Disruption of the MreB Elongasome Is Overcome by Mutations in the Tricarboxylic Acid Cycle.
Disruption of the MreB Elongasome Is Overcome by Mutations in the Tricarboxylic Acid Cycle.
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DOI：
10.3389/fmicb.2021.664281
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发表时间：
2021
影响因子：
5.2
通讯作者：
Morgenstein RM
中科院分区：
文献类型：
--
作者：
Barton B;Grinnell A;Morgenstein RM
细菌肌动蛋白同源基因MreB在杆状细菌中高度保守，对正常生长条件下的生长至关重要。MreB指导细胞壁合成的定位，MreB的丢失导致圆形细胞和死亡。使用MreB解聚药物A22，我们证明了通过从三羧酸(TCA)循环中缺失苹果酸脱氢酶来改变中枢代谢，导致细胞对A22的耐受性增加。我们假设苹果酸脱氢酶的缺失导致糖异生上调，从而导致细胞壁前体的增加。与这一观点一致，代谢产物分析显示，苹果酸脱氢酶(MDH)缺失细胞中几种糖酵解/糖异生化合物和细胞壁前体尿苷二磷酸N-乙酰氨基葡萄糖(UDP-NAG)水平升高。与这些结果一致，增加的A22抗性表型可以通过在培养液中添加葡萄糖来概括。最后，我们证明这种抗生素耐受性的增加并不是A22所特有的，也适用于针对细胞壁的抗生素美西林。
The bacterial actin homolog, MreB, is highly conserved among rod-shaped bacteria and essential for growth under normal growth conditions. MreB directs the localization of cell wall synthesis and loss of MreB results in round cells and death. Using the MreB depolymerizing drug, A22, we show that changes to central metabolism through deletion of malate dehydrogenase from the tricarboxylic acid (TCA) cycle results in cells with an increased tolerance to A22. We hypothesize that deletion of malate dehydrogenase leads to the upregulation of gluconeogenesis resulting in an increase in cell wall precursors. Consistent with this idea, metabolite analysis revealed that malate dehydrogenase (mdh) deletion cells possess elevated levels of several glycolysis/gluconeogenesis compounds and the cell wall precursor, uridine diphosphate N-acetylglucosamine (UDP-NAG). In agreement with these results, the increased A22 resistance phenotype can be recapitulated through the addition of glucose to the media. Finally, we show that this increase in antibiotic tolerance is not specific to A22 but also applies to the cell wall-targeting antibiotic, mecillinam.
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