Persister cells

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Persister cells are subpopulations of cells that resist treatment, and become antimicrobial tolerant by changing to a state of dormancy or quiescence. [1] [2] Persister cells in their dormancy do not divide. [3] The tolerance shown in persister cells differs from antimicrobial resistance in that the tolerance is not inherited and is reversible. [4] When treatment has stopped the state of dormancy can be reversed and the cells can reactivate and multiply. Most persister cells are bacterial, and there are also fungal persister cells, [5] yeast persister cells, and cancer persister cells that show tolerance for cancer drugs. [6]

Contents

History

Recognition of bacterial persister cells dates back to 1944 when Joseph Warwick Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculate a culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic exposure. The important observation that Bigger made was that this new population could again be almost eliminated by the use of penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’. [7] The formation of bacterial persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment [8] or in response to a variety of antibiotics. [9]

Relevance to chronic infections

Antimicrobial tolerance is achieved by a small subpopulation of microbial cells termed persisters. [7] Persisters are not mutants, but rather are dormant cells that can survive the antimicrobials that effectively eliminate their much greater number. Persister cells have entered a non-growing, or extremely slow-growing physiological state which makes them tolerant (insensitive or refractory) to the action of antimicrobials. When such persisting pathogenic microbes cannot be eliminated by the immune system, they become a reservoir from which recurrence of infection will develop. [10] Such non-growing bacteria have been observed to persist during infections from Salmonella. [11] Persister cells are the main cause of relapsing and chronic infections. [2] [5]

The bacteria species Listeria monocytogenes , the main causal agent of listeriosis, has been shown to demonstrate persistence during infection in hepatocyte and trophoblast cells. The usual active lifestyle can change and the bacteria can remain in intracellular vacuoles entering into a slow non-growing state of persistence thus promoting their survival from antibiotics. [12]

Fungal persister cells are a common cause of recurring infections due to Candida albicans a common biofilm infection of implants. [5]

Medical importance

Antibiotic tolerance poses medically important challenges. It is largely responsible for the inability to eradicate bacterial infections with antibiotic treatment. Persister cells are highly enriched in biofilms, and this makes biofilm-related diseases difficult to treat. Examples are chronic infections of implanted medical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease. [13]

Resistance vs tolerance

Unlike multiple drug resistance, and antimicrobial resistance, antimicrobial tolerance is transient, and not inherited. [2] [7] [10] Antibiotic tolerant persister cells are not antibiotic resistant mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer) that are heritable and confer the ability to grow at elevated concentrations of antibiotics. In contrast, tolerant bacteria have the same minimum inhibitory concentration (MIC) as susceptible bacteria, [3] and differ in the duration of the treatment that they can survive. Antibiotic tolerance can be caused by a reversible physiological state in a small subpopulation of genetically identical cells, [2] [7] [10] similar to a differentiated cell type. [14] It enables this small subpopulation of bacteria to survive their complete elimination by antibiotic use. Persisting cells resume growth when the antibiotic is removed, and their progeny is sensitive to antibiotics. [2] [7] [10]

Molecular mechanisms

The molecular mechanisms that underlie persister cell formation, and antimicrobial tolerance are largely unknown. [2] [10] Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch, [10] [4] although inducible mechanisms of persister cell formation have been described. [10] [15] For instance, toxin-antitoxin systems, [16] and a number of different stress responses such as the SOS response, [15] the envelope stress response, [17] and the starvation response have also been associated with persister cell formation in biofilms. [18] Owing to their transient nature and relatively low abundance, it is hard to isolate persister cells in sufficient numbers for experimental characterization, and only a few relevant genes have been identified to date. [2] [10] The best-understood persistence factor is the E. coli high persistence gene, commonly abbreviated as hipA. [19]

Although tolerance is widely considered a passive state, there is evidence indicating it can be an energy-dependent process. [20] Persister cells in E. coli can transport intracellular accumulations antibiotic using an energy requiring efflux pump called TolC. [21]

A persister subpopulation has also been demonstrated in budding yeast Saccharomyces cerevisiae . Yeast persisters are triggered in a small subset of unperturbed exponentially growing cells by spontaneously occurring DNA damage, which leads to the activation of a general stress response and protection against a range of harsh drug and stress environments. As a result of the DNA damage, yeast persisters are also enriched for random genetic mutations that occurred prior to the stress, and are unrelated to the stress survival. [22]

