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Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):9797-9802. doi: 10.1073/pnas.1804525115. Epub 2018 Sep 10.

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

Author information

1
Department of Microbiology and Immunology, McGill University, Montreal, QC H3A OG4, Canada.
2
Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
3
Department of Chemistry and Biochemistry, Concordia University, Montreal, QC H3G 1M8, Canada.
4
Department of Microbiology and Immunology, McGill University, Montreal, QC H3A OG4, Canada; dao.nguyen@mcgill.ca.
5
Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.

Abstract

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.

KEYWORDS:

(p)ppGpp stringent response; Pseudomonas aeruginosa; antibiotic tolerance; stationary phase; superoxide dismutase

PMID:
30201715
PMCID:
PMC6166797
DOI:
10.1073/pnas.1804525115
[Indexed for MEDLINE]
Free PMC Article

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