JP2013535974A - 微生物における抗生物質耐性の特徴付けの方法および手段 - Google Patents
微生物における抗生物質耐性の特徴付けの方法および手段 Download PDFInfo
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Abstract
Description
a) 抗菌剤化合物、その酵素的改変生成物、その分子標的、またはその改変酵素の基質化合物の参照マススペクトルを提供する工程と、
b) 微生物、その細胞溶解物、またはその培地上清を、水性液中の前記抗菌剤化合物または前記基質化合物に曝露させることにより、曝露済みサンプルを提供する工程と、
c) その曝露済みサンプルのマススペクトルを取得する工程と、
d) 工程c)で取得したマススペクトルを、工程a)の参照マススペクトルと比較する工程と、
e) 前記曝露の後に、前記抗菌剤化合物、その改変生成物、または前記基質の改変、あるいは分子標的の過剰生成が起こったか否かを、前記比較から決定し、かつ前記改変が観察されたときに前記微生物が前記抗菌剤化合物に対して潜在的耐性を有することを確認する工程。
a) 微生物を溶解させるための溶解緩衝液、
b) 少なくとも1つの抗菌剤化合物、または抗菌化合物改変酵素の基質、および
c) MALDIマトリックス材料、
前記部品キットは更に次のものを含む:
d) 前記の少なくとも1つの抗菌剤化合物または基質を担うキャリヤ、前記キャリヤは所望により、使い捨てのマススペクトル用サンプル支持体の形態である。
− 少なくとも1つの抗菌剤化合物、または抗菌化合物改変酵素の基質、
− 微生物、その細胞溶解物、またはその培地上清を、水性液中で少なくとも1つの抗菌剤化合物に曝露させるための容器であって、好ましくは、前記少なくとも1つの基質化合物が前記容器内に提供される、
− 前記微生物を溶解させるための溶解緩衝液、
− MALDIマトリックス材料、
− 質量分析装置、
− 抗菌剤化合物、その酵素的改変生成物、その分子標的、またはその改変酵素の基質化合物の参照マススペクトル、
− マススペクトル用サンプル支持体、
所望により更に次のものを含む:
− 液体取扱いのための自動化ピペッター、
− 前記プログラムがコンピュータ上で作動するときに、上述の本発明の方法の全工程を実施するためのコンピュータプログラムコード手段を含むコンピュータプログラム、例えば、結果解釈のためのアルゴリズムや、インタフェースソフトウェア、エキスパートシステムソフトウェアを含む。
用語「抗生物質」および「抗生物質化合物」は本明細書において互換可能な語として使用され、本明細書において、細菌の生存可能性を低減させるか、あるいは細菌の成長または繁殖を阻害する、化合物または組成物を指す。「成長または繁殖を阻害する」とは、世代周期が少なくとも2倍に増加し、好ましくは少なくとも10倍に増加し、好ましくは少なくとも100倍に増加し、最も好ましくは無期限に全細胞死亡となることを意味する。本開示に使用されるとき、抗生物質はさらに、抗菌剤、細菌発育阻止剤、または殺菌剤を含むことが意図される。本発明の態様に有用な抗生物質の非制限的な例としては、ペニシリン、セファロスポリン、アミノグリコシド、スルホンアミド、マクロライド、テトラサイクリン、リンコサミド、キノロン、クロラムフェニコール、グリコペプチド、メトロニダゾール、リファムピン、イソニアジド、スペクチノマイシン、葉酸阻害剤、スルファメトキサゾール等が挙げられる。
本発明は、微生物の抗生物質耐性を特徴付けるための方法を提供する。この方法の第一工程は、耐性を特徴付ける抗生物質、またはその好適な擬似基質、または抗生物質化合物の分子標的の、1つ以上の参照マススペクトルを得ることである。参照スペクトルは、サンプルの分析に使用される任意のマススペクトル(MS)技法を用いて生成することができる。好ましいMS技法はMALDI−MSである。
1.サンプルをMS装置に搭載する。所望により(MALDIと呼ばれる特殊な形態のMSの場合)マトリックスと合わせたサンプルを、マススペクトルサンプル支持体に塗布し、溶媒を蒸発させてその支持体上のサンプルまたは混合物を乾燥させる。
2.さまざまな方法のうち1つ(例えば電子ビームを衝突させる方法)によってサンプルの組成物をイオン化し、これにより荷電粒子(イオン)が形成される。
3.電場により陽イオンを加速させる。
4.イオンが電磁場を通過する際のイオンの動きの詳細情報に基づいて粒子の質量電荷比(m/z)を計算する。
5.イオンを検出する。このイオンは、工程4で、m/zに従って分類されている。
Claims (17)
- 微生物の抗生物質耐性を特徴付けるための方法であって、
a) 抗菌剤化合物、その改変生成物、その分子標的、またはその改変酵素の基質化合物の参照マススペクトルを提供する工程と、
b) 微生物、その細胞溶解物、またはその培地上清を、水性液中の前記抗菌剤化合物または前記基質化合物に曝露させることにより、曝露済みサンプルを提供する工程と、
