Multidrug+Efflux+Pumps

Multidrug efflux pumps constitute one of the most important mechanisms underlying antibiotic resistance, via the extrusion of the drug compounds. They are found in a variety of bacterial species, both gram positive and gram negative and play a major role in conferring antibiotic resistance, leading to subsequently high minimum inhibitory concentrations (MICs) of antibiotics (Nikaido, 1998). This resistance is further increased when the expression levels of these efflux pumps are elevated due to either genetic alteration or physiological regulation.

__**Properties of Multidrug Efflux Pumps**__

As their name suggests, multidrug effflux pumps have a wide specificity and can pump out an extremely wide variety of detergents, dyes and antibiotics, as well as compounds such as beta-lactams which do not cross the cytoplasmic membrane so easily. Multidrug transporters in bacteria are generally classified into five families on the basis of sequence similarity (Nishino et al, 2003).

These families are:
 * The Major Facilitator Superfamily (MFS)
 * The Resistance-Nodulation-Cell Division (RND) family
 * The Small Multidrug Resistance (SMR) family
 * The Multidrug and Toxic compound Extrusion (MATE) family
 * The ATP-Binding Cassette (ABC) family

__**The Resistance-Nodulation-Cell Division (RND) Family**__ RND family transporters play a major role in producing both intrinsic and elevated levels of resistance to a very wide range of noxious compounds in gram negative bacteria, including beta-lactam antibiotics (Nishino et al, 2003). RND transporters usually need two other proteins in order to function: a membrane fusion protein (MFP), located in the bacterial periplasm and an outer-membrane channel protein. For example, the AcrB transport protein functions with the membrane fusions protein AcrA and the outer membrane channel TolC.

There are two types of multidrug efflux pumps reported in gram negative bacteria. The first is represented by the EmrE (MvrC) pump of E. coli and is a member of the SMR family. However, while the overproduction of the EmrE protein through the introduction of multicopy plasmids containing the gene makes E. coli slightly more resistant to tetracycline, erythromycin and sulfadiazine, the pumps of the Smr type are not known to make significant contributions to clinically relevant resistance amongst gram-negative bacteria (Yerushalmi et al, 1995).

The second type of efflux pump are far more relevant to antibiotic resistance. They are constructed in a totally different manner, consisting of three subunits: a transporter protein, located in the cytoplasmic membrane; an outer membrane channel and a periplasmic linker protein connecting the two. The transporters in these efflux pumps are energised by the proton-motive force and may belong to either the Major Facilitator (MF) family, or to the Resistance-Nodulation-Division (RND) family.

Members of the second type of efflux pump in E. coli, particularly significant to antibiotic resistance are detailed in the pages below:
 * The acrAB Efflux Pump