JP2022513550A - 抗微生物特性を有する化合物 - Google Patents
抗微生物特性を有する化合物 Download PDFInfo
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- JP2022513550A JP2022513550A JP2021502945A JP2021502945A JP2022513550A JP 2022513550 A JP2022513550 A JP 2022513550A JP 2021502945 A JP2021502945 A JP 2021502945A JP 2021502945 A JP2021502945 A JP 2021502945A JP 2022513550 A JP2022513550 A JP 2022513550A
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- Prior art keywords
- administration
- alkyl
- compound
- compounds
- infection
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- 238000000034 method Methods 0.000 claims description 35
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- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
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- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 2
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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Abstract
Description
R1、R2、R3、R4、R5、およびR6は、各々独立して、水素、アルキル、アルケニル、アルキニル、ヒドロキシル、ヒドロキシアルキル、ハロゲン、-CN、-O-アルキル、-C(O)-アルキル、-C(O)O-アルキル、-C(O)OH、-C(O)NH2、-C(O)NH-アルキル、-NH2、-NO2、-CF3、-NH-アルキル、-N-(アルキル)2、-NHC(O)-アルキルおよびアリールから成る群から選択され、前記アルキル、アルケニル、アルキニルおよびアリールは各々置換されていてもよく;
R7およびR8は、各々独立して、水素、直鎖または分岐鎖C1~C5アルキル、直鎖または分岐鎖C2~C6アルケニル、直鎖または分岐鎖C2~C6アルキニルから成る
群から選択され;前記アルキル、アルケニルおよびアルキニルは各々置換されていてもよく;
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19およびR20は、各々独立して、水素、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロアルキル、ヒドロキシル、ヒドロキシアルキル、ハロゲン、-CN、-O-アルキル、-C(O)-アルキル、-C(O)O-アルキル、-C(O)OH、-C(O)NH2、-C(O)NH-アルキル、-NH2、-NO2、-CF3、-NH-アルキル、-NHC(O)-アルキルから成る群から選択され;前記アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロアルキルは各々置換されていてもよく;
Aは、結合または-(CH2)n-であり、nは、0~10の整数であり;
Xは、-C(O)-、-CH2-、-C(OH)-、-C(O)O-アルキル、-C((O)アルキル)-である)
および/またはその薬剤的に許容可能な塩、立体異性体(鏡像異性体を含む)、互変異性体、もしくは水和物、ならびに類似体式(I)(以後、まとめて「式(I)化合物」と呼ぶ)、により表される新規化合物を含む、該化合物から本質的に成るまたは該化合物から成る。本発明はまた、式(I)化合物、式(I)化合物の使用、および1つ以上の式(I)化合物を用いた細菌感染症の治療方法または予防方法を含む、またはこれらから本質的に成る医薬組成物を含む。