c) 前記曝露済みサンプルのマススペクトルを取得する工程と、
d) 工程c)で取得した前記マススペクトルを、工程a)の前記参照マススペクトルと比較する工程と、
e) 前記曝露の後に、前記抗菌剤化合物、その改変生成物、または前記分子標的、あるいは前記基質の改変が起こったか否かを、前記比較から決定し、かつ前記改変が観察されたときに前記微生物が前記抗菌剤化合物に対して潜在的に耐性を有することを確認する工程と、
を含む、方法。 - 前記改変には、前記抗菌剤化合物または前記基質の酵素的不活性化または酵素的分解、および/またはその分子標的のメチル化または過剰生成が含まれる、請求項1に記載の方法。
- 前記酵素的分解が、ベータラクタマーゼによる分解によるものである、請求項2に記載の方法。
- 前記ベータラクタマーゼ酵素が、Ambler分類によるグループAおよびDのベータラクタマーゼ酵素から選択され、かつ、Bush分類によるグループ2に属するベータラクタム酵素である、請求項3に記載の方法。
- 前記ベータラクタマーゼ酵素が、基質特異性拡張型ベータラクタマーゼ(ESBL)である、請求項4に記載の方法。
- 前記微生物が、ESBL産生が疑われる微生物であり、好ましくはクレブシエラ・ニューモニエ(Klebsiella pneumoniae)、大腸菌(Escherichia coli)、クレブシエラ・オキシトカ(Klebsiella oxytoca)およびプロテウス・ミラビリス(Proteus mirabilis)から選択される、請求項1乃至5のいずれか一項に記載の方法。
- 前記抗菌剤化合物がベータラクタム抗生物質であり、好ましくは、ペニシリン、セファロスポリン、セファマイシン、およびカルバペネムからなる群から選択され、より好ましくは、セフタジジム、セフォタキシム、セフトリアキソン、セフポドキシム、およびアズトレオナムからなる群から選択される、請求項1乃至6のいずれか一項に記載の方法。
- 前記方法が、微生物の抗生物質改変酵素の特徴付けのための方法の一部であり、好ましくは、前記抗生物質改変酵素は、基質特異性拡張型ベータラクタマーゼ(ESBL)酵素である、請求項1乃至7のいずれか一項に記載の方法。
- 前記酵素の特徴付けのための前記方法は、前記抗菌剤化合物または前記基質化合物の改変速度、好ましくは分解速度、および/または、前記化合物または基質の酵素的改変生成物の生成速度、または、前記化合物の分子標的の過剰生成速度を決定することを含み、これらにより、前記酵素のミカエリス・メンテン(Km)定数と最大反応速度(Vmax)を決定する、請求項8に記載の方法。
- 工程(b)の後に、前記曝露済みサンプルをマトリックス材料と合わせて、質量分析用サンプル支持体に塗布し、
前記サンプルを前記サンプル支持体の上で乾燥させて、マトリックス支援レーザー脱離イオン化質量分析(MALDI−MS)のためのマススペクトル用サンプルを生成する、請求項1乃至9のいずれか一項に記載の方法。 - 前記マススペクトルが、MALDIトリプル四重極MSを使用して取得される、請求項10に記載の方法。
- 前記曝露済みサンプルが、前記微生物の、抗菌剤化合物曝露済み未精製細胞分解物である、請求項1乃至11のいずれか一項に記載の方法。
- 工程(b)において、前記微生物が前記サンプル中で、前記微生物に由来する1つ以上の構造的生体分子または代謝生成物を定量することによって定量され、
好ましくは、前記構造的生体分子または代謝生成物はDNA分子である、請求項1乃至12のいずれか一項に記載の方法。 - 微生物の抗生物質耐性を特徴付けるための部品キットであって、次のもの:
a) 微生物を溶解させるための溶解緩衝液と、
b) 少なくとも1つの抗菌剤化合物、または抗菌化合物改変酵素の基質と、
c) MALDIマトリックス材料と、
を含み、この部品キットは更に次のもの:
d) 前記の少なくとも1つの抗菌剤化合物または基質を担うキャリヤ前記キャリヤは所望により、使い捨ての質量分析用サンプル支持体の形態である、を含む、部品キット。 - 微生物の抗生物質耐性を特徴付けるためのシステムであって、次のもの:
− 少なくとも1つの抗菌剤化合物、または抗菌化合物改変酵素の基質と、
− 微生物、その細胞溶解物、またはその培地上清を、水性液中で前記少なくとも1つの抗菌剤化合物に曝露させるための容器、好ましくはここにおいて、前記少なくとも1つの基質化合物は前記容器内に提供される、と、
− 前記微生物を溶解させるための溶解緩衝液と、
− MALDIマトリックス材料と、
− 質量分析装置と、
− 抗菌剤化合物、その酵素的改変生成物、その分子標的、またはその改変酵素の基質化合物の参照マススペクトルと、
− マススペクトル用サンプル支持体と、
を含み、また所望により更に、
− 液体取扱いのための自動化ピペッターと、
