20に記載の医薬組成物。
- メチシリン耐性Staphylococcus aureus(MRSA)およびバンコマイシン耐性Staphylococcus aureus(VRSA)を含むStaphylococcus aureusによる感染症の治療用および/または予防用の請求項21に記載の医薬組成物。
- 請求項4に記載の化合物を製造する方法であって、
1.Staphylococcus lugdunensis菌種の細菌を提供する工程、および
2.前記細菌から請求項4に記載の化合物を精製する工程
を含む方法。 - 工程(1)の後かつ工程(2)の前に、前記細菌および前記細菌の培養液を抽出処理に供し、前記細菌からの抽出物および前記培養液からの抽出物を工程(2)に供して、これらの抽出物から前記化合物を精製することを特徴とする、請求項23に記載の方法。
- 工程(2)の精製が、高速液体クロマトグラフィー(HPLC)を使用して、前記化合物に関連するシグナルピークを確認することを含む、請求項23または24に記載の方法。
- 前記シグナルピークが、650Da〜950Daの分子量に対応することを特徴とする、請求項25に記載の方法。
- 前記シグナルピークが、700Da〜850Daの分子量に対応することを特徴とする、請求項26に記載の方法。
- 前記シグナルピークが、750Da〜800Daの分子量に対応することを特徴とする、請求項27に記載の方法。
- 前記シグナルピークが、770Da〜790Daの分子量に対応することを特徴とする、請求項28に記載の方法。
- 前記シグナルピークが、782.5Daの分子量に対応することを特徴とする、請求項29に記載の方法。
- 請求項4に記載の化合物を製造する方法であって、
1.生体系(ただしヒトを除く)においてStaphylococcus lugdunensis菌種の非リボソームペプチド合成酵素系II(NRPS−II)を発現させる工程、
2.発現させたNRPS−IIを、請求項4に記載の化合物の合成が可能な条件下でインキュベートする工程、および
3.前記化合物を精製する工程
を含む方法。 - 前記NRPS−IIが、遺伝子lugA、lugB、lugCおよびlugDのコード配列と、任意で、GntRファミリー転写制御因子、ABCトランスポーター(GdmF型の多剤輸送システム)、ABC−2型輸送システムの透過酵素タンパク質、ABCトランスポーター、仮定上の膜蛋白質、TetR/AcrRファミリー制御因子、チオエステラーゼファミリータンパク質、4’−ホスホパンテテイニルトランスフェラーゼおよび(バチルス属菌の)sigYの推定上の負の制御因子のコード配列のいずれかを含む核酸分子でコードされていることを特徴とする、請求項31に記載の方法。
- 前記条件が、アミノ酸、チオエステラーゼおよび緩衝液を含むことを特徴とする、請求項31または32に記載の方法。
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