R3、R4、R5、R6、R7およびR8は、上記に定義されている通りである)
および/またはその薬剤的に許容可能な塩、立体異性体(鏡像異性体を含む)、互変異性体、もしくは水和物、ならびに類似体式(Ia)(以後、まとめて「式(Ia)化合物」と呼ぶ)を含む。本発明はまた、式(Ia)化合物、式(Ia)化合物の使用、および1つ以上の式(Ia)化合物を用いた細菌感染症の治療方法または予防方法を含む、ま
たはこれらから本質的に成る医薬組成物を含む。
に対する最後の手段の抗菌薬である。
、メチルプロピニル、4-メチル-1-ブチニル、4-プロピル-2-ペンチニル、および4-ブチル-2-ヘキシニルが挙げられるが、これらに限定されない。
リル、チアジアゾリル、テトラヒドロピラニル、チアモルホリニル、チアモルホリニルスルホキシド、チアモルホリニルスルホン、およびオキサジアゾリルが挙げられるが、これらに限定されない。
、「アルキル」、「アルケニル」、「アルキニル」および「アリール」は本明細書で定義されている。
ることができる。かかる塩の例としては、アルカリ金属塩またはアルカリ土類金属塩、特に、カルシウム、マグネシウム、ナトリウム、リチウム、亜鉛、カリウムおよび鉄塩が挙げられる。
皮膚が挙げられるが、これらに限定されない。投与の好ましい方法は、開業医の裁量に任されており、部分的に、内科的疾患の部位に依存するだろう。
Langer and Wise (eds.),CRC Pres.,Boca Raton,Fla.(1974);Controlled Drug Bioavailability,Drug Product Design and Performance,Smolen and Ball(eds.),Wiley,New York(1984);Ranger and Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61参照;Levy et al.,1985,Science 228:190;During et al.,1989,Ann.Neurol.25:351 Howard et al.,1989,J.Neurosurg.71:105も参照)。更に別の実施形態では、放出制御系を、臓器、例えば、肝臓の近くに配置することができ、したがって、僅かな全身投与量しか必要としない(例えば、Goodson,in Medical Applications of Controlled Release,supra,vol.2,pp.115-138(1984)参照)。Langer,1990,Science 249:1527-1533によるレビューで考察されている他の放出制御系を使用してよい。
nce and Practice of Pharmacy(21st ed.,Hendrickson,R.,et al.,Eds.,Lippincott Williams & Wilkins,Baltimore,MD (2006)、参照により本明細書に組み入れられる)に記載されている。
ートなどの時間遅延材料を使用してもよい。経口用組成物は、マンニトール、ラクトース、デンプン、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース、炭酸マグネシウム、他などの標準的媒体を含むことができる。かかる媒体は、好ましくは、医薬品グレードである。
用することができる。ハイドロゲルは、概して、当技術分野において公知である。ハイドロゲルは、通常、ネットワーク中に高分子量生体適合性ポリマーを架橋することによって製造し、水中で膨潤してゲル様物質を生成する。好ましくは、ハイドロゲルは、生分解性または生体吸収性である。本発明の目的のため、ポリエチレングリコール、コラーゲン、またはグリコール酸/L-乳酸共重合体から製造されたハイドロゲルは有用であり得る。例えば、Phillips et al.(1984)J.Pharmaceut.Sci.,73:1718-1720参照。
gonorrhoeae)による感染症の治療に有用である。
なる。
めてよい。
フォトラブダス・カニ(Photorhabdus khanii)DSM3369を、10mlのLuria Bertani培地(LBB)に播種し、50mlのファルコンチューブ中で振盪(200rpm)しながら28℃においてインキュベートした。10ミリリットルの一晩培養した培養液を、2Lエルレンマイヤーフラスコ中、1Lのトリプシンソイ培地(TSB)に播種し、8~10日間振盪(200rpm)しながら28℃においてインキュベートした。
