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1. 发明申请

US20130164221A1 USE OF BACTERIAL BETA-LACTAMASE FOR IN VITRO DIAGNOSTICS AND IN VIVO IMAGING, DIAGNOSTICS AND THERAPEUTICS 有权
标题翻译：用于体外诊断和体内成像，诊断和治疗的细菌β-乳糖酶的使用
公开(公告)号：US20130164221A1
公开(公告)日：2013-06-27
申请号：US13693706
申请日：2012-12-04
申请人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
发明人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
IPC分类号： A61K49/00 , G01N21/64
CPC分类号： A61K49/0021 , A61K49/0013 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C09B57/02 , C12Q1/04 , C12Q1/34 , G01N21/6486 , G01N2333/986
摘要： Provided herein are methods for detecting, quantifying, differentiating, diagnosing and imaging pathogenic bacteria or condition associated therewith using substrates for bacterial enzymes. Fluorescent, luminescent or colorimetric signals emitted by substrates or enzyme products in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring a signal emitted from the substrates or products in the presence and absence of the potential therapeutic agent and a diagnostic method for detecting a mycobacterial infection in a subject by contacting biological samples with a substrate and imaging for signals emitted from a mycobacterial beta-lactamase product. Also provided are fluorogenic substrates or substrates comprising a colored dye or a chemical reagent effective to induce a color or pH change.
摘要翻译：本文提供了用于细菌酶底物检测，定量，鉴别，诊断和成像病原菌或与其相关的病症的方法。将在细菌存在下由底物或酶产物发射的荧光，发光或比色信号与对照物进行比较以检测和定位病原菌。本发明提供了一种用于筛选治疗剂以治疗病理生理状况的方法，该方法是通过在存在和不存在潜在治疗剂的情况下测量从底物或产物发出的信号，以及用于通过使生物样品与生物样品接触来检测受试者中的分枝杆菌感染的诊断方法底物和成像从分枝杆菌β-内酰胺酶产物发射的信号。还提供了含有色素或有效诱导颜色或pH变化的化学试剂的荧光底物或底物。

2. 发明申请

US20110020240A1 Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics 审中-公开
标题翻译：使用细菌β-内酰胺酶进行体外诊断和体内成像，诊断和治疗
公开(公告)号：US20110020240A1
公开(公告)日：2011-01-27
申请号：US12802340
申请日：2010-06-04
申请人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
发明人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
IPC分类号： A61K49/00 , C07D501/30 , C07D501/34 , C07D501/57 , A61P43/00 , G01N33/569
CPC分类号： A61K49/0013 , A61K49/0021 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C12Q1/04 , C12Q1/34 , G01N2333/986
摘要： Provided herein are imaging methods for detecting, diagnosing and imaging pathogenic bacteria or a pathophysiological condition associated therewith using fluorogenic substrates for bacterial enzymes. Fluorescent, luminescent or colorimetric signals emitted by substrates or enzyme products in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring a signal emitted from the fluorogenic substrates or products in the presence and absence of the potential therapeutic agent. In addition, a diagnostic method for detecting a mycobacterial infection in a subject by contacting biological samples with a fluorogenic substrate and imaging for signals emitted from a mycobacterial beta-lactamase product. Provided are fluorogenic substrates CC1, CC2, CHPQ, CR2, CNIR1, CNIR2, CNIR3, CNIR4, CNIR5, CNIR5-QSY22, CNIR7, CNIR9, CNIR10, CNIR-TAT, CDC-1, CDC-2, CDC-3, CDC-4, CDC-5, XHX2-81, XHX2-91, XHX3-26, or XHX3-32 or a derivative thereof.
摘要翻译：本文提供了用于细菌酶的荧光底物检测，诊断和成像病原菌或与之相关的病理生理条件的成像方法。将在细菌存在下由底物或酶产物发射的荧光，发光或比色信号与对照物进行比较以检测和定位病原菌。本发明提供了通过在存在和不存在潜在治疗剂的情况下测量从荧光底物或产物发出的信号来筛选治疗剂以治疗病理生理状况的方法。另外，用于通过使生物样品与荧光底物接触并对从分枝杆菌β-内酰胺酶产物发射的信号进行成像来检测受试者中的分枝杆菌感染的诊断方法。提供的是荧光底物CC1，CC2，CHPQ，CR2，CNIR1，CNIR2，CNIR3，CNIR4，CNIR5，CNIR5-QSY22，CNIR7，CNIR9，CNIR10，CNIR-TAT，CDC-1，CDC-2，CDC-3， 4，CDC-5，XHX2-81，XHX2-91，XHX3-26或XHX3-32或其衍生物。

