Multidrug Efflux Pumps in Bacteria and Efflux Pump Inhibitors

Abstract

Antimicrobial resistance is becoming a paramount health concern nowadays. The increasing drug resistance in microbes is due to improper medications or over usage of drugs. Bacteria develop many mechanisms to extrude the antibiotics entering the cell. The most prominent are the efflux pumps (EPs). EPs play a significant role in intrinsic and acquired bacterial resistance, mainly in Gram-negative bacteria. EPs may be unique to one substrate or transport several structurally different compounds (including multi-class antibiotics). These pumps are generally associated with multiple drug resistance (MDR). EPs are energized by a proton motive force and can pump a vast range of detergents, drugs, antibiotics and also β-lactams, which are impermeable to the cytoplasmic membrane. There are five leading efflux transporter families in the prokaryotic kingdom: MF (Major Facilitator), MATE (Multidrug And Toxic Efflux), RND (Resistance-Nodulation-Division), SMR (Small Multidrug Resistance) and ABC (ATP Binding Cassette). Apart from the ABC family, which utilizes ATP hydrolysis to drive the export of substrates, all other systems use the proton motive force as an energy source. Some molecules known as Efflux Pump Inhibitors (EPI) can inhibit EPs in Gram-positive and Gram-negative bacteria. EPIs can interfere with the efflux of antimicrobial agents, leading to an increase in the concentration of antibiotics inside the bacterium, thus killing it. Therefore, identifying new EPIs appears to be a promising strategy for countering antimicrobial drug resistance (AMR). This mini-review focuses on the major efflux transporters of the bacteria and the progress in identifying Efflux Pump Inhibitors.