Exogenous glutamate plus antibiotics kills multidrugresistant bacteria through a novel pathway that controls the TCA cycle

The emergence and ongoing spread of multidrug-resistant bacteria puts humans and other species at risk of potentially lethal infections. Thus, novel antibiotics or alternative approaches are needed to kill the drug-resistant bacteria. Here, the mechanism by which multidrugresistant Edwardsiella tarda evades killing by the traditional antibiotic kanamycin is explored using a reprogramming metabolomicsbased approach. The results demonstrate that exogenous glutamate restores the ability of kanamycin to kill E. tarda in vitro and in vivo. It stimulates the P cycle containing the TCA cycle, which stimulates production of NDAH, increases proton-motive force and stimulates antibiotic uptake.