公开(公告)号：US20070178111A1

公开(公告)日：2007-08-02

申请号：US11636379

申请日：2006-12-08

申请人： Vickie Brown-Driver ,  Kedar GC ,  John Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

发明人： Vickie Brown-Driver ,  Kedar GC ,  John Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

IPC分类号： A61K48/00 ,  A61K39/40 ,  A61K31/43 ,  A61K31/545

CPC分类号： A61K31/43 ,  A61K31/545 ,  A61K39/40 ,  A61K45/06 ,  Y02A50/469 ,  Y02A50/47 ,  Y02A50/482 ,  Y02A50/484 ,  A61K2300/00

摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

摘要翻译： 本发明提供了用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂的抗菌有效组合，特别是GlmU ，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。 进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞 对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

公开(公告)号：US20110143359A1

公开(公告)日：2011-06-16

申请号：US13033128

申请日：2011-02-23

申请人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Mark Stidham

发明人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Mark Stidham

IPC分类号： C12Q1/68

CPC分类号： C12N15/111 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2320/11 ,  C12N2330/30 ,  C12Y101/01158 ,  C12Y105/01003 ,  C12Y205/01031 ,  C12Y601/0101

摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.

摘要翻译： 本发明提供了生产和选择药物敏化反义DNA片段的方法。 在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。 该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

公开(公告)号：US07910337B2

公开(公告)日：2011-03-22

申请号：US11636394

申请日：2006-12-08

申请人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar Gc ,  John M. Finn ,  Mark Stidham

发明人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar Gc ,  John M. Finn ,  Mark Stidham

IPC分类号： C12P19/34 ,  C07H21/04 ,  C12N15/63 ,  C07K16/00

CPC分类号： C12N15/111 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2320/11 ,  C12N2330/30 ,  C12Y101/01158 ,  C12Y105/01003 ,  C12Y205/01031 ,  C12Y601/0101

摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.

摘要翻译： 本发明提供了生产和选择药物敏化反义DNA片段的方法。 在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。 该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

公开(公告)号：US20070218481A1

公开(公告)日：2007-09-20

申请号：US11636394

申请日：2006-12-08

申请人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar Gc ,  John M. Finn ,  Mark Stidham

发明人： Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Vickie Brown-Driver ,  Kedar Gc ,  John M. Finn ,  Mark Stidham

IPC分类号： C12Q1/68 ,  C07H21/02 ,  C12N15/74 ,  C12N1/21

CPC分类号： C12N15/111 ,  C12N15/1137 ,  C12N2310/11 ,  C12N2320/11 ,  C12N2330/30 ,  C12Y101/01158 ,  C12Y105/01003 ,  C12Y205/01031 ,  C12Y601/0101

摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.

摘要翻译： 本发明提供了生产和选择药物敏化反义DNA片段的方法。 在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。 该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

公开(公告)号：US08298543B2

公开(公告)日：2012-10-30

申请号：US13102856

申请日：2011-05-06

申请人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

发明人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

IPC分类号： A61K31/00 ,  A61K31/43 ,  A61K39/00

CPC分类号： A61K31/43 ,  A61K31/545 ,  A61K39/40 ,  A61K45/06 ,  Y02A50/469 ,  Y02A50/47 ,  Y02A50/482 ,  Y02A50/484 ,  A61K2300/00

摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

摘要翻译： 本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY，和UppS。 进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞 对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

公开(公告)号：US20110294774A1

公开(公告)日：2011-12-01

申请号：US13102856

申请日：2011-05-06

申请人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

发明人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

IPC分类号： A61K31/545 ,  A61P31/04 ,  A61K31/43 ,  A61K31/431 ,  A61K31/546 ,  A61K31/5365

CPC分类号： A61K31/43 ,  A61K31/545 ,  A61K39/40 ,  A61K45/06 ,  Y02A50/469 ,  Y02A50/47 ,  Y02A50/482 ,  Y02A50/484 ,  A61K2300/00

摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

摘要翻译： 本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。 进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞 对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

公开(公告)号：US08021665B2

公开(公告)日：2011-09-20

申请号：US11636379

申请日：2006-12-08

申请人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

发明人： Vickie Brown-Driver ,  Kedar GC ,  John M. Finn ,  Robert Haselbeck ,  Mark Hilgers ,  Karen Shaw ,  Mark Stidham