細菌細胞を、遠心分離(8,000xg、10分)により取り除き、上澄み液を回収した。上澄み液を活性化されたスチレン-ジビニルベンゼン樹脂(AMBERLITE XAD16N、SIGMA-ALDRICH)と共に混合し(4:1、体積/体積)、次いで、周囲温度下で一夜緩やかに振盪した。デカンテーションにより非結合物質を除去し、樹脂に吸着された化合物、ダロバクチンA(式(II)に相当)を、樹脂体積の6倍量のDD水で洗浄した。ダロバクチンAを、30分間ロータリーシェーカーで緩やかに振盪することによって、樹脂体積の0.1%(体積/体積)ギ酸を含む4倍量の50%メタノールを用いて溶出した。有機溶媒を除去するためにロータリーエバポレーターによって溶出液を濃縮した。残水性溶出液を、0.1%(体積/体積)ギ酸で酸性化し、次いで、ルーズレジンバルク法(loose-resin bulk process)で陽イオン交換(SPセファロースXL、GE Healthcare)クロマトグラフィーに付した。活性化陽イオン交換樹脂を酸性化水性溶出液に添加し、4℃で一夜緩やかに振盪した。非結合物質をデカントして、樹脂を0.1%(体積/体積)ギ酸DD水で洗浄した。抗菌活性物を、pH5の50mM酢酸アンモニウム、pH7の50mM酢酸アンモニウム、およびpH8の50mM酢酸アンモニウムのステップグラジエントにより溶出した。抗菌活性溶出物を合わせて、凍結乾燥し、次いで、0.1%(体積/体積)ギ酸DD水中に再懸濁した。再懸濁液を、段階pH勾配を有する溶離によって直列接続された4HiTrap
SP XLの第二陽イオン交換クロマトグラフィー(カートリッジ当たり5mL;合計20mLの総容積)に付した。非結合物質を0.1%(体積/体積)ギ酸DD水で洗浄し、次いで、pH5の50mM酢酸アンモニウム、pH7の50mM酢酸アンモニウム、およびpH8の50mM酢酸アンモニウムのステップグラジエントにより溶出した。抗菌活性溶出物を合わせて、凍結乾燥し、次いで、0.1%(体積/体積)ギ酸DD水中に再懸濁して、C18半分取カラム(Agilent、C18、5μm;250×10mm、Restek)で、流速5mL/分で14分間、溶媒Aとして水+0.1%(体積/体積)ギ酸/溶媒Bとしてアセトニトリル+0.1%(体積/体積)ギ酸を2%Bから開始して14%Bまでの直線勾配、ダイオードアレイ検出器でモニターする210~400nmのUV検出を使用した逆相高性能クロマトグラフィー(RP-HPLC)に付して、12.25分にダロバクチンAを得た(純度:95%UV)。
ダロバクチンAを凍結乾燥後、非結晶白色粉末として単離した。
SIMS)は、m/z483.70874における[M+2H]2+ピークおよびm/z966.41046における[M+H]+ピークを示した。同位体パターンは、ClまたはBrが存在しないことを示した。正確な質量および同位体分布は、元素式C47H55O12N11と一致した。
ダロバクチンAの最小発育阻止濃度(MIC)を、ブロス微量希釈アッセイによって決定した。次の試験生物をダロバクチンAのスペクトルの評価に使用した:シュードモナス・エルジノーサ(Pseudomonas aeruginosa)、エシェリキア・コリ(Escherichia coli)、アシネトバクター・バウマニ(Acinetobactor baumannii)、クレブシエラ・ニューモニエ(Klebsiella pneumoniae)、スタフィロコッカス・アウレウス(Staphylococcus aureus)、サルモネラ・ティフィムリウム(Salmonella Typhimurium)、シゲラ・ソネイ(Shigella sonnei)、エンテロバクター・クロアカ(Enterobacter cloacae)、バクテロイデス・フラジリス(Bacteroides fragilis)、ラクトバチルス・ロイテリ(Lactobacillus reuteri)、およびエンテロコッカス・フェカリス(Enterococcus faecalis)。
