Bacterial persisters tolerate antibiotics by not producing hydroxyl radicals

Kim, Jun‐Seob; Heo, Pilwon; Yang, Tae Jun; Lee, Ki Sung; Liu, Jing Jing; Kim, Sung Koo; Shin, Dongwoo; Kweon, Dae Hyuk

doi:10.1016/j.bbrc.2011.08.063

Cited by 49 publications

(34 citation statements)

References 21 publications

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“…Our work focuses on the small persister subpopulation within a larger culture, and we demonstrate that this subpopulation is differentiated from the larger antibiotic-susceptible population by different sensitivities to hydroxyl-radical-mediated damage from antibiotic exposure. Our findings are supported by recent work demonstrating that E. coli persisters produce fewer hydroxyl radicals following antibiotic challenge, and a possible mechanism is suggested by work demonstrating that E. coli secretes the signaling molecule indole that activates oxidative stress responses and increased drug tolerance (19,42,43). Although the lack of oxygen in anaerobic or microaerophilic conditions has long been known to affect the efficacy of antibiotics, we demonstrate that just a 20% change in oxygen saturation significantly affects antibiotic efficacy by allowing the survival of a subpopulation of cells.…”

Section: Discussionsupporting

confidence: 85%

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Grant

Kaufmann²,

Chand³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

211

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During Mycobacterium tuberculosis infection, a population of bacteria likely becomes refractory to antibiotic killing in the absence of genotypic resistance, making treatment challenging. We describe an in vitro model capable of yielding a phenotypically antibiotic-tolerant subpopulation of cells, often called persisters, within populations of Mycobacterium smegmatis and M. tuberculosis . We find that persisters are distinct from the larger antibiotic-susceptible population, as a small drop in dissolved oxygen (DO) saturation (20%) allows for their survival in the face of bactericidal antibiotics. In contrast, if high levels of DO are maintained, all cells succumb, sterilizing the culture. With increasing evidence that bactericidal antibiotics induce cell death through the production of reactive oxygen species (ROS), we hypothesized that the drop in DO decreases the concentration of ROS, thereby facilitating persister survival, and maintenance of high DO yields sufficient ROS to kill persisters. Consistent with this hypothesis, the hydroxyl-radical scavenger thiourea, when added to M. smegmatis cultures maintained at high DO levels, rescues the persister population. Conversely, the antibiotic clofazimine, which increases ROS via an NADH-dependent redox cycling pathway, successfully eradicates the persister population. Recent work suggests that environmentally induced antibiotic tolerance of bulk populations may result from enhanced antioxidant capabilities. We now show that the small persister subpopulation within a larger antibiotic-susceptible population also shows differential susceptibility to antibiotic-induced hydroxyl radicals. Furthermore, we show that stimulating ROS production can eradicate persisters, thus providing a potential strategy to managing persistent infections.

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Section: Discussionsupporting

confidence: 85%

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Grant

Kaufmann²,

Chand³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

211

View full text Add to dashboard Cite

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“…Therefore, it was deemed plausible that a way for persisters to survive in the presence of bactericidal antibiotics was to protect themselves from oxidative stress. For instance, flow cytometer analysis demonstrated that in a population of antibiotic-treated E. coli cells, persisters did not overproduce hydroxyl radicals, whereas most bacteria killed had a high level of hydroxyl radicals (148). Alongside the previously described stringent response-mediated defense against oxidative stress damages, another group reported that antioxidant strategies could lead to tolerance of bactericidal antibiotics.…”

Section: Persisters Play a Central Role In Biofilm Recalcitrance Towamentioning

confidence: 99%

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

Lebeaux

Ghigo

Beloin

2014

Microbiol Mol Biol Rev

1,005

862

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International audienceSurface-associated microbial communities, called biofilms, are present in all environments. Although biofilms play an important positive role in a variety of ecosystems, they also have many negative effects, including biofilm-related infections in medical settings. The ability of pathogenic biofilms to survive in the presence of high concentrations of antibiotics is called "recalcitrance" and is a characteristic property of the biofilm lifestyle, leading to treatment failure and infection recurrence. This review presents our current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved our capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections

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“…This process was accompanied by hyperactivation of NADH dehydrogenases and depletion of NADH. Based on the results, they concluded that generation of hydroxyl radicals is a common mechanism of bacterial cell death caused by antibiotics (Kohanski et al, 2007;Kim et al, 2011).…”

Section: Antibacterial Activity With Detergents and Atpase Inhibitorsmentioning

confidence: 99%

“…Moreover, recent articles have shown that lethal doses of bactericidal antibiotics create genetic and biochemical changes and promote the formation of highly detrimental oxidative radical species (Kim et al, 2011). For instance, the various different classes of bactericidal antibiotics induce hydroxyl radical formation, whilst the other classes of bacteriostatic drugs do not (Kohanski et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects between silver nanoparticles and antibiotics and the mechanisms involved

Hwang

Choi

et al. 2012

Journal of Medical Microbiology

236

146

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Silver nanoparticles (nano-Ags), which have well-known antimicrobial properties, are used extensively in various medical and general applications. In this study, the combination effects between nano-Ags and the conventional antibiotics ampicillin, chloramphenicol and kanamycin against various pathogenic bacteria were investigated. The MIC and fractional inhibitory concentration index (FICI) were determined to confirm antibacterial susceptibility and synergistic effects. The results showed that nano-Ags possessed antibacterial effects and synergistic activities. The antibiofilm activities of nano-Ags alone or in combination with antibiotics were also investigated. Formation of biofilm is associated with resistance to antimicrobial agents and chronic bacterial infections. The results indicated that nano-Ags also had antibiofilm activities. To understand these effects of nano-Ags, an ATPase inhibitor assay, permeability assay and hydroxyl radical assay were conducted. The antibacterial activity of nano-Ags was influenced by ATPassociated metabolism rather than by the permeability of the outer membrane. Additionally, nanoAgs generated hydroxyl radicals, a highly reactive oxygen species induced by bactericidal agents. It was concluded that nano-Ags have potential as a combination therapeutic agent for the treatment of infectious diseases by bacteria.

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Bacterial persisters tolerate antibiotics by not producing hydroxyl radicals

Cited by 49 publications

References 21 publications

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

Synergistic effects between silver nanoparticles and antibiotics and the mechanisms involved

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