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Active efflux is a mechanism responsible for extrusion of toxic substances and antibiotics outside the cell, this is considered to be a vital part of xenobiotic metabolism. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa 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 This mechanism is important in medicine as it can contribute to bacterial antibiotic resistance. Antibiotic resistance is the ability of a Microorganism to withstand the effects of Antibiotics.

Efflux systems function via an energy-dependent mechanism (Active transport) to pump out unwanted toxic substances through specific efflux pumps. Active transport is the mediated process of moving particles across Biological membrane against the concentration gradient Some efflux systems are drug-specific while others may accommodate multiple drugs, and thus contribute to bacterial multidrug resistance (MDR).

Contents

Efflux in bacteria

Bacterial efflux pumps

Efflux pumps are proteinaceous transporters localized in the cytoplasmic membrane of all kinds of cells. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer They are active transporters meaning that they require a source of chemical energy to perform their function. Active transport is the mediated process of moving particles across Biological membrane against the concentration gradient Some are primary active transporters utilizing Adenosine triphosphate hydrolysis as a source of energy, while others are secondary active transporters (uniporters, symporters or antiporters) in which transport is coupled to an electrochemical potential difference created by pumping out hydrogen or sodium ions outside the cell. Active transport is the mediated process of moving particles across Biological membrane against the concentration gradient Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy Active transport is the mediated process of moving particles across Biological membrane against the concentration gradient A uniporter is an Integral membrane protein that is involved in Facilitated diffusion. A symporter is an Integral membrane protein that is involved in movement of two or more different molecules or ions across a phospholipid membrane such as the Plasma membrane An antiporter (also called exchanger or counter-transporter) is an Integral membrane protein which is involved in Secondary active transport In Electrochemistry, the electrochemical potential, \bar{\mu} sometimes confusingly abbreviated to ECP is a Thermodynamic measure that combines the Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Sodium (ˈsoʊdiəm is an element which has the symbol Na( Latin natrium, from Arabic natrun) atomic number 11 atomic mass 22 An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge
Bacterial efflux transporters are classified into five major superfamilies, based on the amino acid sequence and the energy source used to export their substrates:

  1. The major facilitator superfamily (MFS);
  2. The ATP-binding cassette superfamily (ABC);
  3. The small multidrug resistance family (SMR);
  4. The resistance-nodulation-cell division superfamily (RND); and
  5. The multidrug and toxic compound extrusion family (MATE). In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Peptide sequence or amino acid sequence is the order in which Amino acid residues connected by Peptide bonds lie in the chain in Peptides Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy

Of these only the ABC superfamily are primary transporters, the rest being secondary transporters utilizing proton or sodium gradient as a source of energy. The proton ( Greek πρῶτον / proton "first" is a Subatomic particle with an Electric charge of one positive In Cellular biology, an electrochemical gradient is a spatial variation of both Electrical potential and chemical Concentration across a membrane While MFS dominates in Gram positive bacteria , the RND family is unique to Gram-negatives. Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. Gram-negative bacteria are those Bacteria that do not retain Crystal violet dye in the Gram staining protocol

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 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 and ionizable character rather than on defined chemical properties, as in classical enzyme-substrate or ligand-receptor recognition. Physical chemistry, is the application of Physics to macroscopic microscopic atomic subatomic and particulate phenomena in chemical systems It is mostly defined as a large In Chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of Ionization is the physical process of converting an Atom or Molecule into an Ion by adding or removing charged particles such as Electrons Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling Because most antibiotics are amphiphilic molecules - possessing both hydrophilic and hydrophobic characters, they are easily recognized by many efflux pumps. Amphiphile (from the Greek αμφις amphis both and φιλíα Philia: love friendship is a term describing a Chemical compound possessing both

Impact on antimicrobial resistance

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

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 transporter (MCT), organic anion transporter (OAT), multiple drug resistance (MDR)- also referred as p-glycoprotein, multidrug resistance-associated protein (MRP), peptide transporter (PEPT), Na+ phosphate transporter (NPT) and organic cation transporter (OCT). These transporters are distributed all along the kidney, intestine, liver and brain cells.

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 can inhibit P-glycoprotein mediated efflux which can increase oral absorption of some compounds. Verapamil (brand names Isoptin, Verelan, Calan, Bosoptin, Covera-HS) is an L-type Calcium channel blocker.

See also

References

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