3. 发明授权

US06566121B1 Insertional mutations in mycobacteria 失效
标题翻译：分枝杆菌中的插入突变
公开(公告)号：US06566121B1
公开(公告)日：2003-05-20
申请号：US08850977
申请日：1997-05-05
申请人： William R. Jacobs, Jr. , Barry Bloom , Ganjam V. Kalpana , Jeffrey D. Cirillo , Ruth McAdam
发明人： William R. Jacobs, Jr. , Barry Bloom , Ganjam V. Kalpana , Jeffrey D. Cirillo , Ruth McAdam
IPC分类号： C12N112
CPC分类号： A61K39/04 , A61K39/00 , C07K14/35 , C12N15/74 , Y10S435/863 , Y10S435/864 , Y10S435/865 , Y10S435/866
摘要： A mutated mycobacterium selected from the class consisting of mutated M.bovis-BCG, mutated M.tuberculosis, and mutated M. leprae. The mutation of M.bovis-BCG, M.tuberculosis, or M. leprae is preferably effected through an insertional mutation of a mycobacterial gene. The insertional mutagenesis may be effected, for example, through illegitimate recombination or by a mycobacterial transposon. Such mutated mycobacteria may then be transformed with an expression vector(s) containing a complement gene to the gene which is mutated, and preferably also including a heterologous gene.
摘要翻译：选自突变的M.bovis-BCG，突变的结核分枝杆菌和突变的麻疯病的类别的突变的分枝杆菌。 M.bovis-BCG，结核分枝杆菌或麻疯病毒的突变优选通过分枝杆菌基因的插入突变来实现。插入诱变可以例如通过非法重组或通过分枝杆菌转座子进行。然后可以将这种突变的分枝杆菌用含有突变基因的补体基因的表达载体转化，并且优选还包括异源基因。

4. 发明申请

US20160376629A1 Use of Bacterial Beta-Lactamase for In Vitro Diagnostics and In Vivo Imaging, Diagnostics and Therapeutics 审中-公开
标题翻译：使用细菌β-内酰胺酶进行体外诊断和体内成像，诊断和治疗
公开(公告)号：US20160376629A1
公开(公告)日：2016-12-29
申请号：US15262374
申请日：2016-09-12
申请人： Jeffrey D. Cirillo , Jianghong Rao
发明人： Jeffrey D. Cirillo , Jianghong Rao
IPC分类号： C12Q1/18 , G01N21/64 , G01N21/78
CPC分类号： C12Q1/18 , A61K49/0013 , A61K49/0021 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C09B57/02 , C12Q1/04 , C12Q1/34 , C12Q1/66 , G01N21/6408 , G01N21/6428 , G01N21/78 , G01N2021/6417 , G01N2201/061 , G01N2333/986
摘要： Provided herein provided is an assay system for monitoring drug susceptibility of a pathogenic bacteria comprising color-producing substrates for a beta-lactamase of the pathogenic bacteria, an assay device for visibly detecting a product of the beta-lactamase on the substrate thereof and a reader configured to quantify the visibly detected product. Also provided is an in vitro method to determine susceptibility to a drug effective against a pathogenic bacteria, for example, a pathogenic Mycobacteria, that has a beta-lactamase activity. An excitation wavelength is delivered to a biological sample obtained from a subject having an infection from the pathogenic bacteria in the presence of a beta-lactamase substrate. The intensity of a signal, such as a fluorescent, luminescent or colorimetric signal, at an emission wavelength of a product of the beta-lactamase on the subject is correlated to drug susceptibility.
摘要翻译：本文提供了一种用于监测病原细菌的药物敏感性的测定系统，其包括致病细菌的β-内酰胺酶的着色产生底物，用于可见地检测其底物上的β-内酰胺酶的产物和读数器配置为量化可见检测到的产品。还提供了一种体外方法来确定对具有β-内酰胺酶活性的致病细菌例如致病分枝杆菌有效的药物的易感性。在β-内酰胺酶底物的存在下，将激发波长输送到从具有病原菌感染的受试者获得的生物样品。在受试者的β-内酰胺酶的产物的发射波长处的信号强度，例如荧光，发光或比色信号与药物敏感性相关。

