''Enterococcus faecalis'' – formerly classified as part of the group D ''

Streptococcus ''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occu ...

'' system – is a

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bacte ...

commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...

bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...

inhabiting the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...

s of humans. Like other species in the

genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial no ...

Enterococcus ''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 charac ...

'', ''E. faecalis'' is found in healthy humans and can be used as a probiotic. The probiotic strains such as Symbioflor1 and EF-2001 are characterized by the lack of specific genes related to drug resistance and pathogenesis. As an opportunistic pathogen, ''E. faecalis'' can cause life-threatening infections, especially in the nosocomial (hospital) environment, where the naturally high levels of

antibiotic resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...

found in ''E. faecalis'' contribute to its pathogenicity. ''E. faecalis'' has been frequently found in reinfected, root canal-treated teeth in prevalence values ranging from 30% to 90% of the cases. Re-infected root canal-treated teeth are about nine times more likely to harbor ''E. faecalis'' than cases of primary infections.

Physiology

''E. faecalis'' is a nonmotile microbe; it ferments

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

without gas production, and does not produce a

catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...

reaction with

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...

. It produces a reduction of litmus milk, but does not liquefy gelatin. It shows consistent growth throughout nutrient broth which is consistent with being a facultative anaerobe. It catabolizes a variety of energy sources, including

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids know ...

, lactate,

malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric form ...

citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...

, agmatine, and many

keto acids Keto may refer to: * The Ket people (also known as Кето), an ethnic group of the Siberian North * Ceto or Keto, a sea goddess in Greek mythology * Ketone or keto group, the functional group in the chemical compounds ketones * Ketoconazole, a ...

. Enterococci survive very harsh environments, including extremely alkaline pH (9.6) and salt concentrations. They resist bile salts,

detergent A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are mor ...

heavy metals upright=1.2, Crystals of osmium, a heavy metal nearly twice as dense as lead">lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead Heavy metals are generally defined as ...

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant appl ...

, and

desiccation Desiccation () is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic (attracts and holds water) substance that induces or sustains such a state in its local vicinity in a moderately sealed container. ...

. They can grow in the range of 10 to 45 °C and survive at temperatures of 60 °C for 30 min.

Pathogenesis

''E. faecalis'' is found in most healthy individuals, but can cause

endocarditis Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or ...

and

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, urinary tract infections (UTIs),

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

, and other infections in humans. Several virulence factors are thought to contribute to ''E. faecalis'' infections. A

plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; howe ...

-encoded

hemolysin Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acqu ...

, called the cytolysin, is important for pathogenesis in animal models of infection, and the cytolysin in combination with high-level

gentamicin Gentamicin is an antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not ...

resistance is associated with a five-fold increase in risk of death in human bacteremia patients. A

-encoded adhesin called "aggregation substance" is also important for virulence in animal models of infection. ''E. faecalis'' contains a tyrosine decarboxylase enzyme capable of decarboxylating L-dopa, a crucial drug in the treatment of Parkinson's disease. If L-dopa is decarboxylated in the

gut microbiome Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut m ...

, it cannot pass through the blood-brain barrier and be decarboxylated in the brain to become dopamine. Enterococcus faecalis

Antibacterial resistance

Multi drug resistance

''E. faecalis'' is usually resistant to many commonly used

antimicrobial An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...

agents (

aminoglycosides Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

, aztreonam and

quinolones Quinolone may refer to: * 2-Quinolone * 4-Quinolone * Quinolone antibiotic A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They a ...

. The resistance is mediated by the presence of multiple genes related to drug resistance in the chromosome or plasmid. Resistance to

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

in ''E. faecalis'' is becoming more common. Treatment options for vancomycin-resistant ''E. faecalis'' include

nitrofurantoin Nitrofurantoin is an antibacterial medication used to treat urinary tract infections, but it is not as effective for kidney infections. It is taken by mouth. Common side effects include nausea, loss of appetite, diarrhea, and headaches. Rarely ...

(in the case of uncomplicated UTIs),

linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vanc ...

, quinupristin, tigecycline and

daptomycin Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. Daptomycin was removed from the World Health Organiza ...

, although

ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B strepto ...

is preferred if the bacteria are susceptible. Quinupristin/dalfopristin can be used to treat ''

Enterococcus faecium ''Enterococcus faecium'' is a Gram-positive, gamma-hemolytic or non-hemolytic bacterium in the genus ''Enterococcus''. It can be commensal (innocuous, coexisting organism) in the gastrointestinal tract of humans and animals, but it may also be ...

'' but not ''E. faecalis''. In root-canal treatments, NaOCl and

chlorhexidine Chlorhexidine (CHX) (commonly known by the salt forms chlorhexidine gluconate and chlorhexidine digluconate (CHG) or chlorhexidine acetate) is a disinfectant and antiseptic that is used for skin disinfection before surgery and to sterilize surg ...

(CHX) are used to fight ''E. faecalis'' before isolating the canal. However, recent studies determined that NaOCl or CHX showed low ability to eliminate ''E. faecalis''.

