Bacterial topoisomerase I as a target for discovery of antibacterial compounds.
Bacterial topoisomerase I as a target for discovery of antibacterial compounds.
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DOI：
10.1093/nar/gkn936
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发表时间：
2009-02
影响因子：
14.9
通讯作者：
Tse-Dinh YC
中科院分区：
文献类型：
--
作者：
Tse-Dinh YC
细菌拓扑异构酶I是发现新的抗菌化合物的潜在靶标。通过SOS诱导筛选鉴定的突变型拓扑异构酶证明由IA型拓扑异构酶形成的DNA切割复合物的积累是杀菌的。鼠疫耶尔森氏菌和大肠杆菌拓扑异构酶I的这些突变体的表征表明，可以抑制DNA连接，同时保持DNA切割活性，通过降低镁（II）离子的结合亲和力。这可以通过直接参与Mg（II）结合的TOPRIM基序的突变或通过改变活性位点区域的电荷分布来实现。除了用于阐明控制切割-再连接平衡的关键元件外，Y。鼠疫和E.大肠杆菌拓扑异构酶I也被用作模型来研究细菌拓扑异构酶I切割复合物积累后的细胞反应。细菌拓扑异构酶I是防止转录过程中DNA超负螺旋所必需的。它在细菌胁迫反应中对胁迫基因的转录起重要作用。当细菌病原体响应宿主防御时，或在诱导细菌应激反应的其他抗生素存在下，靶向毒素的拓扑异构酶I可能特别有效。
Bacterial topoisomerase I is a potential target for discovery of new antibacterial compounds. Mutant topoisomerases identified by SOS induction screening demonstrated that accumulation of the DNA cleavage complex formed by type IA topoisomerases is bactericidal. Characterization of these mutants of Yersinia pestis and Escherichia coli topoisomerase I showed that DNA religation can be inhibited while maintaining DNA cleavage activity by decreasing the binding affinity of Mg(II) ions. This can be accomplished either by mutation of the TOPRIM motif involved directly in Mg(II) binding or by altering the charge distribution of the active site region. Besides being used to elucidate the key elements for the control of the cleavage-religation equilibrium, the SOS-inducing mutants of Y. pestis and E. coli topoisomerase I have also been utilized as models to study the cellular response following the accumulation of bacterial topoisomerase I cleavage complex. Bacterial topoisomerase I is required for preventing hypernegative supercoiling of DNA during transcription. It plays an important role in transcription of stress genes during bacterial stress response. Topoisomerase I targeting poisons may be particularly effective when the bacterial pathogen is responding to host defense, or in the presence of other antibiotics that induce the bacterial stress response.
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