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Nature:多药物耐受性的结构基础

标签:药物耐受 HipA
摘要 : 多药物耐受性在细菌病原体中的传播主要是由于所谓的“persisters”的存在,它们是表型变体,处于休眠状态,因此不易受抗生素的影响,后者只对积极生长的细胞有效。

 多药物耐受性在细菌病原体中的传播主要是由于所谓的“persisters”的存在,它们是表型变体,处于休眠状态,因此不易受抗生素的影响,后者只对积极生长的细胞有效。Maria Schumacher等人在这项研究中发现,野生型HipA (一种丝氨酸蛋白激酶,抑制蛋白合成并促使细胞进入休眠状态)在大肠杆菌中帮助persister形成,“hipA7 high-persister突变体”存在于尿道感染患者体内。作者确定了由启动子DNA和 “HipA–HipB”复合物组成的“转录自抑制复合物”的结构。这些结构显示,高持久性突变通过干扰HipA–HipA相互作用、将HipA从higher-order复合物中释放出来和触发多药物耐受性来发挥功能。

原文标题:HipBA–promoter structures reveal the basis of heritable multidrug tolerance

原文摘要:Multidrug tolerance is largely responsible for chronic infections and caused by a small population of dormant cells called persisters. selecion for survival in the presence of antibiotics produced the first genetic link to multidrug tolerance: a mutant in the Escherichia coli hipA locus. HipA encodes a serine-protein kinase, the multidrug tolerance activity of which is neutralized by binding to the transcriptional regulator HipB and hipBA promoter. The physiological role of HipA in multidrug tolerance, however, has been unclear. Here we show that wild-type HipA contributes to persister formation and that high-persister hipA mutants cause multidrug tolerance in urinary tract infections. Perplexingly, high-persister mutations map to the N-subdomain-1 of HipA far from its active site. Structures of higher-order HipA–HipB–promoter complexes reveal HipA forms dimers in these assemblies via N-subdomain-1 interactions that occlude their active sites. High-persistence mutations, therefore, diminish HipA–HipA dimerization, thereby unleashing HipA to effect multidrug tolerance. Thus, our studies reveal the mechanistic basis of heritable, clinically relevant antibiotic tolerance.

来源: Nature 浏览次数:0

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