A novel gyrase inhibitor from toxin-antitoxin system expressed by Staphylococcus aureus
A novel gyrase inhibitor from toxin-antitoxin system expressed by Staphylococcus aureus
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DOI：
10.1111/febs.16634
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发表时间：
2022-09-28
期刊：
影响因子：
5.4
通讯作者：
Inouye，Masayori
中科院分区：
文献类型：
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作者：
Kato，Fuminori;Yamaguchi，Yoshihiro;Inouye，Masayori
毒素-抗毒素(TA)系统由一种抑制细胞基本功能(如DNA、RNA和蛋白质合成)的毒素和其同源抗毒素中和毒性组成。最近，我们在金黄色葡萄球菌基因组中发现了一个称为TsbA/TsbT的TA系统。在大肠杆菌中诱导的etsbT基因停止了DNA和RNA的合成，减少了超螺旋质粒，导致DNA变得越来越松弛。这些结果表明DNA旋转酶是TsbT的靶标。此外，TsbT还能抑制 和 金黄色葡萄球菌的DNA旋转酶活性，并在 体外诱导DNA线性化。综上所述，这些结果表明，TsbT毒素在 体内针对DNAgyrase.定点突变实验表明，TsbT中的E27和D37残基是毒性的关键。结合真空-紫外圆二色谱分析和神经网络方法的二级结构预测表明，TsbT的第22-32个残基形成α-螺旋结构，E27残基位于α-螺旋片段的中心附近。这些发现不仅为S.DNAaureusTA系统提供了新的见解，也为针对 拓扑异构酶的细菌毒素提供了新的见解。
Toxin–antitoxin (TA) systems consist of a toxin inhibiting essential cellular functions (such as DNA, RNA and protein synthesis), and its cognate antitoxin neutralizing the toxicity. Recently, we identified a TA system termed TsbA/TsbT in theStaphylococcus aureusgenome. The induction of thetsbTgene inEscherichia colihalted both DNA and RNA synthesis, reduced supercoiled plasmid and resulted in increasingly relaxed DNA. These results suggested that DNA gyrase was the target of TsbT. In addition, TsbT inhibited bothE. coliandS. aureusDNA gyrase activity and induced linearization of plasmid DNAin vitro. Taken together, these results demonstrate that the TsbT toxin targets DNA gyrasein vivo. Site‐directed mutagenesis experiments showed that the E27 and D37 residues in TsbT are critical for toxicity. Secondary structure prediction combining the analysis of vacuum‐ultraviolet circular‐dichroism spectroscopy and neural network method demonstrated that the 22nd–32nd residues of TsbT form an α‐helix structure, and that the E27 residue is located around the centre of the α‐helix segment. These findings give new insights not only intoS. aureusTA systems, but also into bacterial toxins targeting DNA topoisomerases.