Fig. 9.

Proposed model. Pyruvate as a metabolic state reprogramming metabolite was used to potentiate gentamicin killing to multidrug-resistant E. tarda, which was involved in ROS dependence. This metabolic reprogramming leads to the finding on pyruvate–cysteine–glutathione system/glycine–ROS metabolic pathway. Specifically, the conversion of pyruvate to cysteine facilitates the synthesis of glutathione (GSH). The elevated GSH is subsequently metabolized into glycine to inhibit the activity of GR, thereby diminishing the availability of GSH. The decreased GSH reduces the GSSG/GSH ratio and thus compromises the capacity to scavenge intracellular ROS. The resulting ROS accumulation effectively potentiates the bactericidal effects of gentamicin. Furthermore, the metabolic pathway was physically demonstrated and determined as an antibiotic resistance mechanism in laboratory-evolved and other clinically isolated multidrug- and carbapenem-resistant pathogens.