Transcriptomic Analysis of the Activity and Mechanism of Action of a Ruthenium(II)-Based Antimicrobial That Induces Minimal Evolution of Pathogen Resistance
Transcriptomic Analysis of the Activity and Mechanism of Action of a Ruthenium(II)-Based Antimicrobial That Induces Minimal Evolution of Pathogen Resistance
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诱导病原体抗性最小化进化的钌 (II) 基抗菌药物的活性和作用机制的转录组分析
DOI：
10.1021/acsptsci.0c00159
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发表时间：
2020
影响因子：
--
通讯作者：
Varney A
中科院分区：
文献类型：
--
作者：
Varney A
人们越来越关注病原菌中抗生素耐药性的上升，促使人们大力研究开发抗生素治疗的有效替代品。此前，我们报道了双核钌(II)络合物对致病性、多重耐药细菌病原体的治疗活性。在此，我们报告说，这种先导化合物的溶解度特性与口服治疗剂所表现出的溶解度特性相当，与临床相关抗生素相比，它在尿路致病性、治疗耐药性大肠杆菌中诱导非常缓慢的耐药性进化。大肠杆菌菌株 EC958，当暂时去除与该化合物的接触时，这种抵抗力就会消失。为了进一步研究该化合物的作用机制，还研究了与膜、DNA 损伤以及暴露于该化合物引起的其他应激反应相关的九个靶基因的调节。该分析证实，该化合物会导致参与膜转运和三羧酸循环的基因显着转录下调。相比之下，伴侣蛋白编码基因spy的表达显着增加，表明需要修复外膜区域受损的蛋白。还发现该复合物显示出与 E 中的活性相当的活性。大肠杆菌感染一系列其他治疗相关的革兰氏阴性病原体。
Increasing concern over rising levels of antibiotic resistance among pathogenic bacteria has prompted significant research into developing efficacious alternatives to antibiotic treatment. Previously, we have reported on the therapeutic activity of a dinuclear ruthenium(II) complex against pathogenic, multi-drug-resistant bacterial pathogens. Herein, we report that the solubility properties of this lead are comparable to those exhibited by orally available therapeutics that in comparison to clinically relevant antibiotics it induces very slow evolution of resistance in the uropathogenic, therapeutically resistant,E. colistrain EC958, and this resistance was lost when exposure to the compound was temporarily removed. With the aim of further investigating the mechanism of action of this compound, the regulation of nine target genes relating to the membrane, DNA damage, and other stress responses provoked by exposure to the compound was also studied. This analysis confirmed that the compound causes a significant transcriptional downregulation of genes involved in membrane transport and the tricarboxylic acid cycle. By contrast, expression of the chaperone protein-coding gene,spy, was significantly increased suggesting a requirement for repair of damaged proteins in the region of the outer membrane. The complex was also found to display activity comparable to that inE. coliin a range of other therapeutically relevant Gram-negative pathogens.