Angucycline antibiotic waldiomycin recognizes common structural motif conserved in bacterial histidine kinases
Angucycline antibiotic waldiomycin recognizes common structural motif conserved in bacterial histidine kinases
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DOI：
10.1038/ja.2016.151
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发表时间：
2017-03-01
影响因子：
3.3
通讯作者：
Utsumi, Ryutaro
中科院分区：
文献类型：
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作者：
Eguchi, Yoko;Okajima, Toshihide;Utsumi, Ryutaro
二组分信号转导系统(TCSs)由一个组氨酸激酶传感器(HK)及其同源反应调节因子组成，负责感知和响应环境变化，并与病原菌的毒力有关。TCS是替代抗生素和抗毒力药物的潜在靶点。我们发现，在革兰氏阳性菌中抑制生长必需的HK、Walk的环素类抗生素Walk也能抑制来自革兰氏阴性杆菌的几种I类HKs。核磁共振分析和利用渗透压敏感型EnvZ的定点突变研究表明，沃尔迪霉素直接与HKS的H盒和X区结合，这两个区域是HKS二聚化诱导和含组氨酸磷酸转移(DHP)结构域中的两个保守区域。沃尔迪霉素抑制H-盒中保守组氨酸的磷酸化。对瓦尔迪霉素衍生物的分析表明，在瓦尔迪霉素-EnvZ DHP结构域复合体模型中，位于H盒附近的去环环是抑制活性的原因。我们证明了瓦尔迪霉素是一种结合在H-盒区域的HK抑制剂，具有抑制广谱HKS的潜力。
Two-component signal transduction systems (TCSs), composed of a histidine kinase sensor (HK) and its cognate response regulator, sense and respond to environmental changes and are related to the virulence of pathogens. TCSs are potential targets for alternative antibiotics and anti-virulence agents. Here we found that waldiomycin, an angucycline antibiotic that inhibits a growth essential HK, Walk, in Gram-positive bacteria, also inhibits several class I HKs from the Gram-negative Escherichia coll. NMR analyses and site-directed mutagenesis studies using the osmo-sensing EnvZ, a prototypical HK of E. coli, showed that waldiomycin directly binds to both H-box and X-region, which are the two conserved regions in the dimerization-inducing and histidine-containing phosphotransfer (DHp) domain of HKs. Waldiomycin inhibits phosphorylation of the conserved histidine in the H-box. Analysis of waldiomycin derivatives suggests that the angucyclic ring, situated near the H-box in the waldiomycin-EnvZ DHp domain complex model, is responsible for the inhibitory activity. We demonstrate that waldiomycin is an HK inhibitor binding to the H-box region and has the potential of inhibiting a broad spectrum of HKs.