Disrupting the ArcA regulatory network increases tetracycline susceptibility of TetR Escherichia coli
biorxiv(2020)
摘要
There is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing >700,000 deaths annually. Here, we demonstrate that tetracycline resistant (TetR) Escherichia coli undergoes global transcriptional and metabolic remodeling, including down-regulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Targeted knockout of ArcA, identified by network analysis as a master regulator among 25 transcription factors of this new compensatory physiological state, significantly increased the susceptibility of TetR E. coli to tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as the arcA knockout strain also synergistically re-sensitized TetR E. coli to tetracycline. The potentiating effect of sertraline was eliminated upon knocking out arcA , demonstrating that the mechanism of synergy was through action of sertraline on the tetracycline-induced ArcA network in the TetR strain. Our findings demonstrate that targeting mechanistic drivers of compensatory physiological states could be a generalizable strategy to re-sensitize AMR pathogens to lost antibiotics.
### Competing Interest Statement
The authors have declared no competing interest.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要