Antibiotics are one
of the most successful treatment worldwide. Their use has aided to reduce
childhood mortality and increased life expectancy. They have successfully
prevented or treated infections in many patients such as those who have
received chemotherapy and those with complex surgeries. However, there has been
an increase in incidence of antibiotic resistance worldwide, which lead to a
rise in untreatable infections.5   Antibiotic
resistance infections has become an economic burden for the patients, their
families and health care system. It has been found that in Europe alone 25,000
people die each year due to multidrug-resistant bacterial infections and concurrent
cost to the European Union economy is roughly €1.5 billion annually 2. Antibiotic
resistance infections are found to be more common in hospitals due to the high
number of vulnerable patients who are admitted, the elevated use of antibiotic
and invasive surgeries that take place in these settings. The development of
resistance can delay the administration of antibiotic therapy which means
patients will require prolonged hospital stay (from 6.4 to 12.7 days) and
therefore greater hospital charge. It is challenging and takes massive amount of time to develop
new antibiotics. Thus it becomes essential to protect the current antibiotics
from 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 to
overcome the spread of antibiotic resistance. 6

 

There are several
mechanisms in which gram-negative bacteria such as E.coli can develop resistance. Resistance can occur due to;
mutations involved in specific antimicrobial targets, antimicrobial
inactivation through production of B-lactamase enzymes, acquisition of mobile
genetic material via plasmids, transposons, or integrons, alteration in the
cell wall composition, reduced number or porins in the cell wall, and over
production of efflux pumps. 3 Out of all these different mechanisms of
resistance to antibiotics, efflux pumps interact synergistically with other
resistance mechanisms such as membrane permeability and those that have been
mentioned above. Efflux pumps, therefore plays a huge role in antibiotic
resistance and currently presents a major challenge during development of
antibiotics 7.   In E.coli
there are five different antibiotic efflux transporters (Fig 1). These include;
Small Multidrug Resistance (SMR) family, the Multidrug And Toxic compound
Extrusion (MATE) family, the Major Facilitator Superfamily (MFS), the
ATP-Binding Cassette (ABC) family and the Resistance-Nodulation-cell Division
(RND) family. Out of the five family of efflux pumps, the ABC pump require
energy released from the hydrolysis of ATP to remove antibiotic out of the
cell, whereas the other four efflux pumps use electrochemical gradient. 4 The
RND transporter is part of a tripartite complex, which includes three subunits;
acrB, tolC, and acrA (which links together acrB and tolC). The RND tripartite
complex span the inner membrane, the periplasm and the outer membrane channel. The
RND pump are much more efficient in creating intrinsic and acquired resistance
to antibiotics (in particular the AcrB subunit), because the pump actively
pumps out antibiotic out into the external medium, whereas the other pumps
excrete the antibiotic into the periplasm and therefore there is a rapid back
diffusion of drug back into the cytosol. The AcrB subunit, has two binding
pockets, which can bind to substrates of different sizes and properties. This
property is responsible for the resistance seen in large number of drugs such
as quinolones, tetracycline, macrolides, chloramphenicol, novobiocin and
B-lactams 11. However, it’s important to note, all three components of the RND
pump is needed for drug efflux property, the absence of just one subunit could
make the whole pump non-functional. For example the AcrA subunit is needed to stimulate the activity of the pump. 

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