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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.

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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 several mechanisms in whichgram-negative bacteria such as E.

colican develop resistance. Resistance can occur due to; mutations involved inspecific antimicrobial targets, antimicrobial inactivation through productionof B-lactamase enzymes, acquisition of mobile genetic material via plasmids,transposons, or integrons, alteration in the cell wall composition, reducednumber or porins in the cell wall, and over production of efflux pumps. 3 Outof all these different mechanisms of resistance to antibiotics, efflux pumpsinteract synergistically with other resistance mechanisms such as membranepermeability and those that have been mentioned above. Efflux pumps, therefore playsa huge role in antibiotic resistance and currently presents a major challenge duringdevelopment of antibiotics 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. 12   Since efflux pumps plays a major role inantibiotic resistance, inhibiting these pumps would be a promising strategy toprotect the efficiency of various antibiotics and possibly could help the re-introductionof ineffective antibiotics back into use. There have been many efflux pump inhibitorsthat have been studied in the past including natural products, syntheticmolecules and antibiotics. Inhibiting the efflux pump has many advantage. ithelps to increase the intracellular concentration of antibiotic within abacterial cell to a level that is required to show its activity and thereforehelp to reduce the minimal inhibitory concentration that is needed for theantibiotic to kill the resistant organism.

It also helps to reduce the capability ofbacteria to acquire additional resistance and to re-establish the drug susceptibilityof resistant strains in clinics.  Natural products that have been obtainedby plants have shown weak antimicrobial effect and have very little or notoxicity when used clinically. Therefore, natural products can be usedclinically to overcome resistance in bacteria by inhibiting efflux pumps. Ithas been also known before that some antibiotics seems to exert synergy whenused in combination with Efflux Pump Inhibitors (EPI). Chequerboard assay havebeen used in the past to identify such EPI 8. Currently there are noEPI/antimicrobial drug combinations that are commercially available forclinical use. However, research is still ongoing in finding a suitable EPI.

Manyplant compounds that have been previously studied has shown to act synergisticallywith antibiotics on gram-positive bacteria 9, 10.  In this study, two natural products were selected;Reserpine and Quercetin both of which is isolated from plants to act as EPI. Quercetin is a typical flavonol-type flavonoid andlimited studies have been carried out to test its ability as efflux pumpinhibitor. Reserpine which is isolated from theroots of Rauwolfia vomitoria Afz hasshown EPI activity against the efflux pump called Bmr of Bacillus subtilis. However, not many studies have been carried outto show the EPI activity of Reserpine in gram-negative bacteria such as in E.coli strain.

Gram-negative species arethe most problematic bacteria to treat in the future.8 New treatments againstgram-negative bacteria is needed due to the intrinsic high drug resistance andthe increased incidence of drug-resistant Gram-negative infections.  The aim of the study was to investigatethe synergic effects of natural products as efflux pump inhibitors withantibiotics. Reserpine and Queceptin  were used in combination with two differentanitbiotics; tetracycline and chloramphenicol on both mutant (M843 ACRA- has anon-functioning RND efflux pump) and wildtype(BW25113-has a functioning RNDefflux pump) strains of E.coli. Anotheraim of the study was to determine the Minimal Bactericidal Concentration (MBC),to see if natural product/ antimicrobial drug combinations had a bactericidalor bacteriostatic effect.

 

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