Drug Efflux Pump Inhibitors: A Promising Approach to Counter Multidrug Resistance in Gram-Negative Pathogens by Targeting AcrB Protein from AcrAB-TolC Multidrug Efflux Pump from Escherichia coli

SIMPLE SUMMARY: Multidrug-resistant bacterial infections, especially that caused by Gram-negative bacteria, have posed serious health issues worldwide. Bacteria have different mechanisms that can confer multidrug resistance to bacteria, among these mechanisms are drug efflux pumps that play the main role in conferring multidrug resistance by recognizing then expelling a wide range of compounds, especially antibiotics, and reducing their concentration to sub-toxic levels. Small molecule inhibitors that target drug efflux pumps especially the AcrAB-TolC multidrug efflux pump, from E. coli, appear as a new promising and attractive approach that could increase the required accumulation of antimicrobials to eliminate bacteria as well as leading to reverse antibiotic resistance and prevent the development of resistance in clinically relevant bacterial pathogens and enhances the activity of antibiotics or prolong their effectiveness. ABSTRACT: Infections caused by multidrug resistance (MDR) of Gram-negative bacteria have become one of the most severe public health problems worldwide. The main mechanism that confers MDR to bacteria is drug efflux pumps, as they expel a wide range of compounds, especially antibiotics. Among the different types of drug efflux pumps, the resistance nodulation division (RND) superfamily confers MDR to various Gram-negative bacteria species. The AcrAB-TolC multidrug efflux pump, from E. coli, a member of RND, is the best-characterized example and an excellent model for understanding MDR because of an abundance of functional and structural data. Small molecule inhibitors that target the AcrAB-TolC drug efflux pump represent a new solution to reversing MDR in Gram-negative bacteria and restoring the efficacy of various used drugs that are clinically relevant to these pathogens, especially in the high shortage of drugs for multidrug-resistant Gram-negative bacteria. This review will investigate solutions of MDR in Gram-negative bacteria by studying the inhibition of the AcrAB-TolC multidrug efflux pump.