Mao Li-Chun, Li Shao-Hua, Peng Xuan-Xian, Li Hui
State Key Laboratory of Bio-Control, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou, China.
Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Front Microbiol. 2022 Sep 7;13:1003586. doi: 10.3389/fmicb.2022.1003586. eCollection 2022.
Bacterial metabolism is related to resistance and susceptibility to antibiotics. Fumarate and nitrate reduction regulatory protein (FNR) is a global transcriptional regulator that regulates metabolism. However, the role of FNR in antibiotic resistance is elusive. Here, deletion mutant was constructed and used to test the role in EIB202 (EIB202). Δ exhibited elevated sensitivity to aminoglycosides. The mutant had a globally enhanced metabolome, with activated alanine, aspartate, and glutamate metabolism and increased abundance of glutamic acid as the most impacted pathway and crucial biomarker, respectively. Glutamate provides a source for the pyruvate cycle (the P cycle) and thereby relationship between exogenous glutamate-activated P cycle and gentamicin-mediated killing was investigated. The activated P cycle elevated proton motive force (PMF). Consistently, exogenous glutamate potentiated gentamicin-mediated killing to EIB202 as the similarity as the loss of FNR did. These findings reveal a previously unknown regulation by which FNR downregulates glutamate and in turn inactivates the P cycle, which inhibits PMF and thereby exhibits the resistance to aminoglycosides.
细菌代谢与对抗生素的耐药性和敏感性相关。延胡索酸和硝酸盐还原调节蛋白（FNR）是一种调节代谢的全局转录调节因子。然而，FNR在抗生素耐药性中的作用尚不清楚。在此，构建了缺失突变体并用于测试其在EIB202中的作用。Δ对氨基糖苷类药物表现出更高的敏感性。该突变体具有全局增强的代谢组，丙氨酸、天冬氨酸和谷氨酸代谢被激活，谷氨酸丰度增加，分别作为受影响最大的途径和关键生物标志物。谷氨酸为丙酮酸循环（P循环）提供了一个来源，因此研究了外源谷氨酸激活的P循环与庆大霉素介导的杀伤之间的关系。激活的P循环提高了质子动力势（PMF）。一致地，外源谷氨酸增强了庆大霉素对EIB202的杀伤作用，与FNR缺失的情况相似。这些发现揭示了一种以前未知的调节机制，即FNR下调谷氨酸，进而使P循环失活，抑制PMF，从而表现出对氨基糖苷类药物的耐药性。
