Role of Oxidative Stress in Persister Tolerance
Open Access
- 1 September 2012
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (9), 4922-4926
- https://doi.org/10.1128/aac.00921-12
Abstract
Persisters are dormant phenotypic variants of regular cells that are tolerant to antibiotics and play an important role in recalcitrance of chronic infections to therapy. Persisters can be produced stochastically in a population untreated with antibiotics. At the same time, a deterministic component of persister formation has also been documented in a population of cells with DNA damaged by fluoroquinolone treatment. Expression of the SOS response under these conditions induces formation of persisters by increasing expression of the TisB toxin. This suggests that other stress responses may also contribute to persister formation. Of particular interest is oxidative stress that pathogens encounter during infection. Activated macrophages produce reactive oxygen and nitrogen species which induce the SoxRS and OxyR regulons. Genes controlled by these regulons deactivate the oxidants and promote repair. We examined the ability of oxidative stress induced by paraquat (PQ) to affect persister formation. Preincubation of cells with PQ produced a dramatic increase in the number of persisters surviving challenge with fluoroquinolone antibiotics. PQ did not affect killing by kanamycin or ampicillin. Persisters in a culture treated with PQ that survived a challenge with a fluoroquinolone were also highly tolerant to other antibiotics. PQ induces SoxRS, which in turn induces expression of the AcrAB-TolC multidrug-resistant (MDR) pump. Fluoroquinolones are extruded by this MDR pump, and the effect of PQ on antibiotic tolerance was largely abolished in a mutant that was defective in the pump. It appears that PQ, acting through AcrAB-TolC, reduces the concentration of fluoroquinolones in the cells. This allows a larger fraction of cells to become persisters in the presence of a fluoroquinolone. Analysis of a lexA3 mutant indeed showed a dependence of persister induction under these conditions on SOS. These findings show that induction of a classical resistance mechanism, MDR efflux, by oxidative stress leads to an increase in multidrug-tolerant persister cells.Keywords
This publication has 41 references indexed in Scilit:
- Bacterial persistence by RNA endonucleasesProceedings of the National Academy of Sciences of the United States of America, 2011
- Characterization and Transcriptome Analysis of Mycobacterium tuberculosis PersistersmBio, 2011
- Patients with Long-Term Oral Carriage Harbor High-Persister Mutants of Candida albicansAntimicrobial Agents and Chemotherapy, 2010
- Contribution of Oxidative Damage to Antimicrobial LethalityAntimicrobial Agents and Chemotherapy, 2009
- Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipBScience, 2009
- Kinase Activity of Overexpressed HipA Is Required for Growth Arrest and Multidrug Tolerance in Escherichia coliJournal of Bacteriology, 2006
- Candida albicans Biofilms Produce Antifungal-Tolerant Persister CellsAntimicrobial Agents and Chemotherapy, 2006
- A comprehensive library of fluorescent transcriptional reporters for Escherichia coliNature Methods, 2006
- Increased Persistence in Escherichia coli Caused by Controlled Expression of Toxins or Other Unrelated ProteinsJournal of Bacteriology, 2006
- Construction of Escherichia coli K‐12 in‐frame, single‐gene knockout mutants: the Keio collectionMolecular Systems Biology, 2006