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Persistent bacterial infections and persister cells

Key Points

  • Many bacterial infections persist in the host for long periods of time despite antibiotic treatment.

  • This persistence is an important medical concern, as it leads to the overuse of antibiotics and therefore contributes to antimicrobial resistance.

  • The role of antibiotic-tolerant persister cells in the recalcitrance and relapse of bacterial infections has gained recognition in recent years.

  • Persisters are often growth-arrested bacteria with a reduced metabolism that are able to restart growth after a stress.

  • The stresses that bacteria encounter during the infection of a host are triggers for the formation of persisters.

  • Toxin–antitoxin modules have an important role in the formation of growth-arrested persisters.

  • Understanding how growth-arrested persisters regrow is necessary to design better therapeutic strategies.

Abstract

Many bacteria can infect and persist inside their hosts for long periods of time. This can be due to immunosuppression of the host, immune evasion by the pathogen and/or ineffective killing by antibiotics. Bacteria can survive antibiotic treatment if they are resistant or tolerant to a drug. Persisters are a subpopulation of transiently antibiotic-tolerant bacterial cells that are often slow-growing or growth-arrested, and are able to resume growth after a lethal stress. The formation of persister cells establishes phenotypic heterogeneity within a bacterial population and has been hypothesized to be important for increasing the chances of successfully adapting to environmental change. The presence of persister cells can result in the recalcitrance and relapse of persistent bacterial infections, and it has been linked to an increase in the risk of the emergence of antibiotic resistance during treatment. If the mechanisms of the formation and regrowth of these antibiotic-tolerant cells were better understood, it could lead to the development of new approaches for the eradication of persistent bacterial infections. In this Review, we discuss recent developments in our understanding of bacterial persisters and their potential implications for the treatment of persistent infections.

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Figure 1: Antibiotic killing kinetics of resistant, tolerant and persister cells.
Figure 2: Mechanisms of persister formation.
Figure 3: Mechanisms of persister regrowth.

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Acknowledgements

The authors thank members of the Helaine laboratory for critical reading of the manuscript. R.A.F. is supported by a UK Medical Research Council (MRC) Centre for Molecular Bacteriology and Infection (CMBI) studentship (grant MR/J006874/1). S.H. and B.G. are supported by an MRC Career Development Award (grant MR/M009629/1).

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Glossary

Nosocomial infections

Infections acquired when under medical care, also known as hospital-acquired infections (HAIs).

Interleukin-10

(IL-10). A cytokine that suppresses the interferon (IFN)-mediated transcriptional response.

Interferon-γ response

(IFNγ response). The transcriptional changes that take place in a cell due to the detection of the cytokine interferon-γ (IFNγ), some of these changes increase the antibacterial capabilities of phagocytes.

Type III secretion system

(T3SS). A protein needle-like appendage that is used by bacteria to translocate effector proteins into eukaryotic cells to manipulate host cellular processes.

MHC class II antigen presentation

The process of presenting antigen bound to MHC class II on the cell plasma membrane for recognition by cells of the adaptive immune system.

Granulomas

Organized groupings of macrophages and other cell types around foreign material that the immune system is unable to eliminate.

Bactericidal antibiotic

An antibiotic that kills bacteria, as opposed to a bacteriostatic antibiotic, which only inhibits growth.

Salmonella-containing vacuole

(SCV). A membrane-bound compartment that resembles that of a modified late endosome, in which Salmonella spp. typically reside within host cells.

Fluoroquinolones

A class of antibiotics that target DNA gyrase activity to induce the formation of lethal double-stranded breaks in bacterial DNA.

Genovar

A classification used for differentiating between strains of the same serovar that differ substantially in their genetic content.

Lag time

The time taken before resumption of the growth of growth-arrested bacteria.

Diauxic shift

A shift in metabolism from one carbon source to another.

Stochastic gene expression

The random (or noisy) fluctuations in the transcription of a particular gene.

Stringent response

A global change in gene expression and protein regulation following amino acid starvation signalled by the alarmones guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p)ppGpp) in bacteria and plants, directing resources away from growth and towards amino acid synthesis to promote survival.

Post-segregational killing

A mechanism of plasmid maintenance that is used by some low-copy-number plasmids through the action of toxin–antitoxin modules, whereby any progeny bacterial daughter cells produced after division that have not received a copy of the plasmid will be killed through unregulated toxin activity.

SOS response

A global change in gene expression and protein regulation due to the degradation of the LexA repressor caused by the detection of DNA damage in a bacterial cell by the RecA recombinase.

Alarmones

Intracellular signalling molecules that are produced in response to stress.

Proton motive force

The movement of protons down an electrochemical gradient across a membrane to drive ATP synthesis and motility in bacteria.

DNA gyrase

A topoisomerase enzyme that decreases the supercoiling of DNA during replication and transcription through cleaving, rotating and re-ligating the DNA double-strand.

Trans-translation

A quality control mechanism in protein synthesis that uses transfer-messenger RNA (tmRNA) to rescue a ribosome that has stalled during translation.

Isoniazid

An antibiotic that is commonly used for the treatment of tuberculosis. Isoniazid is a pro-drug that is converted into its active form by the catalase enzyme KatG inside bacterial cells, it is then able to inhibit the cytochrome P450 system, leading to the production of lethal free radicals.

Antimicrobial peptides

(AMPs). Small peptides synthesized by plants and animals that have antimicrobial properties and often target the bacterial membrane.

PhoPQ two-component system

Two-component systems comprise a sensor and a regulator that are able to detect environmental changes and mediate transcriptional changes in response. The PhoPQ system regulates the glycerophospholipid and protein content of the outer membrane in response to pH.

Conditional cooperativity

The autoregulation of certain toxin–antitoxin modules, whereby the antitoxin and toxin are able to form a complex only at a certain stoichiometric ratio, which can then effectively repress transcription of the module.

Transfer-messenger RNA

(tmRNA). A specialized form of RNA that mimics a tRNA with an mRNA-like coding element that is used during trans-translation to continue stalled protein synthesis and target the resultant aberrant protein for degradation.

Deampylation

The removal of an adenylyl group.

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Fisher, R., Gollan, B. & Helaine, S. Persistent bacterial infections and persister cells. Nat Rev Microbiol 15, 453–464 (2017). https://doi.org/10.1038/nrmicro.2017.42

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