IPC分类号： A61K31/00 ,  A61K31/43 ,  A61K39/00

CPC分类号： A61K31/43 ,  A61K31/545 ,  A61K39/40 ,  A61K45/06 ,  Y02A50/469 ,  Y02A50/47 ,  Y02A50/482 ,  Y02A50/484 ,  A61K2300/00

摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

摘要翻译： 本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。 进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞 对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

公开(公告)号：US20120136014A1

公开(公告)日：2012-05-31

申请号：US13151683

申请日：2011-06-02

申请人： Zhiyong Chen ,  Christopher J. Creghton ,  Mark Cunningham ,  John Finn ,  Mark Hilgers ,  Michael Jung ,  Lucy Aguirre Kohnen ,  Thanh Lam ,  Xiaoming Li ,  Mark Stidham ,  Les Tari ,  Michael Trzoss ,  Junhu Zhang

发明人： Zhiyong Chen ,  Christopher J. Creghton ,  Mark Cunningham ,  John Finn ,  Mark Hilgers ,  Michael Jung ,  Lucy Aguirre Kohnen ,  Thanh Lam ,  Xiaoming Li ,  Mark Stidham ,  Les Tari ,  Michael Trzoss ,  Junhu Zhang

IPC分类号： A61K31/517 ,  C07D401/14 ,  C07D239/72 ,  A61P31/10 ,  A61P33/00 ,  A61P31/04 ,  A61P29/00 ,  C12N9/99 ,  C07D417/14

CPC分类号： C07D401/14 ,  C07D239/95 ,  C07D417/14

摘要： The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R5, R6 and Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.

摘要翻译： 本公开提供式I化合物或其药学上可接受的盐，其中R 5，R 6和Z如本文所述。 本公开还提供其药物组合物; 和抑制DHFR活性的方法; 以及通过给予式I化合物治疗细胞增殖性疾病，自身免疫疾病，炎性疾病或细菌，真菌或寄生虫感染的方法。

公开(公告)号：US08835445B2

公开(公告)日：2014-09-16

申请号：US13151683

申请日：2011-06-02

申请人： Zhiyong Chen ,  Christopher J. Creighton ,  Mark Cunningham ,  John Finn ,  Mark Hilgers ,  Michael Jung ,  Lucy Aguirre Kohnen ,  Thanh Lam ,  Xiaoming Li ,  Mark Stidham ,  Les Tari ,  Michael Trzoss ,  Junhu Zhang

发明人： Zhiyong Chen ,  Christopher J. Creighton ,  Mark Cunningham ,  John Finn ,  Mark Hilgers ,  Michael Jung ,  Lucy Aguirre Kohnen ,  Thanh Lam ,  Xiaoming Li ,  Mark Stidham ,  Les Tari ,  Michael Trzoss ,  Junhu Zhang

IPC分类号： A01N43/54 ,  A61K31/517 ,  C07D239/72 ,  C07D401/00

CPC分类号： C07D401/14 ,  C07D239/95 ,  C07D417/14

摘要： The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R5, R6 and Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.

摘要翻译： 本公开提供式I化合物或其药学上可接受的盐，其中R 5，R 6和Z如本文所述。 本公开还提供其药物组合物; 和抑制DHFR活性的方法; 以及通过给予式I化合物治疗细胞增殖性疾病，自身免疫疾病，炎性疾病或细菌，真菌或寄生虫感染的方法。

公开(公告)号：US06250783B1

公开(公告)日：2001-06-26

申请号：US09351249

申请日：1999-07-12

申请人： Mark Stidham ,  Dale Gathergood ,  Charles Furlotte

发明人： Mark Stidham ,  Dale Gathergood ,  Charles Furlotte

IPC分类号： B60R112

CPC分类号： B60Q1/2665 ,  B60R1/1207

摘要： An exterior rear view mirror assembly is disclosed which incorporates a warning light actuatable in conjunction with the vehicle turn signals to alert adjacent motor vehicles of an anticipated turn. The warning light is integrated into a first decorative cover member and may be connected to the vehicle turn signal circuit by way of connectable electrical leads or by an integrally formed plug and outlet arrangement. A second decorative cover member may be substituted for the first decorative cover member when it is not desired to incorporate the warning light.