The Role of Integration Host Factor in Escherichia coli Persister Formation.
The Role of Integration Host Factor in Escherichia coli Persister Formation.
复制标题
整合宿主因子在大肠杆菌宿存形成中的作用。
DOI：
10.1128/mbio.03420-21
复制
发表时间：
2022-02-22
期刊：
影响因子：
6.4
通讯作者：
Lewis K
中科院分区：
文献类型：
--
作者：
Nicolau SE;Lewis K
持续性细胞是一个小的细胞亚群，能够耐受抗生素的杀伤作用，并与慢性感染对抗生素治疗的耐受性有关。关于由不同细菌物种形成的持留菌，出现了一个一般主题，即以抗生素靶标活性降低为特征的相对休眠状态。在此框架内，许多研究将持久存在的形成与能量产生成分的随机减少联系起来，从而导致ATP和靶点活性降低。在这项研究中，我们筛选大肠杆菌的主要全球监管机构的敲除对持久性的影响。敲除整合宿主因子（IHF）使ATP水平升高，持久性降低。这是伴随着过表达的异柠檬酸脱氢酶（Icd）和下调的异柠檬酸裂解酶（AceA），两个基因位于三羧酸（TCA）循环和乙醛酸旁路之间的分叉。使用翻译的ihfA-mVenus融合，我们挑选出罕见的明亮细胞，这个亚群富含持久细胞。我们的研究结果表明，ihf表达中的噪音产生了具有低Icd/高AceA的稀有细胞，将底物转移到乙醛酸旁路中，从而减少ATP，导致抗生素耐受性持久存在。我们进一步研究噪音在一个简单的模型，乳糖操纵子，并表明，敲除的lacI阻遏增加操纵子的表达，并减少持续形成。我们的研究结果表明，噪音淬火过表达作为一种通用的方法来确定在各种细菌物种和条件下的持久性基因的性质。
Persisters represent a small subpopulation of cells that are tolerant of killing by antibiotics and are implicated in the recalcitrance of chronic infections to antibiotic therapy. One general theme has emerged regarding persisters formed by different bacterial species, namely, a state of relative dormancy characterized by diminished activity of antibiotic targets. Within this framework, a number of studies have linked persister formation to stochastic decreases in energy-generating components, leading to low ATP and target activity. In this study, we screen knockouts in the main global regulators of Escherichia coli for their effect on persisters. A knockout in integration host factor (IHF) had elevated ATP and a diminished level of persisters. This was accompanied by an overexpression of isocitrate dehydrogenase (Icd) and a downregulation of isocitrate lyase (AceA), two genes located at the bifurcation between the tricarboxylic acid (TCA) cycle and the glyoxylate bypass. Using a translational ihfA-mVenus fusion, we sort out rare bright cells, and this subpopulation is enriched in persisters. Our results suggest that noise in the expression of ihf produces rare cells with low Icd/high AceA, diverting substrates into the glyoxylate bypass, which decreases ATP, leading to antibiotic-tolerant persisters. We further examine noise in a simple model, the lac operon, and show that a knockout of the lacI repressor increases expression of the operon and decreases persister formation. Our results suggest that noise quenching by overexpression serves as a general approach to determine the nature of persister genes in a variety of bacterial species and conditions.
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DOI：
10.1073/pnas.56.6.1891
发表时间：
1966-01-01
影响因子：
11.1
作者：
GILBERT, W;MULLERHI.B
通讯作者：
MULLERHI.B
影响因子：
16
作者：
Amato, Stephanie M.;Orman, Mehmet A.;Brynildsen, Mark P.
通讯作者：
Brynildsen, Mark P.
影响因子：
2.8
作者：
Bradley, Meranda D.;Beach, Michael B.;Osuna, Robert
通讯作者：
Osuna, Robert
影响因子：
3.2
作者：
ERNSTING, BR;ATKINSON, MR;MATTHEWS, RG
通讯作者：
MATTHEWS, RG
影响因子：
3.6
作者：
Berghoff, Bork A.;Hoekzema, Mirthe;Wagner, E. Gerhart H.
通讯作者：
Wagner, E. Gerhart H.