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Persister cells, dormancy and infectious disease

Key Points

  • Bacterial populations produce persisters, which are phenotypic variants of the wild type whose function is survival. Persisters are dormant, non-dividing cells that exhibit multidrug tolerance and survive treatment by all known antimicrobials. The mechanism of persister tolerance is distinct from the well-understood mechanisms of antibiotic resistance. Bactericidal antibiotics kill cells not by inhibiting functions, but by corrupting their targets into producing lethal products. For example, fluoroquinolones convert DNA gyrase into a DNA endonuclease. The activity of antibiotic targets is apparently diminished in dormant persisters, accounting for antibiotic tolerance.

  • Biofilms account for most bacterial infections in the developed world, and persisters that are produced in biofilms might confer multidrug tolerance to biofilms. Biofilms are protected from the immune system by exopolymer matrices, and a combination of protection from the immune system coupled with antibiotic multidrug tolerance makes these infections very hard to eradicate.

  • Persisters have been isolated by lysing a growing population of Escherichia coli cells with ampicillin and by the sorting of cells with decreased translation of a green fluorescent protein reporter. The analysis of the transcriptome of persisters has indicated a decrease in the expression of genes that code for biosynthetic pathway enzymes, consistent with dormancy, and an increase in the expression of toxin–antitoxin (TA) genes. Ectopic expression of several TA genes, including hipA, relE and mazF, induces a state of reversible dormancy, and produces a multidrug tolerant state that mimics naturally formed persisters.

  • Using an expression library and selecting for antibiotic tolerance led to the identification of GlpD (glycerol-3-phosphate dehydrogenase) as a persister gene. The glycerol-3-phosphate acyltransferase gene plsB seems to be a persister-maintenance gene.

  • Entrance of cells into a dormant, non-dividing state appears to be a common adaptive strategy that might be responsible for several seemingly unrelated puzzling problems in microbiology. Yeast biofilms produce drug-tolerant infections, and the nature of their tolerance remains unsolved. It was recently reported that Candida albicans biofilms produce tolerant persister cells, pointing to a convergent evolution of this survival strategy among unrelated groups of microorganisms. Latent infections such as lyme disease, caused by Borrelia burgdorferi, and the carrier state of tuberculosis have been characterized by the presence of cells that are not eradicated by known antibiotics. Productions of persisters by these species could account for latency.

  • Finally, most bacterial species are 'uncultivable'. Existing evidence indicates that most bacterial species enter into growth arrest when sensing the presence of an unfamiliar environment. From this perspective, dormancy might be the default mode of most bacterial life.

  • Persisters might constitute the ultimate microbial adversary, having specifically evolved to resist killing by all possible mechanisms, whether environmental or therapeutic. Approaches to anti-persister therapy are considered in this Review, including combination therapy with agents aimed at disabling persister maintenance components, pulse-dosing of antibiotics, sterile surface materials and sterilizing prodrug antibiotics.

Abstract

Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.

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Figure 1: Formation of persister cells.
Figure 2: Resistance versus tolerance to bactericidal antibiotics.
Figure 3: A method for isolating persisters.
Figure 4: Biofilm drug resistance.
Figure 5: The perfect antibiotic.

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Acknowledgements

Work described in this paper was supported by a grant from the National Institutes of Health.

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DATABASES

Entrez Genome Project

Borrelia burgdorferi

Candida albicans

Escherichia coli

Mycobacterium tuberculosis

Pelagibacter ubique

Pseudomonas aeruginosa

Salmonella typhimurium

Staphylococcus aureus

Staphylococcus epidermidis

Treponema pallidum

FURTHER INFORMATION

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Glossary

Dormant

A dormant cell has a global slowdown of metabolic processes and does not divide.

Tolerance

The ability of cells to survive killing by antibiotics without expressing or using resistance mechanisms.

Non-proliferation

A cell that does not divide.

Chaperone

A protein that mediates the assembly of another polypeptide-containing structure, but does not form part of the completed structure, or participate in its biological function.

Quorum sensing

The ability of bacteria to sense their own cell density by detecting the concentration of signalling molecules that have been released in their environment.

Signalling molecule

A chemical, similar to a pheromone, that is produced by an individual bacterium. Signalling molecules can affect the behaviour of surrounding bacteria.

Chemotaxis

The movement of bacteria towards nutrients and away from toxins.

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Lewis, K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol 5, 48–56 (2007). https://doi.org/10.1038/nrmicro1557

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