Persister-promoting bacterial toxin TisB produces anion-selective pores in planar lipid bilayers. FEBS letters 586(16), 2529-2534

Program in Physical Biology, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
FEBS letters (Impact Factor: 3.17). 06/2012; 586(16):2529-34. DOI: 10.1016/j.febslet.2012.06.021
Source: PubMed


We studied membrane activity of the bacterial peptide TisB involved in persister cell formation. TisB and its analogs form multi-state ion-conductive pores in planar lipid bilayers with all states displaying similar anionic selectivity. TisB analogs differing by ±1 elementary charges show corresponding changes in selectivity. Probing TisB pores with poly-(ethylene glycol)s reveals only restricted partitioning even for the smallest polymers, suggesting that the pores are characterized by a relatively small diameter. These findings allow us to suggest that TisB forms clusters of narrow pores that are essential for its mechanism of action.

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Available from: Philip A Gurnev, Mar 28, 2014
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    • "In contrast, most of the toxins of the type I and type V TA systems, such as TisB and GhoT, target the inner membrane (26,47,99–101) (Table 2). They inhibit ATP synthesis by depleting the proton motive force, leading to dramatic RNA decay, thus halting protein synthesis (47). "
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    ABSTRACT: One of the simplest classes of genes involved in programmed death is that containing the toxin–antitoxin (TA) systems of prokaryotes. These systems are composed of an intracellular toxin and an antitoxin that neutralizes its effect. These systems, now classified into five types, were initially discovered because some of them allow the stable maintenance of mobile genetic elements in a microbial population through postsegregational killing or the death of cells that have lost these systems. Here, we demonstrate parallels between some TA systems and restriction–modification systems (RM systems). RM systems are composed of a restriction enzyme (toxin) and a modification enzyme (antitoxin) and limit the genetic flux between lineages with different epigenetic identities, as defined by sequence-specific DNA methylation. The similarities between these systems include their postsegregational killing and their effects on global gene expression. Both require the finely regulated expression of a toxin and antitoxin. The antitoxin (modification enzyme) or linked protein may act as a transcriptional regulator. A regulatory antisense RNA recently identified in an RM system can be compared with those RNAs in TA systems. This review is intended to generalize the concept of TA systems in studies of stress responses, programmed death, genetic conflict and epigenetics.
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    • "Notably, this phenotype was only observed in logarithmically growing E. coli populations, whereas we found HokB to induce persistence in both the exponential and stationary-phase cultures. TisB was shown to form ion-conductive channels in lipid bilayers in vitro, suggesting that TisB induces persistence by reducing the PMF and cellular energy levels (Gurnev et al., 2012). Similarly, toxin GhoT was demonstrated to evoke membrane damage, leading to a drop in PMF and ATP levels, thereby increasing E. coli persistence (Cheng et al., 2013). "

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    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.
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