Development of antibiotic resistance

Combined drug therapies

According to one study combined drug therapy has shown some efficacy in cases of severe infections (e.g. heart valves infections) against susceptible strains of ''E. faecalis''.

Ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B strepto ...

- and

-sensitive '' E. faecalis'' (lacking high-level resistance to

aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

s) strains can be treated by

and

antibiotics. A less nephrotoxic combination of ampicillin and

ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and jo ...

(even though ''E. faecalis'' is resistant to cephalosporins,

is working synergistically with ampicillin) may be used alternatively for ampicillin-susceptible ''E. faecalis''.

Daptomycin Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. Daptomycin was removed from the World Health Organiza ...

may also show efficacy in case ampicillin and vancomycin resistance. A combination of

penicillin Penicillins (P, PCN or PEN) 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 usin ...

and

streptomycin Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, ''Mycobacterium avium'' complex, endocarditis, brucellosis, ''Burkholderia'' infection, plague, tularemia, and rat bite fever. ...

therapy was used in the past. Tedizolid, telavancin, dalbavancin, and oritavancin antibiotics are FDA approved as treatments against EF.

Survival and virulence factors

* Endures prolonged periods of nutritional deprivation * Binds to

dentin Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by en ...

and proficiently spreads into dentinal tubules via chain propagation * Alters host responses * Suppresses the action of

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...

* Possesses lytic enzymes, cytolysin, aggregation substance,

pheromone A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavi ...

s, and

lipoteichoic acid Lipoteichoic acid (LTA) is a major constituent of the cell wall of gram-positive bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. The structure of LTA varies be ...

* Utilizes serum as a nutritional source * Produces extracellular superoxide under selected growth conditions that can generate chromosomal instability in mammalian cells * Resists intracanal medicaments (e.g. calcium hydroxide), although a study proposes elimination from root canals after using a mixture of a tetracycline isomer, an acid, and a detergent ** Maintains pH homeostasis ** Properties of dentin lessen the effect of calcium hydroxide * Competes with other cells * Forms a

biofilm A biofilm comprises any syntrophic consortium 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 p ...

* Activates the host protease plasminogen in a fashion that increases local tissue destruction

DNA repair

In human blood, ''E. faecalis'' is subjected to conditions that damage its DNA, but this damage can be tolerated by the use of

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolism, metabolic activities and environmental factors such as r ...

processes.Ha KP, Clarke RS, Kim GL, Brittan JL, Rowley JE, Mavridou DAI, Parker D, Clarke TB, Nobbs AH, Edwards AM. Staphylococcal DNA Repair Is Required for Infection. mBio. 2020 Nov 17;11(6):e02288-20. doi: 10.1128/mBio.02288-20. PMID: 33203752; PMCID: PMC7683395 This damage tolerance depends, in part, on the two protein complex RexAB, encoded by the ''E. faecalis'' genome, that is employed in the recombinational repair of DNA double-strand breaks.

Historical

Prior to 1984, enterococci were members of the genus ''

''; thus, ''E. faecalis'' was known as ''Streptococcus faecalis''. In 2013, a combination of cold denaturation and NMR spectroscopy was used to show detailed insights into the unfolding of the ''E. faecalis'' homodimeric repressor protein CylR2.

Genome structure

The ''E. faecalis'' genome consists of 3.22 million base pairs with 3,113 protein-coding genes.

Treatment research

Glutamate racemase, hydroxymethylglutaryl-CoA synthase, diphosphomevalonate decarboxylase, topoisomerase

DNA gyrase DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-po ...

B, D-alanine—D-serine ligase, alanine racemase, phosphate acetyltransferase,

NADH peroxidase In enzymology, a NADH peroxidase () is an enzyme that catalyzes the chemical reaction :NADH + H+ + H2O2 \rightleftharpoons NAD+ + 2 H2O The presumed function of NADH peroxidase is to inactivate H2O2 generated within the cell, for example by gly ...

,Phosphopantetheine adenylyltransferase (PPAT),

acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide biosynthesis machinery. It is one of the most abundant proteins in cells of ''E. coli.'' In both cases, the growing chain is bound to the ACP via a thioester derived fro ...

, 3‐Dehydroquinate dehydratase and Deoxynucleotide triphosphate triphosphohydrolase are all potential molecules that may be used for treating EF infections.

Small RNA

Bacterial small RNA Bacterial small RNAs (bsRNA) are small RNAs produced by bacteria; they are 50- to 500- nucleotide non-coding RNA molecules, highly structured and containing several stem-loops. Numerous sRNAs have been identified using both computational analysis a ...

s play important roles in many cellular processes; 11 small RNAs have been experimentally characterised in ''E. faecalis V583'' and detected in various growth phases. Five of them have been shown to be involved in stress response and virulence. A genome-wide sRNA study suggested that some sRNAs are linked to the antibiotic resistance and stress response in another ''Enteroccocus'': '' E. faecium''.

References

External links

Type strain of ''Enterococcus faecalis'' at Bac''Dive'' – the Bacterial Diversity Metadatabase
{{Taxonbar, from=Q140014 faecalis Bacteria described in 1906