Antibiotic resistance has become a global threat. In addition to acquiring resistance via horizontal gene transfer, bacteria can evade killing by temporarily modifying their cell envelope to prevent antibiotic-bacterial interactions. A critical gap in knowledge is how bacteria balance the metabolic needs of altering the cell envelope with the constant need to generate energy. Cross-regulation between two signaling networks in Escherichia coli increases resistance to positively charged antibiotics. We show that increased resistance is supported by metabolic re-wiring controlled by the QseB transcription factor. QseB controls the increase in 2-oxoglutarate required for lipid A modification, by upregulating three anaplerotic pathways that feed acetyl Co-A, succinate and fumarate into the TCA cycle. Exogenous addition of 2-oxoglutarate restores antibiotic resistance in the qseB deletion mutant. Antibiotic resistant clinical isolates bear mutations within QseB-mediated anaplerotic pathways. These findings are significant, because they uncover a previously unknown mechanism of metabolic control of antibiotic resistance.

中文翻译：

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细菌信号网络可通过调节2-氧戊二酸的动脉硬化来控制抗生素耐药性

抗生素耐药性已成为全球性威胁。除了通过水平基因转移获得抗药性外，细菌还可以通过暂时改变其细胞包膜来防止抗生素与细菌的相互作用来逃避杀伤。知识上的一个关键缺口是细菌如何平衡改变细胞膜的代谢需要与不断产生能量的需求。大肠杆菌中两个信号网络之间的交叉调节会增加对带正电抗生素的抗性。我们表明增加的抵抗力是由QseB转录因子控制的代谢重排支持的。QseB通过上调将乙酰辅酶A，琥珀酸酯和富马酸酯输入TCA循环的三种过失通路来控制脂质A修饰所需的2-氧戊二酸的增加。外源添加2-氧戊二酸酯可恢复qseB缺失突变体中的抗生素抗性。抗生素抗药性临床分离株在QseB介导的动脉粥样硬化途径中具有突变。这些发现意义重大，因为它们揭示了以前未知的抗生素耐药性代谢控制机制。