Metabolite-enabled eradication of bacterial persisters by aminoglycosides

Bacterial cells can enter a dormant 'persister' state that leaves them more resistant to stress conditions, including killing by antibiotics. In a clinical setting, persister formation can lead to incomplete eradication of bacterial pathogens and treatment failure. James Collins and colleagues show that certain metabolic stimuli (including glucose and pyruvate) can increase killing of persister cells by aminoglycoside antibiotics including gentamicin. This raises the prospect that the delivery of metabolites as adjuvants to aminoglycosides could be effective in the treatment of chronic bacterial infections. Bacterial persistence is a state in which a sub-population of dormant cells, or ‘persisters’, tolerates antibiotic treatment1,2,3,4. Bacterial persisters have been implicated in biofilms and in chronic and recurrent infections5,6,7. Despite this clinical relevance, there are currently no viable means for eradicating persisters. Here we show that specific metabolic stimuli enable the killing of both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) persisters with aminoglycosides. This potentiation is aminoglycoside-specific, it does not rely on growth resumption and it is effective in both aerobic and anaerobic conditions. It proceeds by the generation of a proton-motive force which facilitates aminoglycoside uptake. Our results demonstrate that persisters, although dormant, are primed for metabolite uptake, central metabolism and respiration. We show that aminoglycosides can be used in combination with specific metabolites to treat E. coli and S. aureus biofilms. Furthermore, we demonstrate that this approach can improve the treatment of chronic infections in a mouse urinary tract infection model. This work establishes a strategy for eradicating bacterial persisters that is based on metabolism, and highlights the importance of the metabolic environment to antibiotic treatment.