JP2021513865A - 修飾PlySs2溶解素及びその使用 - Google Patents
修飾PlySs2溶解素及びその使用 Download PDFInfo
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Abstract
Description
本願は、2018年2月26日付で出願された米国仮特許出願第62/635,515号の利益を主張し、その出願日に依拠し、その開示全体が引用することにより本明細書の一部をなす。
本願は、ASCIIフォーマットで電子的に提出された配列表を含み、その全体が引用することにより本明細書の一部をなす。2019年2月22日付けで作製された上記ASCIIコピーの名前は0341_0004−PCT_SL.txtであり、36153バイトのサイズである。
本明細書で使用される場合、以下の用語及びその同語源語は、文脈上そうでないことが明示されない限り、下記の意味を有するものとする。
一態様では、本開示は、溶菌活性を有し、野生型PlySs2溶解素と比較して低下した免疫原性を有する修飾溶解素ポリペプチドに関する。本明細書で使用される場合、「溶菌活性」は、細菌を死滅させるか、細菌の菌数を減少させるか、又は細菌増殖を阻害する溶解素の能力を包含する。溶菌活性は、バイオフィルムを除去又は低減する能力、及び/又は抗生物質の最小阻止濃度(MIC)を低下させる能力も包含する。
配列番号1は、翻訳後プロセシング時に除去され、244アミノ酸ポリペプチドを残す最初のメチオニン残基を含む245個のアミノ酸残基を有する。イタリック体のアミノ酸は、CHAPドメイン(アミノ酸1〜146)を示し、点線下線は、SH3bドメイン(アミノ酸157〜245)を示す。2つのドメイン間の自然発生リンカーは、PPGTVAQSAP(配列番号2)である。
一態様では、本開示は、本明細書に開示される修飾溶解素ポリペプチドをコードする核酸分子を含む単離ポリヌクレオチドであって、修飾溶解素ポリペプチドが溶菌活性及び野生型PlySs2溶解素(配列番号1)と比較して低下した免疫原性を有する、単離ポリヌクレオチドに関する。或る特定の実施形態では、コードされる修飾溶解素ポリペプチド又はそのフラグメントは、グラム陽性細菌の少なくとも1つの種の増殖を阻害するか、その菌数を減少させるか、又はそれを死滅させる。
別の態様では、本開示は、本明細書に開示の修飾溶解素ポリペプチドのいずれかをコードする核酸分子を含む単離ポリヌクレオチド又は本単離ポリヌクレオチドの相補配列を含むベクターに関する。幾つかの実施形態では、ベクターはプラスミド又はコスミドである。他の実施形態では、ベクターはウイルスベクターであり、付加的なDNAセグメントをウイルスゲノムにライゲートすることができる。幾つかの実施形態では、ベクターは、それが導入された宿主細胞において自律的に複製することができる。幾つかの実施形態では、ベクターは、宿主細胞への導入時に宿主細胞のゲノムに組み込まれることで、宿主ゲノムと共に複製され得る。
本明細書に開示の修飾溶解素ポリペプチドは、単独で又は1つ以上の従来の抗生物質及び他の殺菌剤と共に抗微生物及び殺菌組成物、並びにその単位剤形に組み込まれ得る。
その高度の活性及び低い毒性と共に、有利な治療指数を示すことから、本明細書に開示の修飾溶解素ポリペプチドは、その影響を受けやすい適応症又は病態の治療、軽減若しくは改善、緩和、又は解消のために、それを必要とする被験体、例えば生きている動物(ヒトを含む)に投与することができる。
投与される投与量は、治療される感染の活性、治療対象の被験体の年齢、健康及び全身的な身体状態、特定の修飾溶解素ポリペプチドの活性、もしあれば、本開示による修飾溶解素ポリペプチドと組み合わされる抗生物質の性質及び活性、並びにかかる組合せの複合効果等の多数の要因によって決まる。或る特定の実施形態では、投与される修飾溶解素ポリペプチドの有効量は、約0.1mg/kg〜100mg/kg(又は1mcg/ml〜100mcg/ml)、例えば0.5mg/kg〜30mg/kgの範囲内であり得る。或る特定の実施形態では、修飾溶解素ポリペプチドは、1日〜14日間の範囲の期間にわたって1日1回〜4回投与することができる。抗生物質も使用される場合、抗生物質は、標準的な投与計画で又は任意の相乗作用を考慮してより少ない量で投与することができる。しかしながら、かかる全ての投与量及び計画は(修飾溶解素ポリペプチド、又はそれと同時に投与される任意の抗生物質のいずれに関わらず)、最適化に供される。最適投与量は、当業者の技能の範囲内であるが、本開示を考慮に入れてin vitro及びin vivo予備有効性実験を行うことで決定することができる。