HepG2およびFaDu細胞を、75cm2組織培養フラスコに20mLの最小必須培地(MEM)+10%ウシ胎仔血清(FBS)および1%抗菌・抗真菌抗生物質中で培養し、37℃、5%CO2において5日間インキュベートした(細胞が70%コンフルエントに達するまで)。増殖培地を取り出し、細胞を5mLの1×リン酸緩衝生理食塩水(PBS)で洗浄した。洗浄後、PBSを取り出し、2mLの0.25%トリプシンを含む1×EDTA溶液を添加した。細胞を、37℃、5%CO2において2分間インキュベートして、細胞をフラスコから剥がした。フラスコに6mLの培養培地の添加によって、トリプシンを不活化し、細胞を、凝集を避けるために緩やかにピペッティングすることによって剥がした。細胞を計数し、MEM+10%FBS中に2×105細胞/mLに希釈し、この懸濁液100μlを、透明平底組織培養治療96ウェルプレートに添加した。プレートを、37℃、5%CO2において一晩インキュベートして、細胞をプレートに接着させた。
大腸菌(E.coli)を、5mLのミューラーヒントンII培地(MHIIB)に播種し、OD600=0.1~0.9まで生育した。細胞懸濁液を、OD600=0.001まで希釈した。98μLの大腸菌(E.coli)培養液を、96ウェルプレートにおいて、2μLのダロバクチンA(16μg/mL、2×MICに相当)で処置し、37℃で20時間インキュベートした。大腸菌(E.coli)培養液を、抗菌薬を含まないLuria Broth寒天上に播き、コロニー形成単位(CFU)を、生細胞計数のためにカウントした(図3)。
ダロバクチンAは、分子量966Daの大きな化合物である。グラム陰性菌への侵入限界は、およそ500Daである。したがって、ダロバクチンAは、リポ多糖(LPS)を標的とするポリミキシンと同様に、細胞表面上で作用する可能性があると思われた。これを試験するために、ダロバクチンAの活性をLPSの存在下試験した。大腸菌(E.coli)を、5mLのMHIIBに播種し、細胞密度がOD600=0.1~0.9に達するまで生育した。細胞懸濁液を、2×MHIIBでOD600=0.002まで希釈した。40μLのLPS溶液(最終濃度範囲0~800μg/mL)および2μLの2×MIC抗菌液剤(最終濃度:ポリミキシン;0.5μg/mL、アンピシリン;16μg/mL、ダロバクチンA;16μg/mL)を、96ウェルプレートにおいて混合し、滅菌DI水によって50μLまで満たした。LPSおよび抗菌液剤を、50μLの大腸菌(E.coli)細胞懸濁液と共に混合し、37℃で20時間インキュベートした。大腸菌(E.coli)の生育を、目視で決定した(表3)。
ダロバクチンAを、2動物有効性モデルにおいて試験した(図5)。敗血症モデルでは、マウスに、24時間以内に未治療群において100%死亡率の原因となる接種菌液として、5%ムチン中の106個の細菌を注射した(腹腔内)(図5A、5C)。感染の1時
間後、3つの群において、ポジティブコントロールとしてのゲンタマイシン20mg/kg、または様々な用量レベルのダロバクチンAで、マウスを治療した。5日間にわたって、生存率をモニターした。ダロバクチンAは、感染症を効果的に治療し、2.5mg/kgにおいて、一般的に使用されるATCC25922株およびポリミキシンに耐性を有する臨床分離株AR350の両方の大腸菌(E.coli)に対して、100%の生存率を示した(図5A)。5時間後、CFU測定のために尾から採血し、ダロバクチンA治療を受けた大腸菌(E.coli)の有意な減少を示した(図5B)。1mg/kgにおいて、ダロバクチンAは生存時間をなお延長したが、もはや100%治癒しなかった(図5A)。ポリミキシンに耐性を有する実験室株を使用して、緑膿菌(P.aeruginosa)敗血症に対してダロバクチンAを50mg/kgで試験し、100%生存率を示した(図5C)。次いで、ダロバクチンAを、好中球減少性マウス大腿モデルにおいて有効性について試験した。マウスに、シクロホスファミドを与えて好中球減少症を誘発(-3日目、0日目)し、次いで、マウスの右大腿において106CFU大腸菌(E.coli)AR350を感染させて、感染の2時間後に治療を開始した。未治療コントロール、群当たり4匹のマウスを、0、2、および24時間において袋詰にして、感染症の進行をモニターした。治療群当たり4匹のマウスにおいて、2時間後に50mg/kg単回注射されたダロバクチンA(腹腔内)を、感染の2、8、14時間後に3回与えられた25mg/kgのダロバクチンA(腹腔内)、および2時間後に20mg/kg単回注射されたゲンタマイシン(腹腔内)と比較した。マウスを24時間において袋詰にして、無菌的に取り出した大腿をホモジナイズして寒天プレートに蒔いてCFUを計数した(図5D)。50mg/kgのダロバクチンAは、未治療コントロールと比較して感染症負荷量を10分の1に低減し、25mg/kgを3回与えると、感染症を100分の1に低減し、2匹のマウスにおける検出限界未満までをも含んだ。
