Role of oxidative stress in persister tolerance
Open accessAbstract
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.
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ROS generated by macrophages targets the enzymes TCA aconitase and succinate dehydrogenase and force S. aureus into a respiration-reduced metabolism, incompatible with the clearance mechanism of most bactericidal antibiotics.
“ROS generated by macrophages targets the enzymes TCA aconitase and succinate dehydrogenase and force S. aureus into a respiration-reduced metabolism, incompatible with the clearance mechanism of most bactericidal antibiotics [198].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [198]
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- Authors
- Wu, Y., Vulić, M., Keren, I., & Lewis, K.
- Affiliations
- Northeastern University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-09
- Volume
- 56
- Issue
- 9
- Pages
- 4922-4926
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3421885
- OpenAlex
- W2118904810
- Cited by
- 276
- References
- 45
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 18 · 2021: 29 · 2020: 22 · 2019: 29 · 2018: 22 · 2017: 23 · 2016: 22 · 2015: 13 · 2014: 18 · 2013: 16 · 2012: 4
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- National Institute of Allergy and Infectious Diseases (R01AI085585, T-RO1 AI085585)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Keywords
- persister cells, antibiotic tolerance, oxidative stress, paraquat, fluoroquinolone resistance, SoxRS regulon, OxyR regulon, SOS response, chronic infection, multidrug tolerance, Escherichia coli
- MeSH terms
- Ampicillin, Anti-Bacterial Agents, Bacterial Proteins, Bacterial Toxins, Carrier Proteins, Drug Tolerance, Escherichia coli, Kanamycin, Microbial Sensitivity Tests, Paraquat, Repressor Proteins, SOS Response, Genetics, Transcription Factors, Transcriptional Activation, Trans-Activators, Oxidative Stress, Fluoroquinolones, Drug Resistance, Multiple, Bacterial, Escherichia coli Proteins
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