本明細書に開示の修飾溶解素ポリペプチドを、野生型PlySs2溶解素の推定T細胞エピトープ(TCE)のコア配列のコンピューターによる計算ガイド特定及び野生型PlySs2溶解素への任意TCEスコアの割当てを含む大規模スクリーニングプログラムによって得た。コンピューターによるスクリーニング方法及びアルゴリズムを商業(個別支払い)方式で用いて、野生型PlySs2溶解素配列の潜在的免疫関連セグメント(推定T細胞エピトープ)を特定し、これらのセグメントを突然変異の標的とした。予測TCEを破壊するように設計される突然変異を特定した。商業サービスを各修飾溶解素ポリペプチドの免疫原性の評定に用いることができる。修飾溶解素ポリペプチドに破壊されたTCEに基づいて免疫原性スコアを割り当てることができる。
本明細書に記載の修飾溶解素ポリペプチドは、触媒ドメイン中で置き換えられるアミノ酸残基の大部分がTCE2、TCE3及びTCE4に集中し、最終候補の1つのみがTCE1にも置換を有するという点で或る特定の類似点を有する。さらに、置き換えられる残基は更に限定され、2つを除く全最終候補がTCE2中のL92W及びTCE3中のV104Sの修飾を有し、1つを除く全最終候補が置換V128T及びY137Sの各々も有する。さらに、TCE2、3及び4中のこれら4つの置換は、活性に実質的に影響を及ぼすことなく(実際に増大させる場合もある)、(結合ドメイン中の置換を有さずに又は最小限にして)免疫原性を実質的に減少させるのに十分であるようである。例えば、pp55、pp400、pp619及びpp388を参照されたい。このため、両方のドメイン中に野生型との差異を有する必要はない。触媒ドメイン中の付加的な置換であるR35Eは、良好な活性及び実質的に(50%超)低下した免疫原性の両方を有するポリペプチド(pp400)をもたらした。修飾溶解素ポリペプチドpp400が結合ドメイン中に置換を有しなかったことが更に注目に値する。しかしながら、概して、触媒ドメイン単独における突然変異は、溶解素を適切に脱免疫化するのに十分でない可能性がある。
野生型PlySs2は、例えばFischetti et alに対する米国特許第9,034,322号に記載されるように得ることができる。同様の手順(アラビノースで誘導可能なプラスミドpBAD24)に従い、突然変異体ポリヌクレオチドのライブラリーから本開示の修飾溶解素ポリペプチドを発現させた。野生型PlySs2溶解素サンプルも修飾溶解素ポリペプチドの精製に用いられる方法によって精製し、精製した野生型PlySs2を付加的な陽性対照として使用した。ThermoFisher(InvitroGen)により、考え得る全てのCHAPドメイン及びSH3b変異体のライブラリーが生成された。表3に特定される修飾を有する配列番号1に基づく配列を有する修飾溶解素ポリペプチドは、例えば部位特異的突然変異誘発によって野生型PlySs2溶解素から生成することができる。
野生型PlySs2及び修飾溶解素ポリペプチドの精製を、イオン交換クロマトグラフィーに続く最終サイズ排除クロマトグラフィーによって行った。簡潔に述べると、再懸濁した細胞溶解物を初めに5mL容Hi Trap DEAEカラム(弱アニオン交換)に通し、次いで5mL容Hi Trap Capto MMCカラム(付加的な疎水性相互作用及びH結合相互作用を有する弱カチオン交換カラム)から塩勾配で溶出した。画分をOD280によって定量化し、それらの純度をSDS−PAGEゲル電気泳動によって評定した。タンパク質を含有する画分をプールし、25mM Tris緩衝液(pH7.4)に対して透析した。透析後に、タンパク質画分を5mL容Hi Trap Q FFカラム(強アニオン交換カラム)にロードし、溶出液を回収し、第2のCapto MMCカラムにロードし、塩勾配によって溶出した。タンパク質を含有する溶離液をプールし、リン酸緩衝生理食塩水に対して透析し、HiLoad 16/600 Superdex 75pgカラムを用いたゲル濾過(サイズ排除)によって更に精製した。全ての精製サンプルをDemo Buffer(7.67mM一塩基性リン酸ナトリウム二水和物、7.33mM二塩基性リン酸ナトリウム一水和物、150mM NaCl、pH7.2)中で保管した。サイズ排除クロマトグラフィー(精製プロセスの最終工程)の溶出ピーク下の画分のSDS−PAGEゲルをpp1149、pp53、pp55、pp61、pp65及びpp296を含む精製した幾つかの修飾溶解素ポリペプチドについて図1に示す(既に精製されている委託製造業者から入手した野生型PlySs2については示さない)。
