Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria

Significance Exogenous metabolites have been documented to potentiate antibiotics to kill multidrug-resistant pathogens, but the mechanisms are largely unknown. The work presented here shows that intermetabolites from the TCA cycle and the phosphoenolpyruvate (PEP)-pyruvate-AcCoA pathway have the potential to improve targeting of these resistant microorganisms. The enzymes that connect the PEP-pyruvate-AcCoA pathway to the TCA cycle are essential for this potentiation, indicating both pathway and cycle can be merged to be considered a pyruvate cycle (P cycle). The P cycle operates routinely as a general mechanism for energy production and regulating the TCA cycle inEscherichia coli andEdwardsiella tarda . The results reported here provide insights into metabolite-facilitated targeting by antibiotics as well as bacterial energy metabolism and homeostasis.