Characterisation of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci.
Characterisation of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci.
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DOI：
10.1016/j.bbagen.2017.05.011
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Hussain R
中科院分区：
文献类型：
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作者：
Hughes CS;Longo E;Phillips-Jones MK;Hussain R
A型耐药的“最后一线”糖肽类抗生素万古霉素的领先医院获得性感染病原体，肠球菌，是最常见的在英国。抗性由VanRASA双组分系统调节，该系统包括组氨酸传感器激酶VanSA和伴侣反应调节剂VanRA。尚未鉴定VanSA的活化配体的性质，因此本工作试图鉴定和鉴定VanSA的配体。体外方法被用来筛选一系列潜在的配体与纯化的VanSA蛋白的结构和活性的影响。在筛选的配体（糖肽类抗生素万古霉素和替考拉宁，以及肽聚糖组分N-乙酰胞壁酸、D-Ala-D-Ala和Ala-D-y-Glu-Lys-D-Ala-D-Ala）中，仅发现糖肽类抗生素万古霉素和替考拉宁以不同的亲和力（万古霉素70 μM;替考拉宁30和170 μM）结合VanSA，并建议通过暴露的芳香残基色氨酸和酪氨酸结合。此外，抗生素的结合诱导VanSA更快，更长的磷酸化状态，提出它们作为肠球菌中A型万古霉素耐药性的激活剂。万古霉素和替考拉宁（非肽聚糖）被提议作为活化配体。结合相互作用涉及色氨酸和酪氨酸。结合导致VanSA的磷酸化活性增加。
A-type resistance towards “last-line” glycopeptide antibiotic vancomycin in the leading hospital acquired infectious agent, the enterococci, is the most common in the UK. Resistance is regulated by the VanRASA two-component system, comprising the histidine sensor kinase VanSA and the partner response regulator VanRA. The nature of the activating ligand for VanSA has not been identified, therefore this work sought to identify and characterise ligand(s) for VanSA. In vitro approaches were used to screen the structural and activity effects of a range of potential ligands with purified VanSA protein. Of the screened ligands (glycopeptide antibiotics vancomycin and teicoplanin, and peptidoglycan components N-acetylmuramic acid, D-Ala-D-Ala and Ala-D-y-Glu-Lys-D-Ala-D-Ala) only glycopeptide antibiotics vancomycin and teicoplanin were found to bind VanSA with different affinities (vancomycin 70 μM; teicoplanin 30 and 170 μM), and were proposed to bind via exposed aromatic residues tryptophan and tyrosine. Furthermore, binding of the antibiotics induced quicker, longer-lived phosphorylation states for VanSA, proposing them as activators of type A vancomycin resistance in the enterococci. Vancomycin and teicoplanin (not peptidoglycan) are proposed as activating ligands. Binding interaction involves tryptophan and tyrosine. Binding results in increased phosphorylation activity for VanSA.