熱安定性は、活性を評定する前に溶解素ポリペプチドをTris緩衝液(pH8.0)中で128μg/mLの一定濃度にて様々な高温(約30℃〜60℃の範囲内)で30分間インキュベートすることによって評定した。次いで、サンプルを氷上で2分間冷却した後、Tris緩衝液中の細菌接種材料(OD600 約0.5〜1.2)を各サンプルの2倍希釈系列(96ウェルマイクロタイタープレートのx軸に沿って128μg/mL〜0.25μg/mLに希釈した)に曝露することによるin vitro溶解アッセイによって活性を評定した。光学密度の低下を室温で15分間追跡し、15分間で50%の光学密度の低下を可能にする酵素濃度に基づいて比活性を決定した。各変異体の酵素活性を野生型CF−301酵素(GMTグレードのPlySs2タンパク質)と比較し、様々な温度にわたる野生型活性の%を算出した。
全PlySs2変異体のin vitro活性をスタフィロコッカス・アウレウス分離株CFS−860(CAIRD−426)に対して100%ヒト血清(HuS)中で評定し、野生型PlySs2(CF−301)及び実験室で精製されたPlySs2(pp1149と称される)と比較した。全ての変異体を、MICを評定するCLSI(米国臨床検査標準協議会(Clinical and Laboratory Standards Institute))の微量液体希釈法に従って以下のように試験した。
(A/MICA)+(B/MICB)=FICA+FICB=FIC指数
(式中、A及びBは、単一ウェルにおける組合せでの各作用物質のMICであり、MICA及びMICBは、個別に使用した場合の各薬物のMICである)。組合せは、FIC指数が0.5以下である場合に強く相乗的とみなし、FIC指数が0.5超〜1未満である場合に相乗的とみなす。
pp296の抗バイオフィルム活性を、17個のMSSA分離株及び20個のMRSA分離株によって形成される、1日経過したバイオフィルムに対して96ウェル微量液体希釈フォーマットで決定した。野生型PlySs2(CF−301)と比較したpp296の最小バイオフィルム根絶濃度(MBEC)値を以下の標準的な方法論によって決定した。細菌をPBSに懸濁し(0.5マクファーランド単位)、TSBg(66%トリプシンソイブロス、0.2%グルコース)で100倍希釈し、0.15mlアリコートとして96ウェルポリスチレンマイクロプレートに添加し、37℃で24時間インキュベートした。次いで、バイオフィルムを洗浄し、TSBg中の2倍希釈系列のCF−301又はpp296によって37℃で24時間処理した。全サンプルを三連で試験した。処理後に、ウェルを洗浄し、37℃で風乾し、0.05%クリスタルバイオレットで10分間染色した。バイオフィルムのバイオマスの減少を目視で評定し、クリスタルバイオレットを33%(体積/体積)酢酸への可溶化によって定量化した。600nmの光学密度(OD600)を、SpectraMax M3 Multimodeマイクロプレートリーダーを用いて決定した。各サンプルのMBECが、クリスタルバイオレット定量化によって評定される、バイオフィルムのバイオマスの95%超を除去するのに必要とされる最小溶解素濃度であった。MBECアッセイを用いることで、全てではないが、殆どの試験したMSSA分離株及びMRSA分離株に対してpp296が野生型PlySs2と比較してより高い活性を有することが決定された。したがって、下記表8に示されるように、pp296抗バイオフィルム活性は、全体として野生型溶解素よりも僅かに良好である。
4つの修飾溶解素ポリペプチドの有効性を、マウス好中球減少性大腿感染(MNTI)モデルを用いる用量応答(0mg/kg〜60mg/kg)アッセイにおいて野生型PlySs2と比較した。
マウス毒物学的スクリーニングから、30mg/kgの野生型PlySs2を投与したマウスが腹部及び胸部の大動脈並びに心基部の大動脈基部に外膜病変(又は外膜所見)を伴う混合炎症細胞集団の血管周囲性浸潤を生じることが示された。外膜所見が、30mg/kgの野生型PlySs2及び野生型PlySs2(pp1149)を投与した全てのマウスにおいて観察された。外膜病変が、PlySs2野生型溶解素とはC末端246位の余分なリシンアミノ酸残基のみが異なるpp53の30mg/kg用量で処理した4匹のマウスのうち3匹で観察された。残りの修飾溶解素ポリペプチドの30mg/kg以上の用量を投与したマウスは、いかなる外膜所見も有しなかった。
