Universal antibiotic tolerance arising from antibiotic-triggered accumulation of redox metabolites

Abstract

AbstractPseudomonas aeruginosais an opportunistic pathogen that often infects open wounds or patients with cystic fibrosis. Once established,P. aeruginosainfections are notoriously difficult to eradicate. This difficulty is in part due to the ability ofP. aeruginosato tolerate antibiotic treatment at the individual-cell level or through collective behaviors. Here we describe a new mechanism by whichP. aeruginosatolerates antibiotic treatment by modulating its global cellular metabolism. In particular, treatment ofP. aeruginosawith sublethal concentrations of antibiotics covering all major classes promoted accumulation of the redox-sensitive phenazine - pyocyanin (PYO). PYO in turn conferred general tolerance against diverse antibiotics for bothP. aeruginosaand other Gram-negative and Gram-positive bacteria. We show that PYO promotes energy generation to enhance the activity of efflux pumps, leading to enhanced antibiotic tolerance. This property is shared by other redox-active phenazines produced byP. aeruginosa. Our discovery sheds new insights into the physiological functions of phenazines and has implications for designing effective antibiotic treatment protocols.Author SummaryAntibiotic tolerance can facilitate the evolution of resistance, and here we describe a previously unknown mechanism of collective antibiotic tolerance inPseudomonas aeruginosa. In particular,P. aeruginosatreated with sublethal concentrations of antibiotics covering all major classes promotes accumulation of pyocyanin (PYO), an important virulence factor. In turn, PYO confers general tolerance against diverse antibiotics for bothP. aeruginosaand other bacteria. Our discovery is a perfect example of what Nietzsche once said:That which does not kill me makes me stronger.