公开(公告)号：US09890111B2

公开(公告)日：2018-02-13

申请号：US14960025

申请日：2015-12-04

申请人： Academia Sinica

发明人： Chi-Huey Wong ,  Che Alex Ma ,  Ting-Jen Rachel Cheng ,  Wei-Chieh Cheng

IPC分类号： C07C235/64 ,  C12Q1/18 ,  C12Q1/48 ,  C07C235/84

CPC分类号： C07C235/64 ,  C07C235/84 ,  C07K2299/00 ,  C12Q1/18 ,  C12Q1/48 ,  G01N2333/91102 ,  G01N2500/00

摘要： The crystal structure at 2.16 Å resolution of the full-length bacterial bifunctional transglycosylase penicillin-binding protein 1b (PBP1b) from Escherichia coli, in complex with its inhibitor moenomycin, is provided. The atomic coordinates of the complex as well as the moenomycin binding site are provided. Three dimensional structures of amino acid residues involved in moenomycin binding and transglycosylation activity are identified. Binding site for peptidoglycan synthesis inhibitors comprising inhibitor-binding site comprises amino acid residues from at least one of transglycosylase (TG), UvrB domain 2 homolog (UB2H) and transmembrane (TM) domains of PBP1b are identified at an atomic level of resolution. Methods for rational drug design based on the atomic coordinates are provided. Methods for screening for antibiotics based on anisotropic binding assay and transglycosylase inhibitor assays are provided. Novel antibiotics based on the screening assays of the invention are disclosed.

公开(公告)号：US20160083337A1

公开(公告)日：2016-03-24

申请号：US14960025

申请日：2015-12-04

申请人： Academia Sinica

发明人： Chi-Huey Wong ,  Che Alex Ma ,  Ting-Jen Rachel Cheng ,  Wei-Chieh Cheng

IPC分类号： C07C235/64 ,  C07C235/84

CPC分类号： C07C235/64 ,  C07C235/84 ,  C07K2299/00 ,  C12Q1/18 ,  C12Q1/48 ,  G01N2333/91102 ,  G01N2500/00

摘要： The crystal structure at 2.16 Å resolution of the full-length bacterial bifunctional transglycosylase penicillin-binding protein 1b (PBP1b) from Escherichia coli, in complex with its inhibitor moenomycin, is provided. The atomic coordinates of the complex as well as the moenomycin binding site are provided. Three dimensional structures of amino acid residues involved in moenomycin binding and transglycosylation activity are identified. Binding site for peptidoglycan synthesis inhibitors comprising inhibitor-binding site comprises amino acid residues from at least one of transglycosylase (TG), UvrB domain 2 homolog (UB2H) and transmembrane (TM) domains of PBP1b are identified at an atomic level of resolution. Methods for rational drug design based on the atomic coordinates are provided. Methods for screening for antibiotics based on anisotropic binding assay and transglycosylase inhibitor assays are provided. Novel antibiotics based on the screening assays of the invention are disclosed.

摘要翻译： 提供了与其抑制剂新霉素复合的大肠杆菌全长细菌双功能转糖苷酶青霉素结合蛋白1b（PBP1b）的分辨率为2.16的晶体结构。 提供复合物的原子坐标以及霉酚霉素结合位点。 鉴定了涉及霉酚霉素结合和转糖基化活性的氨基酸残基的三维结构。 包含抑制剂结合位点的肽聚糖合成抑制剂的结合位点包含以分辨率的原子级别鉴定的来自转糖苷酶（TG），UvrB结构域2同源物（UB2H）和跨膜（TM）结构域中的至少一种的氨基酸残基。 提供了基于原子坐标的合理药物设计方法。 提供了基于各向异性结合测定法和转糖苷酶抑制剂测定法筛选抗生素的方法。 公开了基于本发明筛选试验的新型抗生素。