Efflux (microbiology) | Wikipedia audio article

Active efflux is a mechanism responsible for
moving compounds, like neurotransmitters, toxic substances, and antibiotics, out of
cells; a process 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 with small multidrug resistance (SMR) transporters.==Bacteria=====
Bacterial efflux pumps===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 hydrogen or sodium ions from or to the outside of the
cell. Bacterial efflux transporters are classified
into five major superfamilies, based on their amino acid sequence and the energy source
used to export their substrates: The major facilitator superfamily (MFS)
The ATP-binding cassette superfamily (ABC) The small multidrug resistance family (SMR)
The resistance-nodulation-cell division superfamily (RND)
The Multi antimicrobial extrusion protein family (MATE).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 was once thought to be unique to Gram negative bacteria. They have since been found in all major Kingdoms.===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 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 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. The AcrAB efflux system of Erwinia amylovora
is important for this organism’s virulence, 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 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: The genetic elements encoding efflux pumps
may be encoded on chromosomes 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 mutants that over-express these genes. Being located on transportable genetic elements
as plasmids or transposons 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 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.==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. They 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. As yet, no efflux inhibitor has been approved
for therapeutic use, but some are being used to determine the prevalence of efflux pumps
in clinical isolates and in cell biology research. Verapamil, for example, is used to block P-glycoprotein-mediated
efflux of DNA-binding fluorophores, thereby facilitating fluorescent cell sorting for
DNA content. Various natural products have been shown to
inhibit bacterial efflux pumps including the carotenoids capsanthin and capsorubin, the
flavonoids rotenone and chrysin, and the alkaloid lysergol. Some nanoparticles, for example zinc oxide,
also inhibit bacterial efflux pumps.==See also==
Antibiotic resistance

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