Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach
Structure of the complex between teicoplanin and a bacterial cell-wall peptide: use of a carrier-protein approach
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DOI：
10.1107/s0907444912050469
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发表时间：
2013-04-01
影响因子：
2.2
通讯作者：
Loll, Patrick J.
中科院分区：
文献类型：
--
作者：
Economou, Nicoleta J.;Zentner, Isaac J.;Loll, Patrick J.
多重耐药细菌感染通常使用糖肽类抗生素（如替考拉宁）治疗。这种药物通过结合和隔离细胞壁前体（一种含D-丙氨酸的肽）来抑制细菌细胞壁的生物合成。采用载体-蛋白策略，通过天然化学连接将细胞壁肽与MBP或泛素融合，随后使蛋白肽-抗生素复合物结晶，从而使替考拉宁及其靶肽复合物结晶。2.05埃分辨率MBP肽替考拉宁结构显示，替考拉宁通过5个氢键和多重货车范德华相互作用的组合识别其配体。替考拉宁结构与未配体替考拉宁结构的比较显示，抗生素肽骨架的灵活性对配体识别具有重要意义。衍射实验显示抗生素的第六个氨基酸发生X射线诱导脱氯;结果表明替考拉宁的辐射敏感性显著高于其他类似抗生素，配体结合可增加辐射敏感性。从替考拉宁新结构中获得的见解可能有助于开发旨在克服细菌耐药性的下一代抗菌药物。
Multidrug-resistant bacterial infections are commonly treated with glycopeptide antibiotics such as teicoplanin. This drug inhibits bacterial cell-wall biosynthesis by binding and sequestering a cell-wall precursor: a D-alanine-containing peptide. A carrier-protein strategy was used to crystallize the complex of teicoplanin and its target peptide by fusing the cell-wall peptide to either MBP or ubiquitin via native chemical ligation and subsequently crystallizing the proteinpeptideantibiotic complex. The 2.05 angstrom resolution MBPpeptideteicoplanin structure shows that teicoplanin recognizes its ligand through a combination of five hydrogen bonds and multiple van der Waals interactions. Comparison of this teicoplanin structure with that of unliganded teicoplanin reveals a flexibility in the antibiotic peptide backbone that has significant implications for ligand recognition. Diffraction experiments revealed an X-ray-induced dechlorination of the sixth amino acid of the antibiotic; it is shown that teicoplanin is significantly more radiation-sensitive than other similar antibiotics and that ligand binding increases radiosensitivity. Insights derived from this new teicoplanin structure may contribute to the development of next-generation antibacterials designed to overcome bacterial resistance.