Global transcriptional regulator FNR regulates the pyruvate cycle and proton motive force to play a role in aminoglycosides resistance of .

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.