In response to antifungals, fungal persister cells activate stress-response pathways, and two stress-protective molecules – glycogen, and trehalose accumulate in large amounts. [5]

Potential treatment

A study has shown that adding certain metabolites to aminoglycosides could enable bacterial persisters to be eliminated. This study was carried out on a number of bacterial species including E. coli and S. aureus . [23]

Phage therapy, where applicable, entirely circumvents antibiotic tolerance. [24] [25]

See also

Related Research Articles

<span class="mw-page-title-main">Antibiotic</span> Antimicrobial substance active against bacteria

An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the ones which cause the common cold or influenza; drugs which inhibit growth of viruses are termed antiviral drugs or antivirals rather than antibiotics. They are also not effective against fungi; drugs which inhibit growth of fungi are called antifungal drugs.

<span class="mw-page-title-main">Penicillin</span> Group of antibiotics derived from Penicillium fungi

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

<span class="mw-page-title-main">Biofilm</span> Aggregation of bacteria or cells on a surface

A biofilm is a syntrophic community of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymeric substances (EPSs). The cells within the biofilm produce the EPS components, which are typically a polymeric combination of extracellular polysaccharides, proteins, lipids and DNA. Because they have a three-dimensional structure and represent a community lifestyle for microorganisms, they have been metaphorically described as "cities for microbes".

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

Staphylococcus aureus is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

<i>Enterococcus</i> Genus of bacteria

Enterococcus is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90–95%) and E. faecium (5–10%). Rare clusters of infections occur with other species, including E. casseliflavus, E. gallinarum, and E. raffinosus.

<span class="mw-page-title-main">Drug resistance</span> Pathogen resistance to medications

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

<span class="mw-page-title-main">Colistin</span> Antibiotic

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<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes. P. aeruginosa is able to selectively inhibit various antibiotics from penetrating its outer membrane - and has high resistance to several antibiotics, according to the World Health Organization P. aeruginosa poses one of the greatest threats to humans in terms of antibiotic resistance.

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Filamentation</span> Type of bacteria growth

Filamentation is the anomalous growth of certain bacteria, such as Escherichia coli, in which cells continue to elongate but do not divide. The cells that result from elongation without division have multiple chromosomal copies.

<i>Acinetobacter baumannii</i> Species of bacterium

Acinetobacter baumannii is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromised immune systems, and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples, it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples, its natural habitat is still not known.

<span class="mw-page-title-main">Medical microbiology</span> Branch of medical science

Medical microbiology, the large subset of microbiology that is applied to medicine, is a branch of medical science concerned with the prevention, diagnosis and treatment of infectious diseases. In addition, this field of science studies various clinical applications of microbes for the improvement of health. There are four kinds of microorganisms that cause infectious disease: bacteria, fungi, parasites and viruses, and one type of infectious protein called prion.

Enterococcus faecium is a Gram-positive, gamma-hemolytic or non-hemolytic bacterium in the genus Enterococcus. It can be commensal in the gastrointestinal tract of humans and animals, but it may also be pathogenic, causing diseases such as neonatal meningitis or endocarditis.

Pathogenic <i>Escherichia coli</i> Strains of E. coli that can cause disease

Escherichia coli is a gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms (endotherms). Most E. coli strains are harmless, but pathogenic varieties cause serious food poisoning, septic shock, meningitis, or urinary tract infections in humans. Unlike normal flora E. coli, the pathogenic varieties produce toxins and other virulence factors that enable them to reside in parts of the body normally not inhabited by E. coli, and to damage host cells. These pathogenic traits are encoded by virulence genes carried only by the pathogens.

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<span class="mw-page-title-main">Enzybiotics</span> Experimental antibacterial therapy

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<span class="mw-page-title-main">Universal stress protein</span>

The universal stress protein (USP) domain is a superfamily of conserved genes which can be found in bacteria, archaea, fungi, protozoa and plants. Proteins containing the domain are induced by many environmental stressors such as nutrient starvation, drought, extreme temperatures, high salinity, and the presence of uncouplers, antibiotics and metals.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

A. C. Matin is a Pakistani-American microbiologist, immunologist, academician and researcher. He is a professor of microbiology and immunology at Stanford University School of Medicine.

References

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