Uridine as a potentiator of aminoglycosides through activation of carbohydrate transporters

Aminoglycosides (AGs) are broad-spectrum antibiotics effective against Gram-negative bacteria. AG uptake depends on membrane potential, but the precise mechanisms are incompletely understood. We report here a new mechanism of active AG uptake in Gram-negative bacteria. In E. coli, overexpression of various carbohydrate transporters increases susceptibility to AGs. Conversely, deletion of a single transporter has little impact. We propose a new uptake model where AGs act as substrates for redundant carbohydrate transporters. This mechanism appears to be shared among Gram-negative ESKAPE pathogens. We screened for molecules that induce transporters expression and identified uridine. When uridine is co-administered with AGs under conditions mimicking urinary tract infections, the efficacy of AG therapies is significantly improved against E. coli, including resistant strains, due to enhanced bacterial uptake. Based on previous knowledge on the use of uridine in humans, we propose that uridine can be a potentiating adjuvant to AG treatment of infectious diseases in the hospital.