Role of Oxidative Stress in Persister Tolerance

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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<jats:italic>lexA3</jats:italic>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.</jats:p>

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

“…3d). Factors such as quorum sensing, cell density, nutrient starvation, diauxic carbon source transitions, environmental signals (such as heat shock, oxidative stress and DNA damage) and stringent response pathways contribute to microbial persistence in vitro [54][55][56][57][58][59] . TA modules that are upregulated in persisters are terminal effectors of microbial persistence 60,61 .…”

A Matter of Timing: Contrasting Effects of Hydrogen Sulfide on Oxidative Stress Response in Shewanella oneidensis

“…This protective effect of H 2 S as an iron-sequestering agent seems to coincide with that of superoxide (56). While superoxide can lead to cellular damage and death, its accumulation induces the protective SoxRS and MarRAB regulons (57). Thus, pretreatment with low-to-moderate concentrations of superoxide provides cells a greater ability to cope with subsequent more severe stress and, more importantly, prevents cells from entering programmed cell death (56).…”

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

“…They revealed that paraquat-induced oxidative stress led to an increase in the level of persisters surviving fluoroquinolone antibiotics, but not ampicillin or kanamycin (147). They showed that SoxRS induces overexpression of the AcrAB-TolC MDR pump, which can extrude fluoroquinolones (147).…”