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

Metabolically quiescent bacteria represent a large proportion of those in natural and host environments, and they are often refractory to antibiotic treatment. Such drug tolerance is also observed in the laboratory during stationary phase, when bacteria face stress and starvation-induced growth arre...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-09, Vol.115 (39), p.9797-9802
Main Authors: Martins, Dorival, McKay, Geoffrey, Sampathkumar, Gowthami, Khakimova, Malika, English, Ann M., Nguyen, Dao
Format: Article
Language:English
Subjects:
Ablation
Anti-Bacterial Agents - pharmacology
Antibiotic tolerance
Antibiotics
Antioxidants
Bacteria
Biological Sciences
Complementation
Deactivation
Dose-Response Relationship, Drug
Drug Resistance, Multiple, Bacterial
Drug tolerance
Environment
Gentamicins - pharmacology
Inactivation
Internalization
Ligases - metabolism
Membrane permeability
Microbial Sensitivity Tests
Ofloxacin - pharmacology
Organic chemistry
Pseudomonas aeruginosa
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - enzymology
Signal Transduction
Stationary phase
Stringent response
Superoxide dismutase
Superoxide Dismutase - metabolism
Superoxide Dismutase - physiology
Thienamycins - pharmacology
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Summary:Metabolically quiescent bacteria represent a large proportion of those in natural and host environments, and they are often refractory to antibiotic treatment. Such drug tolerance is also observed in the laboratory during stationary phase, when bacteria face stress and starvation-induced growth arrest. Tolerance requires (p)ppGpp signaling, which mediates the stress and starvation stringent response (SR), but the downstream effectors that confer tolerance are unclear. We previously demonstrated that the SR is linked to increased antioxidant defenses in Pseudomonas aeruginosa. We now demonstrate that superoxide dismutase (SOD) activity is a key factor in SR-mediated multidrug tolerance in stationary-phase P. aeruginosa. Inactivation of the SR leads to loss of SOD activity and decreased multidrug tolerance during stationary phase. Genetic or chemical complementation of SOD activity of the ΔrelA spoT mutant (ΔSR) is sufficient to restore antibiotic tolerance to WT levels. Remarkably, we observe high membrane permeability and increased drug internalization upon ablation of SOD activity. Combined, our results highlight an unprecedented mode of SR-mediated multidrug tolerance in stationary-phase P. aeruginosa and suggest that inhibition of SOD activity may potentiate current antibiotics.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1804525115