Active efflux is a mechanism responsible for extrusion of toxic substances and antibiotic

Antibiotic

An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s outside the cell; this is considered to be a vital part of xenobiotic metabolism

Xenobiotic metabolism

Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons...

. This mechanism is important in medicine as it can contribute to bacterial antibiotic resistance

Antibiotic resistance

Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...

.

Efflux systems function via an energy-dependent mechanism (Active transport

Active transport

Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...

) to pump out unwanted toxic substances through specific efflux pumps. Some efflux systems are drug-specific, whereas others may accommodate multiple drugs, and thus contribute to bacterial multidrug resistance (MDR).

Bacterial efflux pumps

Efflux pumps are protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

aceous transporters localized in the cytoplasmic membrane of all kinds of cells. They are active transport

Active transport

Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...

ers, meaning that they require a source of chemical energy to perform their function. Some are primary active transporters utilizing Adenosine triphosphate

Adenosine triphosphate

Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 hydrolysis as a source of energy, whereas others are secondary active transporters (uniporter

Uniporter

A uniporter is an integral membrane protein that is involved in facilitated diffusion. They can be either a channel or a carrier protein....

s, symporter

Symporter

A cotransporter is an integral membrane protein that is involved in secondary active transport. It works by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient....

s, or antiporter

Antiporter

An antiporter is an integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in opposite directions.In secondary active transport, one species of solute moves along its electrochemical...

s) in which transport is coupled to an electrochemical potential difference created by pumping out hydrogen

Hydrogen

Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

 or sodium

Sodium

Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 ions outside the cell.


Bacterial efflux transporters are classified into five major superfamilies, based on the amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 sequence

Peptide sequence

Peptide sequence or amino acid sequence is the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins. The sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing free carboxyl group...

  and the energy source used to export their substrates:

1. The major facilitator superfamily (MFS)
2. The ATP
   Adenosine triphosphate
   Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
   
   -binding cassette superfamily (ABC)
3. The small multidrug resistance family (SMR)
4. The resistance-nodulation-cell division superfamily (RND)
5. The Multi antimicrobial extrusion protein
   Multi antimicrobial extrusion protein
   Multi antimicrobial extrusion protein also known as multidrug and toxin extrusion or multidrug and toxic compound extrusion is a family of proteins which function as drug/sodium or proton antiporters.- Function :...
   
    family (MATE).

Of these, only the ABC superfamily are primary transporters, the rest being secondary transporters utilizing proton

Proton

The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....

 or sodium gradient as a source of energy. Whereas MFS dominates in Gram positive bacteria, the RND family is unique to Gram-negative

Gram-negative

Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

s.

Function

Although antibiotics are the most clinically important substrates of efflux systems, it is probable that most efflux pumps have other natural physiological functions. Examples include:

• The E. coli
  Escherichia coli
  Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
  
   AcrAB efflux system, which has a physiologic role of pumping out bile acids and fatty acids to lower their toxicity.
• The MFS family Ptr pump in Streptomyces pristinaespiralis appears to be an autoimmunity
  Autoimmunity
  Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
  
   pump for this organism when it turns on production of pristinamycins I and II.
• The AcrAB–TolC system in E.coli is suspected to have a role in the transport of the calcium-channel components in the E. coli membrane.
• The MtrCDE system plays a protective role by providing resistance to faecal lipids in rectal isolates of Neisseria gonorrhoeae
  Neisseria gonorrhoeae
  Neisseria gonorrhoeae, also known as gonococci , or gonococcus , is a species of Gram-negative coffee bean-shaped diplococci bacteria responsible for the sexually transmitted infection gonorrhea.N...
  
  .
• The AcrAB efflux system of Erwinia amylovora is important for this organism's virulence
  Virulence
  Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
  
  , plant (host) colonization, and resistance to plant toxins.
• The MexXY component of the MexXY-OprM multidrug efflux system of P. aeruginosa is inducible by antibiotics that target ribosomes via the PA5471 gene product.

