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

Abstract

SignificanceAntibiotic 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.

Oligoribonuclease Contributes to Tolerance to Aminoglycoside and β-Lactam Antibiotics by Regulating KatA in Pseudomonas aeruginosa

“…Also, in E. coli, mutation of the catalase gene katG increased bacterial susceptibility to nalidixic acid (28). A recent study in P. aeruginosa demonstrated that the SOD plays an essential role in stringent response-mediated tolerance to antibiotics (29).…”

Stringent Response Governs the Virulence and Oxidative Stress Resistance of Francisella tularensis

“…Our results demonstrate that stringent response also modulates the oxidative stress response under normal as well as oxidative stress conditions. Superoxide dismutase and catalase activities are regulated by the stringent response in Pseudomonas aeruginosa (29, 30). We observed that in addition to the transcript levels, the protein levels of primary antioxidant enzymes SodB and KatG of F. tularensis were reduced drastically in both the Δ relA and Δ relA Δ spoT mutants.…”

“…An association has been demonstrated between the SOD activity and the stringent-response-mediated multidrug resistance in P. aeruginosa (29, 30). The stringent response during stationary phase reduces the permeability of the cell envelop to a number of antibiotics and SOD activity contributes to this, resulting in multidrug resistance of P. aeruginosa .…”

Dismantling the bacterial virulence program

“…Moreover, proteins that play a key role in oxidative processes are proposed to confer stringent response-mediated multidrug tolerance. One of these, SodB, an iron co-factored superoxide dismutase that detoxifies intracellular superoxide radicals to oxygen and hydrogen peroxide, is a newly identified effector protein of the stringent response (Martins et al, 2018). Targeting SodB could lead to potentiation of a broad-spectrum of antibiotics since its expression (likely increased in the presence of phagocytic cells in vivo) mediates protection against gentamicin, ofloxacin and meropenem.…”

“…Targeting SodB could lead to potentiation of a broad-spectrum of antibiotics since its expression (likely increased in the presence of phagocytic cells in vivo) mediates protection against gentamicin, ofloxacin and meropenem. Additionally, SodB represents an underexplored link between membrane permeability and antibiotic internalization across several clinically relevant pathogens such as Campylobacter jejuni, Staphylococcus aureus and Pseudomonas aeruginosa (Hwang et al, 2013;Ladjouzi et al, 2013;Martins et al, 2018). Superoxide dismutase activity also correlates with expression of the phosphateresponsive PhoB regulon, and functions to scavenge excess hydrogen peroxide in phosphate-replete environments (Moreau et al, 2001).…”