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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. 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 while others may accommodate multiple drugs, and thus contribute to bacterial multidrug resistance (MDR).
Efflux in bacteria
Bacterial efflux pumps
Efflux pumps are proteinaceous transporters localized in the cytoplasmic membrane of all kind 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, 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.
Of these only the ABC superfamily are primary transporters, the rest being secondary transporters utilizing proton or sodium gradient as a source of energy. While 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.
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.
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.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Efflux_(microbiology)". A list of authors is available in Wikipedia.|