The ability of efflux systems to recognize a large number of compounds other than their natural substrates is probably because substrate recognition is based on physicochemical properties, such as hydrophobicity, aromaticity

Aromaticity

In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 and ionizable

Ionization

Ionization is the process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions. This is often confused with dissociation. A substance may dissociate without necessarily producing ions. As an example, the molecules of table sugar...

 character rather than on defined chemical properties, as in classical enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

-substrate

Substrate (biochemistry)

In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 or ligand

Ligand (biochemistry)

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...

-receptor

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 recognition. Because most antibiotics are amphiphilic molecules - possessing both hydrophilic and hydrophobic characters - they are easily recognized by many efflux pumps.

Impact on antimicrobial resistance

The impact of efflux mechanisms on antimicrobial resistance is large; this is usually attributed to the following:

• The gene
  Gene
  A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
  
  tic elements encoding efflux pumps may be encoded on chromosome
  Chromosome
  A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
  
  s and/or plasmids, thus contributing to both intrinsic (natural) and acquired resistance respectively. As an intrinsic mechanism of resistance, efflux pump genes can survive a hostile environment ( for example in the presence of antibiotics) which allows for the selection of mutant
  Mutant
  In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
  
  s that over-express
  Gene expression
  Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
  
   these genes. Being located on transportable genetic elements as plasmids or transposon
  Transposon
  Transposable elements are sequences of DNA that can move or transpose themselves to new positions within the genome of a single cell. The mechanism of transposition can be either "copy and paste" or "cut and paste". Transposition can create phenotypically significant mutations and alter the cell's...
  
  s is also advantageous for the microorganisms as it allows for the easy spread of efflux genes between distant species.
• Antibiotics can act as inducers and regulators of the expression
  Gene expression
  Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
  
   of some efflux pumps.
• Expression of several efflux pumps in a given bacterial species may lead to a broad spectrum of resistance when considering the shared substrates of some multi-drug efflux pumps, where one efflux pump may confer resistance to a wide range of antimicrobials.

Efflux in eukaryotes

In eukaryotic cells, the existence of efflux pumps has been known since the discovery of p-glycoprotein in 1976 by Juliano and Ling. Efflux pumps are one of the major causes of anticancer drug resistance in eukaryotic cells. These include monocarboxylate transporters (MCTs), multiple drug resistance proteins (MDRs)- also referred as p-glycoprotein, multidrug resistance-associated proteins (MRPs), peptide transporters (PEPTs), and Na+ phosphate transporters (NPTs). These transporters are distributed along particular portions of the renal proximal tubule, intestine, liver, blood-brain barrier, and other portions of the brain.

Efflux inhibitors

Several trials are currently being conducted to develop drugs that can be co-administered with antibiotics to act as inhibitors for the efflux-mediated extrusion of antibiotics. None of the efflux inhibitors tested is yet in clinical use. However, some of them are used to determine the efflux prevalence in clinical isolates. Its shown that Verapamil

Verapamil

Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...

 can inhibit P-glycoprotein mediated efflux which can increase oral absorption of some compounds.
Some chemicals found in plants have potential as reflex pump inhibitors. Chemicals such as Capsanthin and capsorubin, carotenoid

Carotenoid

Carotenoids are tetraterpenoid organic pigments that are naturally occurring in the chloroplasts and chromoplasts of plants and some other photosynthetic organisms like algae, some bacteria, and some types of fungus. Carotenoids can be synthesized fats and other basic organic metabolic building...

s isolated from paprika

Paprika

Paprika is a spice made from the grinding of dried fruits of Capsicum annuum . In many European languages, the word paprika refers to bell peppers themselves. The seasoning is used in many cuisines to add color and flavor to dishes. Paprika can range from mild to hot...

; the flavonoids, rotenone

Rotenone

Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots and stems of several plants such as the jicama vine plant...

, chrysin, phloretin

Phloretin

Phloretin is a dihydrochalcone, a type of natural phenols. It is the phloroglucin ester of paraoxyhydratropic acid. It can be found in apple tree leaves.-Metabolism:Phloretin hydrolase uses phloretin and water to produce phloretate and phloroglucinol....

 and sakuranetin

Sakuranetin

Sakuranetin is a flavanone, a type of flavonoid. It can be found in Polymnia fruticosa and rice, where it acts as a phytoalexin against spore germination of Pyricularia oryzae.-Metabolism:...

.