Persistence: a copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics

Levin, Bruce R.; Concepción-Acevedo, Jeniffer; Udekwu, Klas I.

doi:10.1016/j.mib.2014.06.016

Cited by 75 publications

(54 citation statements)

References 25 publications

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“…Given the ubiquitous cell-to-cell variability in gene expression, it is tempting to assume that persistence is an inevitable byproduct of life (‘persistence as stuff happens’) [54]. However, there is some evidence that bacterial persistence is actually an evolvable trait [55,56].…”

Section: Introductionmentioning

confidence: 99%

Drug persistence – From antibiotics to cancer therapies

Kochanowski

Morinishi

Altschuler

et al. 2018

Current Opinion in Systems Biology

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Drug-insensitive tumor subpopulations remain a significant barrier to effective cancer treatment. Recent works suggest that within isogenic drug-sensitive cancer populations, subsets of cells can enter a ‘persister’ state allowing them to survive prolonged drug treatment. Such persisters are well-described in antibiotic-treated bacterial populations. In this review, we compare mechanisms of drug persistence in bacteria and cancer. Both bacterial and cancer persisters are associated with slow-growing phenotypes, are metabolically distinct from non-persisters, and depend on the activation of specific regulatory programs. Moreover, evidence suggests that bacterial and cancer persisters are an important reservoir for the emergence of drug-resistant mutants. The emerging parallels between persistence in bacteria and cancer can guide efforts to untangle mechanistic links between growth, metabolism, and cellular regulation, and reveal exploitable therapeutic vulnerabilities.

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Section: Introductionmentioning

confidence: 99%

Drug persistence – From antibiotics to cancer therapies

Kochanowski

Morinishi

Altschuler

et al. 2018

Current Opinion in Systems Biology

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“…When a bacterial population is treated with bactericidal antibiotics, biphasic killing is observed, where the death of normal cells is characterized by an initial, rapid killing rate, and the presence of persisters is illuminated by a second regime with a much lower rate of cell death (4,5). When these survivors are recultured, the resulting population exhibits antibiotic sensitivity identical to that of the original culture, demonstrating that persisters are not antibiotic-resistant mutants but phenotypic variants (1,5,6).…”

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confidence: 99%

Impacts of Global Transcriptional Regulators on Persister Metabolism

Mok

Orman

Brynildsen

2015

Antimicrob Agents Chemother

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Bacterial persisters are phenotypic variants with an extraordinary capacity to tolerate antibiotics, and they are hypothesized to be a main cause of chronic and relapsing infections. Recent evidence has suggested that the metabolism of persisters can be targeted to develop therapeutic countermeasures; however, knowledge of persister metabolism remains limited due to difficulties associated with isolating these rare and transient phenotypic variants. By using a technique to measure persister catabolic activity, which is based on the ability of metabolites to enable aminoglycoside (AG) killing of persisters, we investigated the role of seven global transcriptional regulators (ArcA, Cra, cyclic AMP [cAMP] receptor protein [CRP], DksA, FNR, Lrp, and RpoS) on persister metabolism. We found that removal of CRP resulted in a loss of AG potentiation in persisters for all metabolites tested. These results highlight a central role for cAMP/CRP in persister metabolism, as its perturbation can significantly diminish the metabolic capabilities of persisters and effectively eliminate the ability of AGs to eradicate these troublesome bacteria. Bacterial persisters are phenotypic variants that are highly tolerant to antibiotics (1). It is believed that they are a main culprit of the proclivity of biofilm infections to relapse, which imposes a substantial burden on the health care system (2, 3). When a bacterial population is treated with bactericidal antibiotics, biphasic killing is observed, where the death of normal cells is characterized by an initial, rapid killing rate, and the presence of persisters is illuminated by a second regime with a much lower rate of cell death (4, 5). When these survivors are recultured, the resulting population exhibits antibiotic sensitivity identical to that of the original culture, demonstrating that persisters are not antibiotic-resistant mutants but phenotypic variants (1, 5, 6).While persisters largely arise from dormant subpopulations (2,4,7,8), recent studies have demonstrated that they remain metabolically active, with the capacity to catabolize specific carbon sources and generate proton motive force through respiration (9, 10). This metabolic activity, specifically, proton motive force generation, enables aminoglycoside (AG) transport into cells that results in killing of persisters, and several enzymes needed for this process have been identified (9, 10). Knowledge of the enzymes and metabolic pathways present in persisters, as well as how they can be altered, could prove useful for the development of antipersister therapies. A fundamental question in this regard is, what are the cellular components responsible for defining the metabolic network in persisters? Due to the strong dependence of metabolism on transcriptional regulation (11, 12), the goal of this study was to determine the importance of several global transcriptional regulators to persister metabolism. To do this, we measured catabolic activity in persisters from ⌬arcA, ⌬cra, ⌬crp, ⌬dksA, ⌬fnr, ⌬lrp, and ⌬rpoS mutants and...

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“…The above-described process of noise-induced persistence is effectively a variation on the ‘persistence as stuff happens’ or PaSH hypothesis put forward by Levin and colleagues (Johnson and Levin, 2013; Levin et al, 2014). They argued that persister cells arise from random errors and glitches due to antibiotic-induced stress and, as such, are effectively like deleterious mutations.…”

Section: Discussionmentioning

confidence: 99%

“…For example in E. coli persister cell formation appears to be regulated, in part, by whether the cellular concentration of this molecule exceeds a certain threshold (Rotem et al, 2010). However, it is increasingly believed that persister cells form a heterogenous group (Dhar and McKinney, 2007; Zhang, 2007; Joers et al, 2010; Allison et al, 2011; Hofsteenge et al, 2013; Johnson and Levin, 2013; Sanchez-Romero and Casadesus, 2014; Levin et al, 2014), and that there is no single genetic mechanism governing their dynamics (Dhar and McKinney, 2007; Balaban, 2011; Hofsteenge et al, 2013; Willenborg et al, 2014; Germain et al, 2015; Mok et al, 2015). This viewpoint is consistent with the notion that persister cells lie on some biochemical continuum, from ‘shallow’ persisters that readily leave the dormant state to ‘deep’ persisters that take longer to reactivate (Zhang, 2007; Joers et al, 2010; Ma et al, 2010).…”

Section: Phenotypic Drug Tolerance and Persister Cellsmentioning

confidence: 99%

Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance

Day

2016

Molecular Ecology

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Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA, and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components are transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form ‘persister’ cells that are phenotypically resistant or tolerant to antibiotics but most of these results are not interpreted within the context of epigenetic inheritance. Instead persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance.

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Persistence: a copacetic and parsimonious hypothesis for the existence of non-inherited resistance to antibiotics

Cited by 75 publications

References 25 publications

Drug persistence – From antibiotics to cancer therapies

Drug persistence – From antibiotics to cancer therapies

Impacts of Global Transcriptional Regulators on Persister Metabolism

Interpreting phenotypic antibiotic tolerance and persister cells as evolution via epigenetic inheritance

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