Claims (31)
- 式(I):
の化合物および/またはその薬剤的に許容可能な塩、立体異性体、互変異性体、もしくは水和物であって、
前記式中:
R1、R2、R3、R4、R5、およびR6は、各々独立して、水素、アルキル、アルケニル、アルキニル、ヒドロキシル、ヒドロキシアルキル、ハロゲン、-CN、-O-アルキル、-C(O)-アルキル、-C(O)O-アルキル、-C(O)OH、-C(O)NH2、-C(O)NH-アルキル、-NH2、-NO2、-CF3、-NH-アルキル、-N-(アルキル)2、-NHC(O)-アルキルおよびアリールから成る群から選択され、前記アルキル、アルケニル、アルキニルおよびアリールは各々置換されていてもよく;
R7およびR8は、各々独立して、水素、直鎖または分岐鎖C1~C5アルキル、直鎖または分岐鎖C2~C6アルケニル、直鎖または分岐鎖C2~C6アルキニルから成る群から選択され;前記アルキル、アルケニルおよびアルキニルは各々置換されていてもよく;
R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19およびR20は、各々独立して、水素、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロアルキル、ヒドロキシル、ヒドロキシアルキル、ハロゲン、-CN、-O-アルキル、-C(O)-アルキル、-C(O)O-アルキル、-C(O)OH、-C(O)NH2、-C(O)NH-アルキル、-NH2、-NO2、-CF3、-NH-アルキル、-NHC(O)-アルキルから成る群から選択され;前記アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、ヘテロアリール、ハロアルキルは各々置換されていてもよく;
Aは、結合または-(CH2)n-であり、nは、0~10の整数であり;
Xは、-C(O)-、-CH2-、-C(OH)-、-C(O)O-アルキル、-C((O)アルキル)-である、
化合物。 - R3、R4およびR5は、各々独立して、ヒドロキシル、ヒドロキシアルキル、ハロゲン、-CNおよび-O-アルキルから成る群から選択される、請求項1または2に記載の化合物。
- R3は、ヒドロキシルである、請求項1または2に記載の化合物。
- R4は、ヒドロキシルである、請求項1または2に記載の化合物。
- R5は、ヒドロキシルである、請求項1または2に記載の化合物。
- R6は、-NH2である、請求項1または2に記載の化合物。
- R7およびR8は、各々独立して、水素、アルキル、アルケニル、アルキニルおよびアリールから成る群から選択される、請求項1または2に記載の化合物。
- R7は、水素である、請求項1または2に記載の化合物。
- R8は、水素である、請求項1または2に記載の化合物。
- 請求項1~11のいずれか一項に記載の化合物またはその薬剤的に許容可能な塩の治療有効量を含む、グラム陰性菌を原因とする動物における感染症を治療するための医薬組成物。
- 少なくとも1つの薬剤的に許容可能な担体、賦形剤または希釈剤をさらに含む、請求項12に記載の医薬組成物。
- 局所投与、全身投与、非経口投与、皮下投与、経皮投与、直腸内投与、経口投与、腟内投与、鼻腔内投与、気管支内投与、眼内投与、耳内投与、静脈内投与、筋肉内投与、または腹腔内投与の形態である、請求項12または13に記載の医薬組成物。
- 少なくとも1つの追加の治療薬をさらに含む、請求項12~14のいずれか一項に記載の医薬組成物。
- 培養液中で前記化合物を産生する能力を有する微生物を培養することによって得られる、請求項12~15のいずれか一項に記載の医薬組成物。
- 前記微生物は、フォトラブダス・カニ(Photorhabdus khanii)DSM3369である、請求項16に記載の医薬組成物。
- 請求項1~11のいずれか一項に記載の化合物またはその薬剤的に許容可能な塩の治療有効量を、それを必要とする対象に投与することを含む、細菌感染症または疾病の治療方法、寛解方法または予防方法。
- 前記細菌は、グラム陰性である、請求項18に記載の方法。
