Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.
Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.
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新型细菌拓扑异构酶抑制剂：酰胺酶结合基序对三环类似物的独特靶向活性。
DOI：
10.1128/aac.00482-23
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发表时间：
2023
影响因子：
4.9
通讯作者：
Mitton-Fry,MarkJ
中科院分区：
文献类型：
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作者：
Mann,ChelseaA;CarvajalMoreno,JessikaJ;Lu,Yanran;Dellos-Nolan,Sheri;Wozniak,DanielJ;Yalowich,JackC;Mitton-Fry,MarkJ
抗生素耐药性对公共卫生产生了相当大的影响，并继续威胁着抗菌治疗的有效性。新型细菌拓扑异构酶抑制剂（NBTI）是一类有前途的抗菌剂，具有独特的结合模式和独特的药理学，使它们能够逃避现有的耐药机制。NBTI的临床开发一直受到几个问题的困扰，包括心血管安全性。在此，我们报告了一个子系列的三环NBTI轴承酰胺键，显示出有前途的抗菌活性，有效的双靶点抑制DNA促旋酶和拓扑异构酶IV（拓扑IV），以及改善心血管安全性和代谢概况。这些酰胺NBTI诱导pBR 322 DNA的单链和双链断裂由金黄色葡萄球菌DNA回旋酶介导，与原型NBTI，只造成单链断裂。出乎意料的是，酰胺1a和1b靶向人拓扑异构酶IIα（TOP 2 α），导致pBR 322 DNA的单链和双链断裂，并诱导完整的人白血病K562细胞的DNA链断裂。此外，含有降低水平的TOP 2 α的抗癌药物耐药K/VP. 5细胞对酰胺1a和1b具有交叉耐药性。总之，这些结果证明了所选三环NBTI的广谱抗菌特性、理想的安全性特征、诱导DNA双链断裂的不寻常能力以及对人TOP2α的活性。未来的工作将致力于优化和开发具有有效和选择性抗细菌活性的三环NBTI。最后，目前的研究结果可能为选择性抗癌药物的开发提供了一个额外的途径。
Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated byStaphylococcus aureusDNA gyrase, in contrast to prototypical NBTIs that cause only single-strand breaks. Unexpectedly, amides1aand1btargeted human topoisomerase IIα (TOP2α) causing both single- and double-strand breaks in pBR322 DNA, and induced DNA strand breaks in intact human leukemia K562 cells. In addition, anticancer drug-resistant K/VP.5 cells containing decreased levels of TOP2α were cross-resistant to amides1aand1b. Together, these results demonstrate broad spectrum antibacterial properties of selected tricyclic NBTIs, desirable safety profiles, an unusual ability to induce DNA double-stranded breaks, and activity against human TOP2α. Future work will be directed toward optimization and development of tricyclic NBTIs with potent and selective activity against bacteria. Finally, the current results may provide an additional avenue for development of selective anticancer agents.