Superoxide dismutase activity confers (p)ppGpp-mediated antibiotic tolerance to stationary-phase Pseudomonas aeruginosa

Significance Antibiotic tolerance causes antibiotic treatment failure and promotes the emergence of genotypic resistance in chronic infections, such as those caused by the pathogen Pseudomonas aeruginosa . Laboratory stationary-phase bacteria exhibit a slow growing and metabolically quiescent state associated with high levels of multidrug tolerance likely analogous to the in vivo environment during chronic infection. We demonstrate that superoxide dismutases confer multidrug tolerance in stationary-phase bacteria, and identify a link between (p)ppGpp-mediated stress responses, superoxide metabolism, and membrane permeability to antibiotics. Inhibition of superoxide dismutase activity may overcome multidrug tolerance and potentiate current bactericidal antibiotics in the treatment of P. aeruginosa chronic infections.