Persisters—as elusive as ever

Kaldalu, Niilo; Hauryliuk, Vasili; Tenson, Tanel

doi:10.1007/s00253-016-7648-8

Cited by 90 publications

(87 citation statements)

References 104 publications

(137 reference statements)

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“…On the surface, it would seem that the study of persister cells should be straight-forward extension of studies on antimicrobials; the reality has been far different in that insights into the mechanisms by which persister cells arise (e.g., indole, TA systems and ppGpp, higher persistence in less fit cells) has been difficult since no one protein is responsible (Chowdhury et al, 2016a; Kaldalu et al, 2016). For example, many studies using transposon-sequencing (Shan et al, 2015), protein expression (Spoering et al, 2006), and gene knockouts (Hu and Coates, 2005; Hansen et al, 2008) have failed to produce a coherent mechanism for persister cell formation.…”

Section: Resultsmentioning

confidence: 99%

Persistent Persister Misperceptions

Kim

Wood

2016

Front. Microbiol.

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Persister cells survive antibiotic treatment due to their lack of metabolism, rather than through genetic change, as shown via four seminal experiments conducted by the discoverers of the phenotype (Hobby et al., 1942; Bigger, 1944). Unfortunately, over seven decades of persister cell research, the literature has been populated by misperceptions that do not withstand scrutiny. This opinion piece examines some of those misunderstandings in the literature with the hope that by shining some light on these inaccuracies, the field may be advanced and subsequent manuscripts may be reviewed more critically.

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Section: Resultsmentioning

confidence: 99%

Persistent Persister Misperceptions

Kim

Wood

2016

Front. Microbiol.

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“…Therefore, we advocate a model with numerous parallel routes leading to persistence (88). (p)ppGpp, despite being important, is not the sole driver of the phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA -Dependent and relA -Independent Tolerance to β-Lactams

Kudrin

Varik

Oliveira

et al. 2017

Antimicrob Agents Chemother

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The nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance, and virulence. During amino acid starvation, the Escherichia coli (p)ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p)ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p)ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA. In bacterial cultures, the ribosomal inhibitors thiostrepton, chloramphenicol, and tetracycline all efficiently abolish accumulation of (p)ppGpp induced by the Ile-tRNA synthetase inhibitor mupirocin. This abolishment, however, does not reduce the persister level. In contrast, the combination of dihydrofolate reductase inhibitor trimethoprim with mupirocin, tetracycline, or chloramphenicol leads to ampicillin tolerance. The effect is independent of RelA functionality, specific to β-lactams, and not observed with the fluoroquinolone norfloxacin. These results refine our understanding of (p)ppGpp's role in antibiotic tolerance and persistence and demonstrate unexpected drug interactions that lead to tolerance to bactericidal antibiotics.

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“…Many questions about persisters remain unanswered [33]. Bacteria vary considerably in number and type of toxinantitoxin proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Bacteria vary considerably in number and type of toxinantitoxin proteins. Even in E. coli, persisters encompass broad and heterogeneous physiological states dependent on growth conditions and antibiotics [33]. Persisters can form through multiple toxin pathways.…”

Section: Discussionmentioning

confidence: 99%

MazEF toxin-antitoxin proteins alter Escherichia coli cell morphology and infrastructure during persister formation and regrowth

et al. 2017

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When exposed to antibiotics, many bacteria respond by activating intracellular 'toxin' proteins, which arrest cell growth and induce formation of persister cells that survive antibiotics. After antibiotics are removed, persisters can regrow by synthesizing 'antitoxin' proteins that sequester toxin proteins. In Escherichia coli, MazE antitoxin sequesters the activity of MazF toxin, which extensively cleaves cellular RNAs. Although the functions of MazEF proteins are well characterized, there is surprisingly little known about their effects on cell structure. Here, using a combination of microscopy techniques, we visualized the effects of MazEF and three bactericidal antibiotics on E. coli cell morphology and infrastructure. When ectopically expressed in E. coli, MazF temporarily stalled cell growth and induced persister formation, but only mildly elevated DNA mutagenesis. Viewed by electron microscopy, MazF-expressing persister cells were arrested in cell growth and division. Their chromosomal DNAs were compacted into thread-like structures. Their ribosomes were excluded from their nucleoids. After exposure to ciprofloxacin, persister regrowth was activated by MazE. Cell division remained inhibited while cells became extraordinarily elongated, then divided multiple times during stationary growth phase. This extreme filamentation during persister regrowth was unique to ciprofloxacin-treated persisters, likely caused by inhibition of cell division during regrowth, and was not observed with kanamycin-treated persisters.

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Persisters—as elusive as ever

Cited by 90 publications

References 104 publications

Persistent Persister Misperceptions

Persistent Persister Misperceptions

Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA -Dependent and relA -Independent Tolerance to β-Lactams

MazEF toxin-antitoxin proteins alter Escherichia coli cell morphology and infrastructure during persister formation and regrowth

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