5. 发明授权

US09441261B2 Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics 有权
标题翻译：使用细菌β-内酰胺酶进行体外诊断和体内成像，诊断和治疗
公开(公告)号：US09441261B2
公开(公告)日：2016-09-13
申请号：US14044825
申请日：2013-10-02
申请人： Jeffrey D Cirillo , Jianghong Rao
发明人： Jeffrey D Cirillo , Jianghong Rao
IPC分类号： C12Q1/34 , C12Q1/66 , A61K49/00 , C12Q1/04 , C09B57/02
CPC分类号： C12Q1/18 , A61K49/0013 , A61K49/0021 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C09B57/02 , C12Q1/04 , C12Q1/34 , C12Q1/66 , G01N21/6408 , G01N21/6428 , G01N21/78 , G01N2021/6417 , G01N2201/061 , G01N2333/986
摘要： Provided herein are assays and in vitro methods to determine susceptibility to a drug effective against a pathogenic bacteria, for example, a pathogenic Mycobacteria, that has a beta-lactamase activity. An excitation wavelength is delivered to a biological sample obtained from a subject having an infection from the pathogenic bacteria in the presence of a beta-lactamase substrate. The intensity of a signal, such as a fluorescent, luminescent or colorimetric signal, at an emission wavelength of a product of the beta-lactamase on the subject is correlated to drug susceptibility. Also provided is an assay system for monitoring drug susceptibility of a pathogenic bacteria comprising color-producing substrates for a beta-lactamase of the pathogenic bacteria, an assay device for visibly detecting a product of the beta-lactamase on the substrate thereof and a reader configured to quantify the visibly detected product.
摘要翻译：本文提供了测定和体外方法以确定对具有β-内酰胺酶活性的致病细菌例如致病性分枝杆菌有效的药物的易感性。在β-内酰胺酶底物的存在下，将激发波长输送到从具有病原菌感染的受试者获得的生物样品。在受试者的β-内酰胺酶的产物的发射波长处的信号强度，例如荧光，发光或比色信号与药物敏感性相关。还提供了用于监测病原细菌的药物敏感性的测定系统，其包括致病细菌的β-内酰胺酶的着色产生底物，用于可见地检测其底物上的β-内酰胺酶的产物的测定装置和配置量化可见的产品。