種々のドナーに由来する末梢血単核細胞(PBMC)をHLAタイピングし、評価して、包括的なヒト集団にわたる広範な説明を確認する。PBMCをタンパク質若しくは対照と共に、又は変異体に曝露せずに培養する。PBMCサンプルを14日間培養し、4日目、7日目及び11日目に培地交換及びサイトカイン補助を行った。14日目に、各培養物のPBMCサンプルを採取し、対象のサイトカインに対する抗ヒト抗体でプレコートしたFluoroSpot(商標)プレートに分取する。各サンプルをプレートのインキュベーション前に変異体、又は陽性対照として野生型溶解素(チャレンジ又は初回曝露のいずれかとして)、又は陰性対照として無タンパク質で刺激する。
本研究の目的は、2時間の単回静脈内注入としてスプラーグドーリーラットに投与した場合のpp296の潜在的毒性及び毒物動態学プロファイルを評価すると共に、最低3日間の回復期間後に任意の効果の回復、持続又は進行を評価することであった。
本研究の目的は、スプラーグドーリーラットに7日連続で2時間の注入によって毎日投与した場合の修飾溶解素ポリペプチドpp296の潜在的毒性及び毒物動態学プロファイルを評価することであった。
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Claims (34)
- 配列番号1のアミノ酸配列、システイン、ヒスチジン依存性アミドヒドロラーゼ/ペプチダーゼ(CHAP)ドメイン及び細胞壁結合(SH3b)ドメインを有する野生型PlySs2溶解素ポリペプチドと比較して少なくとも1つのアミノ酸置換を含む修飾溶解素ポリペプチドであって、前記少なくとも1つのアミノ酸置換が前記CHAPドメイン及び/又は前記SH3bドメイン中にあり、該修飾溶解素ポリペプチド又はそのフラグメントがグラム陽性細菌の少なくとも1つの種の増殖を阻害するか、その菌数を減少させるか、又はそれを死滅させる、修飾溶解素ポリペプチド。
- 前記少なくとも1つのアミノ酸置換が前記CHAPドメイン中の配列番号1のアミノ酸残基35、92、104、128及び137から選択される少なくとも1つの位置、及び/又は前記SH3bドメイン中の配列番号1のアミノ酸残基164、184、195、198、204、206、212及び214から選択される少なくとも1つの位置にある、請求項1に記載の修飾溶解素ポリペプチド。
- 前記CHAPドメイン中の前記少なくとも1つのアミノ酸置換がR35E、L92W、V104S、V128T及びY137Sの少なくとも1つである、請求項2に記載の修飾溶解素ポリペプチド。
- 前記SH3bドメイン中の前記少なくとも1つのアミノ酸置換がY164N、Y164K、N184D、R195E、S198H、S198Q、V204K、V204A、I206E、V212A、V212E及びV214Gの少なくとも1つである、請求項2に記載の修飾溶解素ポリペプチド。
- R35E、L92W、V104S、V128T及びY137Sからなる群から選択される前記CHAPドメイン中の少なくとも1つのアミノ酸置換と、Y164N、Y164K、N184D、R195E、S198H、S198Q、V204K、V204A、I206E、V212A、V212E及びV214Gからなる群から選択される前記SH3bドメイン中の少なくとも1つのアミノ酸置換とを有する、請求項2に記載の修飾溶解素ポリペプチド。
- 前記CHAPドメイン中に少なくとも2つのアミノ酸置換を含む、請求項1〜5のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記SH3bドメイン中に少なくとも2つのアミノ酸置換又は少なくとも3つのアミノ酸置換を含む、請求項1〜6のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記修飾溶解素ポリペプチドが配列番号1と比較して3つ〜9つのアミノ酸置換を含み、該3つ〜9つのアミノ酸置換がR35E、L92W、V104S、V128T、Y137S、Y164N、Y164K、N184D、R195E、S198H、S198Q、V204K、V204A、I206E、V212E、V