Fig. 1: Antibiotic-resistant metabolic state is reprogrammed into antibiotic-sensitive metabolic state to be susceptible for antibiotic-mediated killing.

Antibiotic-resistant and -sensitive bacteria have respective specific metabolic profiles, designated as antibiotic-resistant and -sensitive metabolic states, which are responsible for low and high antibiotic uptake, respectively. The antibiotic-resistant metabolic state can be reverted into an antibiotic-sensitive metabolic state by metabolic reprogramming mediated by metabolic reprogramming agents to increase membrane permeability. On the other hand, antibiotic resistance is attributed to diverse mechanisms including decreased membrane permeability, expression of chromosomal β-lactamase, high rate of active drug efflux, or mutations that prevent or block antibiotic-mediated inactivation of its intracellular target. The combined impact on drug uptake, degradation, and efflux determines the net effect on the steady-state intracellular drug concentration. High uptake, which rate exceeds the combined rate of drug degradation and efflux, causes high intracellular drug concentration that is lethal to antibiotic-resistant bacteria, whereas low uptake, which rate is a bit higher than the combined rate of drug degradation and efflux, leads to low intracellular concentration that is nonlethal to them. Because of the high uptake, bacterial survival decreases dramatically at or above the MIC of the selected antibiotic. Therefore, antibiotic-mediated killing is greatly elevated. Green, sensitive metabolic state; Pale red, resistant metabolic state.