<i>In Vitro</i>Studies of Persister Cells

Kaldalu, Niilo; Hauryliuk, Vasili; Turnbull, Kathryn Jane; Mensa, Agnese La; Putrinš, Marta; Tenson, Tanel

doi:10.1128/mmbr.00070-20

Cited by 70 publications

(54 citation statements)

References 234 publications

(310 reference statements)

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“…(p)ppGpp is also in part responsible for the induction of slow-growing subpopulations of bacteria that allow them to evade antimicrobial treatment regimes, adding to the ongoing health crisis [119,120]. Given that the role of (p)ppGpp in inducing persistence and tolerance has extensively been reviewed elsewhere [119][120][121], we will briefly focus on inhibitors of the stringent response here.…”

Section: Targeting the Stringent Response For Antimicrobial Therapymentioning

confidence: 99%

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

et al. 2021

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Bacteria inhabit diverse environmental niches and consequently must modulate their metabolism to adapt to stress. The nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) (collectively referred to as (p)ppGpp) are essential for survival during nutrient starvation. (p)ppGpp is synthesized by the RelA-SpoT homologue (RSH) protein family and coordinates the control of cellular metabolism through its combined effect on over 50 proteins. While the role of (p)ppGpp has largely been associated with nutrient limitation, recent studies have shown that (p)ppGpp and related nucleotides have a previously underappreciated effect on different aspects of bacterial physiology, such as maintaining cellular homeostasis and regulating bacterial interactions with a host, other bacteria, or phages. (p)ppGpp produced by pathogenic bacteria facilitates the evasion of host defenses such as reactive nitrogen intermediates, acidic pH, and the complement system. Additionally, (p)ppGpp and pyrophosphorylated derivatives of canonical adenosine nucleotides called (p)ppApp are emerging as effectors of bacterial toxin proteins. Here, we review the RSH protein family with a focus on its unconventional roles during host infection and bacterial competition.

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Section: Targeting the Stringent Response For Antimicrobial Therapymentioning

confidence: 99%

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

et al. 2021

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“…To date, only few hip phenotypes have been characterized in detail (Kaldalu et al ., 2020). In case of the ΔΔ mutant, it was hypothesized that the hip phenotype is caused by stochastic DNA damage and activation of the SOS response, which would enable TisB production due to the lack of post‐transcriptional repression (Pennington and Rosenberg, 2007; Berghoff et al ., 2017; Berghoff and Wagner, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Spontaneous persister formation as a bet‐hedging strategy is not the prevailing mode of persister formation. In many cases, persistence is triggered by stress and other environmental stimuli (Balaban et al ., 2019; Kaldalu et al ., 2020). For example, alarmone (p)ppGpp is produced in response to different stresses and in turn triggers persistence (Korch et al ., 2003), which can be explained by (p)ppGpp‐dependent ribosome dimerization (Song and Wood, 2020).…”

Section: Introductionmentioning

confidence: 99%

Post‐transcriptional deregulation of the tisB/istR‐1 toxin–antitoxin system promotes SOS‐independent persister formation in Escherichia coli

Edelmann

Oberpaul

Schäberle

et al. 2020

Environ Microbiol Rep

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Summary Bacterial dormancy is a valuable strategy to endure unfavourable conditions. The term ‘persister’ has been coined for cells that tolerate antibiotic treatments due to reduced cellular activity. The type I toxin–antitoxin system tisB/istR‐1 is linked to persistence in Escherichia coli, because toxin TisB depolarizes the inner membrane and causes ATP depletion. Transcription of tisB is induced upon activation of the SOS response by DNA‐damaging drugs. However, translation is repressed both by a 5′ structure within the tisB mRNA and by RNA antitoxin IstR‐1. This tight regulation limits TisB production to SOS conditions. Deletion of both regulatory RNA elements produced a ‘high persistence’ mutant, which was previously assumed to depend on stochastic SOS induction and concomitant TisB production. Here, we demonstrate that the mutant generates a subpopulation of growth‐retarded cells during late stationary phase, likely due to SOS‐independent TisB accumulation. Cell sorting experiments revealed that the stationary phase–derived subpopulation contains most of the persister cells. Collectively our data show that deletion of the regulatory RNA elements uncouples the persister formation process from the intended stress situation and enables the formation of TisB‐dependent persisters in an SOS‐independent manner.

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“…The formation of stress-tolerant cells is often enhanced or triggered by stress, which also applies to persister cells [ 4 , 5 , 6 ]. Persister cells were first described in the 1940s [ 7 , 8 ], and are probably present in every bacterial population.…”

Section: Introductionmentioning

confidence: 99%

Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C

et al. 2021

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Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister formation. Transcription of tisB is induced upon DNA damage due to activation of the SOS response by LexA degradation. Transcriptional activation of tisB is counteracted on the post-transcriptional level by structural features of tisB mRNA and RNA antitoxin IstR-1. Deletion of the regulatory RNA elements (mutant Δ1-41 ΔistR) uncouples TisB expression from LexA-dependent SOS induction and causes a ‘high persistence’ (hip) phenotype upon treatment with different antibiotics. Here, we demonstrate by the use of fluorescent reporters that TisB overexpression in mutant Δ1-41 ΔistR inhibits cellular processes, including the expression of SOS genes. The failure in SOS gene expression does not affect the hip phenotype upon treatment with the fluoroquinolone ciprofloxacin, likely because ATP depletion avoids strong DNA damage. By contrast, Δ1-41 ΔistR cells are highly susceptible to the DNA cross-linker mitomycin C, likely because the expression of SOS-dependent repair systems is impeded. Hence, the hip phenotype of the mutant is conditional and strongly depends on the DNA-damaging agent.

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In VitroStudies of Persister Cells

Cited by 70 publications

References 234 publications

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

Post‐transcriptional deregulation of the tisB/istR‐1 toxin–antitoxin system promotes SOS‐independent persister formation in Escherichia coli

Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C

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