212A及びV214Gから選択される、請求項1〜7のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記少なくとも1つのアミノ酸置換がL92W、V104S、V128T、Y137S、Y164K、N184D及びS198Qを含む、請求項1〜8のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記CHAPドメイン中の前記少なくとも1つのアミノ酸置換がL92W、V104S、V128T及びY137Sを含む、請求項1〜9のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記少なくとも1つのアミノ酸置換が、
(i)L92W、V104S、V128T及びY137S、
(ii)Y164N、N184D、R195E、V204K及びV212E、
(iii)L92W、V104S、V128T、Y137S、S198H及びI206E、
(iv)L92W、V104S、V128T、Y137S、S198Q、V204A及びV212A、
(v)L92W、V104S、V128T、Y137S、Y164K、N184D及びS198Q、
(vi)V128T、Y137S及びY164K、
(vii)R35E、L92W、V104S、V128T及びY137S、
(viii)L92W、V104S、V128T、Y137S、Y164K、V204K及びV212E、
(ix)L92W、V104S、V128T、Y137S、Y164K、N184D、S198Q、V204K及びV212E、
(x)L92W、V104S、V128T、Y137S、Y164N及びN184D、
(xi)L92W、V104S、V128T、Y137S、Y164N及びR195E、
(xii)L92W、V104S、V128T、Y137S、N184D、V204A及びV212A、
(xiii)L92W、V104S、V128T、Y137S及びY164K、
(xiv)L92W、V104S、V128T、Y137S、Y164K、I206E及びV214G、並びに、
(xv)L92W、V104S、V128T、Y137S、N184D及びS198H、
からなる群から選択される、請求項1〜10のいずれか一項に記載の修飾溶解素ポリペプチド。 - スタフィロコッカス・アウレウス;リステリア・モノサイトゲネス;スタフィロコッカス・アウレウス;スタフィロコッカス・エピデルミディス群、スタフィロコッカス・サプロフィティカス群、スタフィロコッカス・シミュランス群、スタフィロコッカス・インターメディウス群、スタフィロコッカス・シウリ群及びスタフィロコッカス・ヒイカス群等のコアグラーゼ陰性ブドウ球菌;ストレプトコッカス・スイス;ストレプトコッカス・ピオゲネス;ストレプトコッカス・アガラクティアエ;ストレプトコッカス・ディスガラクティアエ;ストレプトコッカス・ニューモニアエ;ストレプトコッカス・アンギノーサス群、ストレプトコッカス・ミティス群、ストレプトコッカス・サングイニス群、ストレプトコッカス・ボビス群、ストレプトコッカス・サリバリウス群及びストレプトコッカス・ミュータンス群等の緑色レンサ球菌群に含まれる種;エンテロコッカス・フェカーリス;並びにエンテロコッカス・フェシウムの1つ以上に対して野生型PlySs2溶解素の約2倍、約3倍又は約5倍以下の最小阻止濃度(MIC)を有する、請求項1〜11のいずれか一項に記載の修飾溶解素ポリペプチド。
- 前記MICがスタフィロコッカス・アウレウス、ストレプトコッカス・ピオゲネス、リステリア・モノサイトゲネス及びストレプトコッカス・アガラクティアエの1つ以上に対して野生型PlySs2溶解素の約5倍以下である、請求項12に記載の修飾溶解素ポリペプチド。
- 前記MICが野生型PlySs2溶解素の約4倍以下である、請求項12又は13に記載の修飾溶解素ポリペプチド。
- 前記MICが野生型PlySs2溶解素の約2倍以下である、請求項12〜14のいずれか一項に記載の修飾溶解素ポリペプチド。
- 野生型PlySs2溶解素と比較して免疫原性を低下させ、及び/又は炎症応答関連毒性を低下させる、請求項1〜15のいずれか一項に記載の修飾溶解素ポリペプチド。
- グラム陽性細菌の少なくとも1つの種の増殖の阻害、その菌数の減少、又はその死滅がMIC及び/又は最小バイオフィルム根絶濃度(MBEC)としてin vitroで評定される、請求項1〜16のいずれか一項に記載の修飾溶解素ポリペプチド。