6. 发明授权

US09138490B2 Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics 有权
标题翻译：使用细菌β-内酰胺酶进行体外诊断和体内成像，诊断和治疗
公开(公告)号：US09138490B2
公开(公告)日：2015-09-22
申请号：US13693706
申请日：2012-12-04
申请人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
发明人： Jeffrey D. Cirillo , James C. Sacchettini , Jianghong Rao , Hexin Xie
IPC分类号： G01N21/64 , A61K49/00 , C12Q1/04 , C12Q1/34
CPC分类号： A61K49/0021 , A61K49/0013 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C09B57/02 , C12Q1/04 , C12Q1/34 , G01N21/6486 , G01N2333/986
摘要： Provided herein are methods for detecting, quantifying, differentiating, diagnosing and imaging pathogenic bacteria or condition associated therewith using substrates for bacterial enzymes. Fluorescent, luminescent or colorimetric signals emitted by substrates or enzyme products in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring a signal emitted from the substrates or products in the presence and absence of the potential therapeutic agent and a diagnostic method for detecting a mycobacterial infection in a subject by contacting biological samples with a substrate and imaging for signals emitted from a mycobacterial beta-lactamase product. Also provided are fluorogenic substrates or substrates comprising a colored dye or a chemical reagent effective to induce a color or pH change.
摘要翻译：本文提供了用于细菌酶底物检测，定量，鉴别，诊断和成像病原菌或与其相关的病症的方法。将在细菌存在下由底物或酶产物发射的荧光，发光或比色信号与对照物进行比较以检测和定位病原菌。本发明提供了一种用于筛选治疗剂以治疗病理生理状况的方法，该方法是通过在存在和不存在潜在治疗剂的情况下测量从底物或产物发出的信号，以及用于通过使生物样品与生物样品接触来检测受试者中的分枝杆菌感染的诊断方法底物和成像从分枝杆菌β-内酰胺酶产物发射的信号。还提供了含有色素或有效诱导颜色或pH变化的化学试剂的荧光底物或底物。

7. 发明申请

US20100047172A1 Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics 审中-公开
标题翻译：使用细菌β-内酰胺酶进行体外诊断和体内成像，诊断和治疗
公开(公告)号：US20100047172A1
公开(公告)日：2010-02-25
申请号：US12462644
申请日：2009-08-06
申请人： Jeffrey D. Cirillo , Jianghong Rao
发明人： Jeffrey D. Cirillo , Jianghong Rao
IPC分类号： A61K49/00 , C12Q1/34 , C07D513/04
CPC分类号： C12Q1/04 , A61K49/0013 , C12Q1/34 , G01N2333/986
摘要： Provided herein are imaging methods for detecting, diagnosing and imaging pathogenic bacteria or a pathophysiological condition associated therewith using fluorescent, luminescent or colorimetric detection agents, e.g., fluorogenic substrates for bacterial enzymes, caged luciferins and fluorescent proteins, luciferases and enzymes expressed by recombinant bacteria. Signals emitted by the fluorescent, luminescent or colorimetric detection agents in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Also provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring fluorescence or luminescence emitted from the detection agents in the presence and absence of the potential therapeutic agent. In addition, a method for detecting a pathogenic bacteria via PET or SPECT imaging using a positron-emitting or gamma-emitting substrate for a beta-lactamase or other enzyme or protein of the pathogenic bacteria. Further provided are the fluorogenic substrates CNIR-7 or CNIR7-TAT or the radiolabeled substrates.
摘要翻译：本文提供了用于使用荧光，发光或比色检测剂检测，诊断和成像病原菌或病理生理条件的成像方法，例如用于细菌酶，笼状荧光素和荧光蛋白的荧光底物，由重组细菌表达的荧光素酶和酶。将荧光，发光或比色检测剂在细菌存在下发出的信号与对照相比较以检测和定位病原菌。还提供了一种通过在存在和不存在潜在治疗剂的情况下测量从检测剂发出的荧光或发光来筛选治疗剂来治疗病理生理状况的方法。另外，通过使用正电子发射或γ-发射底物的β-内酰胺酶或致病菌的其它酶或蛋白质通过PET或SPECT成像检测致病细菌的方法。还提供了荧光底物CNIR-7或CNIR7-TAT或放射性标记的底物。

