Adenosine Awakens Metabolism to Enhance Growth-Independent Killing of Tolerant and Persister Bacteria across Multiple Classes of Antibiotics
David Kitzenberg, J. Scott Lee, Krista B. Mills, Ju-Sim Kim, Lin Liu, Andrés Vázquez‐Torres, Sean P. Colgan, Daniel J. Kao
Abstract
Antibiotic tolerance, which is a hallmark of persister bacteria, contributes to treatment-refractory infections and the emergence of heritable antimicrobial resistance. Drugs that reverse tolerance and persistence may become part of the arsenal to combat antimicrobial resistance. Here, we demonstrate that salvage of extracellular ADO reduces antibiotic tolerance in nutritionally stressed Escherichia coli, Salmonella enterica, and Staphylococcus aureus. ADO potentiates bacterial killing under aerobic and anaerobic conditions and takes place in bacteria lacking the ATP synthase. However, the sensitization to antibiotic killing elicited by ADO requires an intact NADH dehydrogenase, suggesting a requirement for an energized electron transport chain. ADO antagonizes antibiotic tolerance by activating ATP and GTP synthesis, promoting proton motive force and cellular respiration while simultaneously suppressing the stringent response. These investigations reveal an unprecedented role for purine salvage stimulation as a countermeasure of antibiotic tolerance and the emergence of antimicrobial resistance.