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. This mechanism is important in medicine as it can contribute to bacterial antibiotic resistance.
Efflux systems function via an energy-dependent mechanism (Active transport) 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).
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Efflux pumps are proteinaceous transporters localized in the cytoplasmic membrane of all kinds of cells. They are active transporters, meaning that they require a source of chemical energy to perform their function. Some are primary active transporters utilizing Adenosine triphosphate hydrolysis as a source of energy, whereas 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.
Bacterial efflux transporters are classified into five major superfamilies, based on the amino acid sequence and the energy source used to export their substrates:
Of these, only the ABC superfamily are primary transporters, the rest being secondary transporters utilizing proton or sodium gradient as a source of energy. Whereas MFS dominates in Gram positive bacteria, the RND family is unique to Gram-negatives.
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. Because most antibiotics are amphiphilic molecules - possessing both hydrophilic and hydrophobic characters - they are easily recognized by many efflux pumps.
The impact of efflux mechanisms on antimicrobial resistance is large; this is usually attributed to the following:
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.
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. Some chemicals found in plants have potential as reflex pump inhibitors. Chemicals such as Capsanthin and capsorubin, carotenoids isolated from paprika; the flavonoids, rotenone, chrysin, phloretin and sakuranetin.[2]