公开(公告)号：US20150232417A1

公开(公告)日：2015-08-20

申请号：US14188678

申请日：2014-02-24

Applicant: ACADEMIA SINICA

Inventor： Chi-Huey WONG ,  Che Alex MA ,  Ting-Jen Rachel CHENG ,  Wei-Chieh CHENG

IPC: C07C235/64 ,  G01N33/573

CPC classification number: C07C235/64 ,  C07C235/84 ,  C07K2299/00 ,  C12Q1/18 ,  C12Q1/48 ,  G01N33/573 ,  G01N2333/91102 ,  G01N2500/00 ,  G01N2500/04 ,  G01N2500/20

Abstract: Crystal structure at 2.16 Å resolution of full-length Escherichia coli penicillin-binding protein 1b (PBP1b) in complex with its inhibitor moenomycin, is provided. 3D structures of amino acid residues involved in moenomycin binding and transglycosylation activity are identified. Binding sites for peptidoglycan synthesis inhibitors comprising amino acid residues from transglycosylase (TG), UvrB domain 2 homolog (UB2H) and transmembrane (TM) domains of PBP1b are identified at atomic level resolution. Rational drug design, based on the atomic coordinates, are disclosed. Methods for screening for antibiotics using anisotropic binding and transglycosylase inhibitor assays and novel antibiotics based on the screening assays are provided.

Abstract translation: 提供了全长大肠杆菌青霉素结合蛋白1b（PBP1b）与其抑制剂新霉素复合物的分辨率为2.16Å的晶体结构。 鉴定涉及霉酚霉素结合和转糖基化活性的氨基酸残基的3D结构。 在原子级分辨率下鉴定了包含来自转糖苷酶（TG），UvrB结构域2同源物（UB2H）和PBP1b跨膜（TM）结构域的氨基酸残基的肽聚糖合成抑制剂的结合位点。 公开了基于原子坐标的合理药物设计。 提供了使用各向异性结合和转糖苷酶抑制剂测定法筛选抗生素的方法以及基于筛选试验的新型抗生素。