The Importance of Efflux Systems in Antibiotic Resistance and Efflux Pump Inhibitors in the Management of Resistance

The process of active efflux, the last described resistance mechanism in bacteria, is one of the important factors of acquired antibiotic resistance. Efflux systems which consist of membrane-located pump proteins that exist in all eukaryotic and prokaryotic cells, are responsible for extrusion of the various exogenous and endogenous substances. Bacterial pump proteins, namely ATP Binding Cassette (ABC), Major Facilitator (MFS), Small Multidrug Resistance (SMR), Multidrug and Toxic Compound Extrusion (MATE) and Resistance - Nodulation - Division (RND) are grouped in five super families. Efflux pumps play a role in intrinsic resistance against antibiotics among some pathogens. Besides, pumps give rise to acquired resistance by over-expression and contribute to other resistance mechanisms. Furthermore, pumps can directly or indirectly intensify the virulence properties of bacteria. Thus, for inhibition of efflux-mediated resistance or conversion of resistant bacteria to the susceptible phenotype, potential pump inhibitors combined with traditional antibiotics is one of the research areas of interest in the fight against resistance. There are some compounds known to inhibit bacterial pump systems, such as phenyl-arginine beta naphthylamide (PA beta N), INF271, INF55, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine, 1-(1-naphthylmethyp-piperazine (NMP), biricodar, timcodar, verapamil, milbemycin, chlorpromazine, paroxetine and omeprazole. However, particularly due to the toxicity problems, there has been no clinical use of a pump inhibitor yet. Nevertheless, in the upcoming period, derivatives of efflux pump inhibitor compounds with acceptable level of toxicity and efficacy may be included in antibacterial formulations. Additionally, a number of natural and synthetic compounds with pump inhibition activity are reported by many researchers in industrial and academic areas. In this context, various antibiotic derivatives (tetracycline, fluoroquinolone and aminoglycoside analogs) or non-antibiotic compounds (indole, urea, aromatic acid, piperidine-carboxylic acid, quinoline derivatives and peptidomimetics), some of which already have patent applications, are often studied. Pump inhibitors are shown to reduce the minimum inhibitory concentration (MIC) values of various antibiotics in some studies. In this review article, the structure and functions of bacterial efflux pumps have been summarized and the efflux pump inhibitors with natural and synthetic origins have been evaluated.