- 許容可能な担体と、抗菌量の請求項1〜17のいずれか一項に記載の修飾溶解素ポリペプチドとを含む組成物。
- 前記組成物が医薬組成物であり、前記担体が薬学的に許容可能な担体である、請求項18に記載の組成物。
- 前記抗菌量の修飾溶解素ポリペプチドが、スタフィロコッカス・アウレウス;リステリア・モノサイトゲネス;スタフィロコッカス・エピデルミディス群、スタフィロコッカス・サプロフィティカス群、スタフィロコッカス・シミュランス群、スタフィロコッカス・インターメディウス群、スタフィロコッカス・シウリ群及びスタフィロコッカス・ヒイカス群等のコアグラーゼ陰性ブドウ球菌;ストレプトコッカス・スイス;ストレプトコッカス・ピオゲネス;ストレプトコッカス・アガラクティアエ;ストレプトコッカス・ディスガラクティアエ;ストレプトコッカス・ニューモニアエ;ストレプトコッカス・アンギノーサス群、ストレプトコッカス・ミティス群、ストレプトコッカス・サングイニス群、ストレプトコッカス・ボビス群、ストレプトコッカス・サリバリウス群及びストレプトコッカス・ミュータンス群等の緑色レンサ球菌群に含まれる種;エンテロコッカス・フェカーリス;並びにエンテロコッカス・フェシウムからなる群から選択される1つ以上のグラム陽性細菌の増殖を阻害するか、又はその菌数を減少させるか、又はそれを死滅させるのに効果的である、請求項18又は19に記載の組成物。
- 前記グラム陽性細菌がメチシリン耐性スタフィロコッカス・アウレウス又はバンコマイシン耐性スタフィロコッカス・アウレウスである、請求項18〜20のいずれか一項に記載の組成物。
- 溶液、懸濁液、エマルション、吸入用粉末、エアロゾル又はスプレーである、請求項18〜21のいずれか一項に記載の組成物。
- グラム陽性細菌感染の治療に適した1つ以上の抗生物質を更に含む、請求項18〜22のいずれか一項に記載の組成物。
- 請求項1〜17のいずれか一項に記載の修飾溶解素ポリペプチドをコードする核酸分子。
- 請求項24に記載の核酸分子を含むベクター。
- 前記ベクターがプラスミドであり、前記核酸が異種プロモーターに操作可能に連結する、請求項25に記載のベクター。
- グラム陽性細菌の少なくとも1つの種の増殖を阻害するか、その菌数を減少させるか、又はそれを死滅させる方法であって、前記細菌と請求項18〜23のいずれか一項に記載の組成物とを接触させることを含む、方法。
- グラム陽性細菌の少なくとも1つの種によって引き起こされる細菌感染を予防又は治療する方法であって、細菌感染と診断された、そのリスクがある又はその症状を示す被験体に、(1)第1の量の請求項1〜17のいずれか一項に記載の修飾溶解素ポリペプチド、及び(2)第2の量のグラム陽性細菌感染の治療に適した抗生物質を同時投与することを含む、方法。
- 前記グラム陽性細菌感染の治療に適した抗生物質がメチシリン、バンコマイシン、ダプトマイシン、ムピロシン及びリソスタフィンからなる群から選択される、請求項28に記載の方法。
- 細菌感染の治療に適した抗生物質の有効性を高める方法であって、該抗生物質を請求項1〜17のいずれか一項に記載の修飾溶解素ポリペプチドと組み合わせて同時投与することを含み、同時投与が、細菌の増殖を阻害するか、又はその菌数を減少させるか、又はそれを死滅させる上で、前記抗生物質又は前記修飾溶解素ポリペプチド若しくはそのフラグメントのいずれか個別の投与よりも効果的である、方法。
- 前記抗生物質がメチシリン、バンコマイシン、ダプトマイシン、ムピロシン及びリソスタフィンからなる群から選択される、請求項30に記載の方法。
- ブドウ球菌又はレンサ球菌細菌に感染した被験体においてブドウ球菌又はレンサ球菌細菌の抗生物質耐性の発現を低減する方法であって、前記被験体に、請求項1〜17のいずれか一項に記載の修飾溶解素ポリペプチドとメチシリン、バンコマイシン、ダプトマイシン、ムピロシン及びリソスタフィンから選択される抗生物質との組合せを投与することを含む、方法。
- 前記修飾溶解素ポリペプチドを、該修飾溶解素ポリペプチドの最小阻止濃度(MIC)を下回る濃度に相当する量で投与する、請求項32に記載の方法。
- 前記修飾溶解素ポリペプチド中の少なくとも1つのアミノ酸置換がL92W、V104S、V128T、Y137S、S198Q、V204A及びV212Aを含む、請求項32又は33に記載の方法。
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