- 前記グラム陰性菌は、エシェリキア・コリ(Escherichia coli)、シュードモナス・エルジノーサ(Pseudomonas aeruginosa)、カンジダタス・リベリバクター(Candidatus liberibacter)、アグロバクテリウム・ツメファシエンス(Agrobacterium tumefaciens)、アシネトバクター・バウマニ(Acinetobactor baumannii)、ブランハメラ・カタラーリス(Branhamella catarrhalis)、シトロバクター・ジベルサス(Citrobacter diversus)、エンテロバクター・エロゲネス(Enterobacter aerogenes)、クレブシエラ・ニューモニエ(Klebsiella pneumoniae)、プロテウス・ミラビリス(Proteus mirabilis)、サルモネラ・ティフィムリウム(Salmonella typhimurium)、ナイセリア・メニンギティディス(Neisseria meningitidis)、セラチア・マルセセンス(Serratia marcescens)、シゲラ・ソネイ(Shigella sonnei)、シゲラ・ボイディ(Shigella boydii)、ナイセリア・ゴノレア(Neisseria gonorrhoeae)、アシネトバクター・バウマンニ(Acinetobacter baumannii)、サルモネラ・エンテリティディス(Salmonella enteriditis)、フソバクテリウム・ヌクレアタム(Fusobacterium nucleatum)、ベイロネラ・パルブラ(Veillonella parvula)、アクチノバチルス・アクチノミセタムコミタンス(Actinobacillus actinomycetemcomitans)、アグリゲイティバクター・アクチノミセテムコミタンス(Aggregatibacter actinomycetemcomitans)、ポルフィロモナス・ジンジバリス(Porphyromonas gingivalis)、ヘリコバクター・ピロリ(Helicobacter pylori)、フランシセラ・ツラレンシス(Francisell
a tularensis)、エルシニア・ペスチス(Yersinia pestis)、ビブリオ・コレラエ(Vibrio cholera)、モルガネラ・モルガニー(Morganella morganii)、エドワージエラ・タルダ(Edwardsiella tarda)、カンピロバクター・ジェジュニ(Campylobacter jejuni)、またはヘモフィルス・インフルエンザ(Haemophilus influenza)、エンテロバクター・クロアカ(Enterobacter cloacae)である、請求項19に記載の方法。 - 前記細菌は、感受性があるかまたは多剤耐性である、請求項18~20のいずれか一項に記載の方法。
- 前記細菌は、多剤耐性である、請求項18~21のいずれか一項に記載の方法。
- 前記細菌は、ポリミキシン耐性変異体である、請求項18~22のいずれか一項に記載の方法。
- 前記細菌は、カルバペネム耐性細菌、メチシリン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)、バンコマイシン耐性エンテロコッカス(Enterococci)または多剤耐性ナイセリア・ゴノレア(Neisseria gonorrhoeae)である、請求項18~23のいずれか一項に記載の方法。
- 前記細菌感染症は、呼吸器感染症、皮膚または皮膚組織感染症、尿路感染症、腹腔内感染症、血液感染、胃腸感染症である、請求項18~24のいずれか一項に記載の方法。
- 前記疾病は、皮膚炎症性疾患、炎症性腸疾患(IBD)、潰瘍性大腸炎、クローン病、およびセリアック病から成る群から選択される、請求項18~25のいずれか一項に記載の方法。
- 前記対象は、哺乳類である、請求項18~25のいずれか一項に記載の方法。
- 前記対象は、ヒトである、請求項26に記載の方法。
- 前記対象は、非ヒトである、請求項26に記載の方法。
- 前記細菌感染症は、感受性があるかまたは多剤耐性細菌を含む、請求項18~28のいずれか一項に記載の方法。
- 前記投与ステップは、局所投与、全身投与、非経口投与、皮下投与、経皮投与、直腸内投与、経口投与、腟内投与、鼻腔内投与、気管支内投与、眼内投与、耳内投与、静脈内投与、筋肉内投与、または腹腔内投与を含む、請求項18~29のいずれか一項に記載の方法。
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