8. 发明申请

US20140127712A1 USE OF BACTERIAL BETA-LACTAMASE FOR IN VITRO DIAGNOSTICS AND IN VIVO IMAGING, DIAGNOSTICS AND THERAPEUTICS 有权
标题翻译：用于体外诊断和体内成像，诊断和治疗的细菌β-乳糖酶的使用
公开(公告)号：US20140127712A1
公开(公告)日：2014-05-08
申请号：US14044825
申请日：2013-10-02
申请人： Jeffrey D. Cirillo , Jianghong Rao
发明人： Jeffrey D. Cirillo , Jianghong Rao
IPC分类号： C12Q1/34 , C12Q1/66
CPC分类号： C12Q1/18 , A61K49/0013 , A61K49/0021 , A61K49/0028 , A61K49/0032 , A61K49/0041 , A61K49/0052 , C09B57/02 , C12Q1/04 , C12Q1/34 , C12Q1/66 , G01N21/6408 , G01N21/6428 , G01N21/78 , G01N2021/6417 , G01N2201/061 , G01N2333/986
摘要： Provided herein are assays and in vitro methods to determine susceptibility to a drug effective against a pathogenic bacteria, for example, a pathogenic Mycobacteria, that has a beta-lactamase activity. An excitation wavelength is delivered to a biological sample obtained from a subject having an infection from the pathogenic bacteria in the presence of a beta-lactamase substrate. The intensity of a signal, such as a fluorescent, luminescent or colorimetric signal, at an emission wavelength of a product of the beta-lactamase on the subject is correlated to drug susceptibility. Also provided is an assay system for monitoring drug susceptibility of a pathogenic bacteria comprising color-producing substrates for a beta-lactamase of the pathogenic bacteria, an assay device for visibly detecting a product of the beta-lactamase on the substrate thereof and a reader configured to quantify the visibly detected product.
摘要翻译：本文提供了测定和体外方法以确定对具有β-内酰胺酶活性的致病细菌例如致病性分枝杆菌有效的药物的易感性。在β-内酰胺酶底物的存在下，将激发波长输送到从具有病原菌感染的受试者获得的生物样品。在受试者的β-内酰胺酶的产物的发射波长处的信号强度，例如荧光，发光或比色信号与药物敏感性相关。还提供了用于监测病原细菌的药物敏感性的测定系统，其包括致病细菌的β-内酰胺酶的着色产生底物，用于可见地检测其底物上的β-内酰胺酶的产物的测定装置和配置量化可见的产品。

9. 发明授权

US06752994B2 Insertional mutations in mycobacteria 失效
标题翻译：分枝杆菌中的插入突变
公开(公告)号：US06752994B2
公开(公告)日：2004-06-22
申请号：US09898762
申请日：2001-07-03
申请人： William R. Jacobs, Jr. , Barry Bloom , Ganjam V. Kalpana , Jeffrey D. Cirillo , Ruth McAdam
发明人： William R. Jacobs, Jr. , Barry Bloom , Ganjam V. Kalpana , Jeffrey D. Cirillo , Ruth McAdam
IPC分类号： A61K3904
CPC分类号： A61K39/04 , A61K39/00 , C07K14/35 , C12N15/74 , Y10S435/863 , Y10S435/864 , Y10S435/865 , Y10S435/866
摘要： A mutated mycobacterium selected from the class consisting of mutated M. bovis-BCG, mutated M. tuberculosis, and mutated M. leprae. The mutation of M. bovis-BCG, M. tuberculosis, or M. leprae is preferably effected through an insertional mutation of a mycobacterial gene. The insertional mutagenesis may be effected, for example, through illegitimate recombination or by a mycobacterial transposon. Such mutated mycobacteria may then be transformed with an expression vector(s) containing a complement gene to the gene which is mutated, and preferably also including a heterologous gene.
摘要翻译：选自突变的牛分枝杆菌BCG，突变的结核分枝杆菌和突变的麻疯病菌的突变分枝杆菌。牛分枝杆菌BCG，结核分枝杆菌或麻风杆菌的突变优选通过分枝杆菌基因的插入突变来实现。插入诱变可以例如通过非法重组或通过分枝杆菌转座子进行。然后可以将这种突变的分枝杆菌用含有突变基因的补体基因的表达载体转化，并且优选还包括异源基因。

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