Antibiotics are oneof the most successful treatment worldwide. Their use has aided to reducechildhood mortality and increased life expectancy. They have successfullyprevented or treated infections in many patients such as those who havereceived chemotherapy and those with complex surgeries.
However, there has beenan increase in incidence of antibiotic resistance worldwide, which lead to arise in untreatable infections.5 Antibioticresistance infections has become an economic burden for the patients, theirfamilies and health care system. It has been found that in Europe alone 25,000people die each year due to multidrug-resistant bacterial infections and concurrentcost to the European Union economy is roughly €1.5 billion annually 2. Antibioticresistance infections are found to be more common in hospitals due to the highnumber of vulnerable patients who are admitted, the elevated use of antibioticand invasive surgeries that take place in these settings.
The development ofresistance can delay the administration of antibiotic therapy which meanspatients will require prolonged hospital stay (from 6.4 to 12.7 days) andtherefore greater hospital charge. It is challenging and takes massive amount of time to developnew antibiotics. Thus it becomes essential to protect the current antibioticsfrom developing new modes of resistance and finding ways to overcome resistance.It is also vital to have coordinated efforts to come up with new guidelines,implementation of these guideline’s and new research programmes in order toovercome the spread of antibiotic resistance. 6 There are severalmechanisms in which gram-negative bacteria such as E.coli can develop resistance.
Resistance can occur due to;mutations involved in specific antimicrobial targets, antimicrobialinactivation through production of B-lactamase enzymes, acquisition of mobilegenetic material via plasmids, transposons, or integrons, alteration in thecell wall composition, reduced number or porins in the cell wall, and overproduction of efflux pumps. 3 Out of all these different mechanisms ofresistance to antibiotics, efflux pumps interact synergistically with otherresistance mechanisms such as membrane permeability and those that have beenmentioned above. Efflux pumps, therefore plays a huge role in antibioticresistance and currently presents a major challenge during development ofantibiotics 7. In E.colithere are five different antibiotic efflux transporters (Fig 1).
These include;Small Multidrug Resistance (SMR) family, the Multidrug And Toxic compoundExtrusion (MATE) family, the Major Facilitator Superfamily (MFS), theATP-Binding Cassette (ABC) family and the Resistance-Nodulation-cell Division(RND) family. Out of the five family of efflux pumps, the ABC pump requireenergy released from the hydrolysis of ATP to remove antibiotic out of thecell, whereas the other four efflux pumps use electrochemical gradient. 4 TheRND transporter is part of a tripartite complex, which includes three subunits;acrB, tolC, and acrA (which links together acrB and tolC). The RND tripartitecomplex span the inner membrane, the periplasm and the outer membrane channel. TheRND pump are much more efficient in creating intrinsic and acquired resistanceto antibiotics (in particular the AcrB subunit), because the pump activelypumps out antibiotic out into the external medium, whereas the other pumpsexcrete the antibiotic into the periplasm and therefore there is a rapid backdiffusion of drug back into the cytosol. The AcrB subunit, has two bindingpockets, which can bind to substrates of different sizes and properties. Thisproperty is responsible for the resistance seen in large number of drugs suchas quinolones, tetracycline, macrolides, chloramphenicol, novobiocin andB-lactams 11.
However, it’s important to note, all three components of the RNDpump is needed for drug efflux property, the absence of just one subunit couldmake the whole pump non-functional. For example the AcrA subunit is needed to stimulate the activity of the pump.