Disrupting the ArcA Regulatory Network Amplifies the Fitness Cost of Tetracycline Resistance in Escherichia coli.
Disrupting the ArcA Regulatory Network Amplifies the Fitness Cost of Tetracycline Resistance in Escherichia coli.
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DOI：
10.1128/msystems.00904-22
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发表时间：
2023-02-23
期刊：
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
目前迫切需要找到预防或破坏抗生素耐药性（AMR）的次要药物的策略，AMR每年导致超过70万人死亡。在这里，我们证明，四环素耐药（TetR）大肠杆菌进行全球转录和代谢重塑，包括下调三羧酸循环和破坏氧化还原稳态，以支持四环素流出的质子动力消耗。使用一个汇集的全基因组单基因缺失菌株文库，至少308个基因，包括我们的网络分析确定的四个转录调控因子，被证实是恢复TetR E的适应性所必需的。四环素治疗期间的大肠杆菌。通过网络分析确定ArcA的靶向敲除作为这种新的代偿性生理状态的主调节器，显著损害TetR E的适应性。四环素处理的大肠杆菌。一种药物舍曲林，产生了与arcA敲除菌株相似的代谢组谱，也使TetR E重新敏感。大肠杆菌转化为四环素。我们发现舍曲林的增强作用在敲除arcA后被消除，这表明潜在协同作用的机制是通过舍曲林对TetR菌株中四环素诱导的ArcA网络的作用。我们的研究结果表明，针对代偿性生理状态的机械驱动因素的疗法可以使AMR病原体对失去的抗生素重新敏感。到2050年，抗菌素耐药性（AMR）预计将成为每年超过1000万人死亡的原因。虽然寻找新的强效抗生素的努力是有效的，但它们昂贵，而且新的耐药菌株出现的速度超过了它们。迫切需要一种合理的方法来加速发现有效清除AMR病原体甚至防止新耐药菌株出现的药物和药物组合。使用四环素耐药（TetR）大肠杆菌，我们证明，获得抗性是伴随着失去的健身，这是恢复的补偿性生理变化。我们证明了代偿性生理状态的转录调节因子是有希望的药物靶点，因为它们的破坏增加了TetR E的易感性。大肠杆菌转化为四环素。因此，我们描述了一种可推广的系统生物学方法来识别AMR菌株中的新漏洞，以合理地加速发现延长现有抗生素寿命的治疗方法。
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 downregulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Using a pooled genome-wide library of single-gene deletion strains, at least 308 genes, including four transcriptional regulators identified by our network analysis, were confirmed as essential for restoring the fitness of TetR E. coli during treatment with tetracycline. Targeted knockout of ArcA, identified by network analysis as a master regulator of this new compensatory physiological state, significantly compromised fitness of TetR E. coli during tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as the arcA knockout strain, also resensitized TetR E. coli to tetracycline. We discovered that the potentiating effect of sertraline was eliminated upon knocking out arcA, demonstrating that the mechanism of potential synergy was through action of sertraline on the tetracycline-induced ArcA network in the TetR strain. Our findings demonstrate that therapies that target mechanistic drivers of compensatory physiological states could resensitize AMR pathogens to lost antibiotics. IMPORTANCE Antimicrobial resistance (AMR) is projected to be the cause of >10 million deaths annually by 2050. While efforts to find new potent antibiotics are effective, they are expensive and outpaced by the rate at which new resistant strains emerge. There is desperate need for a rational approach to accelerate the discovery of drugs and drug combinations that effectively clear AMR pathogens and even prevent the emergence of new resistant strains. Using tetracycline-resistant (TetR) Escherichia coli, we demonstrate that gaining resistance is accompanied by loss of fitness, which is restored by compensatory physiological changes. We demonstrate that transcriptional regulators of the compensatory physiologic state are promising drug targets because their disruption increases the susceptibility of TetR E. coli to tetracycline. Thus, we describe a generalizable systems biology approach to identify new vulnerabilities within AMR strains to rationally accelerate the discovery of therapeutics that extend the life span of existing antibiotics.
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影响因子：
13.6
作者：
Cokol M;Kuru N;Bicak E;Larkins-Ford J;Aldridge BB
通讯作者：
Aldridge BB
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
--
作者：
Banerjee D;Parmar D;Bhattacharya N;Ghanate AD;Panchagnula V;Raghunathan A
通讯作者：
Raghunathan A
影响因子：
5.2
作者：
de Cristobal, Ricardo E.;Vincent, Paula A.;Salomon, Raul A.
通讯作者：
Salomon, Raul A.
影响因子：
16
作者：
Campos, Adrian I.;Zampieri, Mattia
通讯作者：
Zampieri, Mattia