− 前記プログラムがコンピュータ上で作動するときに、または、前記コンピュータプログラムがコンピュータで読み取り可能な媒体上に組み込まれている、請求項1乃至13のいずれか一項の全工程を実施するよう適合されたコンピュータプログラムコード手段を含むコンピュータプログラムと、
を含む、システム。 - 前記プログラムがコンピュータ上で作動するときに、請求項1乃至13のいずれか一項の全工程を実施するためのコンピュータプログラムコード手段を含む、コンピュータプログラム。
- 前記プログラム製品がコンピュータ上で作動するときに、請求項1乃至13のいずれか一項の前記方法を実施するため、コンピュータで読み取り可能な媒体に保存されているコンピュータプログラムコード手段を含む、コンピュータプログラム製品。
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JP2017504333A (ja) * | 2014-01-17 | 2017-02-09 | ブルーカー ダルトニック ゲーエムベーハー | 代謝測定によるマススペクトル耐性判定 |
US11142784B2 (en) | 2014-01-17 | 2021-10-12 | Bruker Daltonik Gmbh | Mass spectrometric resistance determination by measuring metabolism |
KR20170041773A (ko) * | 2014-07-30 | 2017-04-17 | 비오메리으 | Maldi-tof를 통한 미생물의 특징 분석 방법 |
JP2017523420A (ja) * | 2014-07-30 | 2017-08-17 | ビオメリューBiomerieux | Maldi−tofを介した微生物の特性解析 |
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KR102374464B1 (ko) * | 2014-07-30 | 2022-03-15 | 비오메리으 | Maldi-tof를 통한 미생물의 특징 분석 방법 |
JP2022062713A (ja) * | 2014-07-30 | 2022-04-20 | ビオメリュー | Maldi-tofを介した微生物の特性解析 |
KR101999574B1 (ko) * | 2018-08-03 | 2019-09-27 | 다이아텍코리아 주식회사 | 질량분석법을 이용한 베타락탐 항생제 가수분해 효소의 활성형 직접 검출법 |
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EP2606145A1 (en) | 2013-06-26 |
US20130244230A1 (en) | 2013-09-19 |
US20160230207A1 (en) | 2016-08-11 |
DK2606145T3 (da) | 2023-09-04 |
AU2010359382A1 (en) | 2013-02-28 |
CN103108958A (zh) | 2013-05-15 |
PT2606145T (pt) | 2023-07-11 |
EP2606145B1 (en) | 2023-06-14 |
JP6042332B2 (ja) | 2016-12-14 |
PL2606145T3 (pl) | 2024-03-11 |
EP3023503A1 (en) | 2016-05-25 |
US9663817B2 (en) | 2017-05-30 |
WO2012023845A1 (en) | 2012-02-23 |
HRP20231085T1 (hr) | 2023-12-22 |
CN103108958B (zh) | 2017-12-08 |
BR112013003763A2 (pt) | 2016-05-31 |
EP3981883A1 (en) | 2022-04-13 |
BR112013003763B1 (pt) | 2019-10-22 |
CN107881210A (zh) | 2018-04-06 |
HUE062700T2 (hu) | 2023-11-28 |
ES2622127T3 (es) | 2017-07-05 |
CA2808485A1 (en) | 2012-02-23 |
ES2950280T3 (es) | 2023-10-06 |
US20150184217A1 (en) | 2015-07-02 |
US9334519B2 (en) | 2016-05-10 |
AU2010359382B2 (en) | 2015-05-07 |
CA2808485C (en) | 2019-02-26 |
US9012174B2 (en) | 2015-04-21 |
EP3023503B1 (en) | 2017-04-05 |
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