Proteolytic Queues at ClpXP Increase Antibiotic Tolerance
Proteolytic Queues at ClpXP Increase Antibiotic Tolerance
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DOI：
10.1021/acssynbio.9b00358
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发表时间：
2020-01-01
影响因子：
4.7
通讯作者：
Butzin, Nicholas C.
中科院分区：
文献类型：
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作者：
Deter, Heather S.;Abualrahi, Alawiah H.;Butzin, Nicholas C.
抗生素耐药是一种普遍存在的现象，它会降低抗生素治疗的效果，并促进抗生素耐药性的产生。在这里，我们使用排队理论(即，排队研究)、计算模型和合成生物学方法，探索蛋白酶在抗生素耐受性、抗生素短期种群生存中的作用。蛋白酶是降解蛋白质的关键细胞成分，在称为持久者的耐多药细胞亚群中发挥重要作用。我们发现，在蛋白酶ClpXP前排队可以提高抗生素耐受性，分别类似于氨苄西林和环丙沙星处理的大肠杆菌种群的80倍和60倍。这似乎对抗生素的持久性没有影响，我们将其与基于种群衰退的耐受性区分开来。这些结果表明，蛋白降解排队是一种实用的方法来探索细菌耐受性和相关基因的蛋白分解活性，同时限制基因敲除和过度表达经常造成的意外后果。
Antibiotic tolerance is a widespread phenomenon that renders antibiotic treatments less effective and facilitates antibiotic resistance. Here we explore the role of proteases in antibiotic tolerance, short-term population survival of antibiotics, using queueing theory (i.e., the study of waiting lines), computational models, and a synthetic biology approach. Proteases are key cellular components that degrade proteins and play an important role in a multidrug tolerant subpopulation of cells, called persisters. We found that queueing at the protease ClpXP increases antibiotic tolerance, similar to 80 and similar to 60 fold in an E. coli population treated with ampicillin and ciprofloxacin, respectively. There does not appear to be an effect on antibiotic persistence, which we distinguish from tolerance based on population decay. These results demonstrate that proteolytic queueing is a practical method to probe proteolytic activity in bacterial tolerance and related genes, while limiting the unintended consequences frequently caused by gene knockout and overexpression.