Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria

Abstract

The increasing multi-drug resistance has become a major threat to the public health. Overexpression of multidrug efflux pumps is one of the major mechanisms of drug resistance in bacteria. Since active efflux of antibacterial agents plays a significant role in mediating drug resistance in bacteria, the inhibition of efflux pumps appears to be a promising strategy to restore antibacterial potency. In recent years, in order to address this grave problem of multiple drug resistance mediated by efflux pump, a large number of efflux pump inhibitors have been discovered and tested, including natural products, antibiotics and synthetic molecules. This review mainly describes recent achievements in the search for new molecules that are able to inhibit efflux pumps in both Gram-positive and Gram-negative bacteria, in particular emphasis on natural and synthetic inhibitors of the NorA efflux pump in Staphylococcus aureus, MexAB-OprM efflux pump in Pseudomonas aeruginosa, and AcrAB-TolC efflux pump in Enterobacteriaceae, giving special attention to their mechanisms of action, structure-activity relationships and synergetic effect with clinically available antibiotics.

Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains

“…Antibiotic accumulation in Gram-negative bacteria is primarily influenced by two factors, membrane permeability and efflux activity6. Studies have recognized activation of efflux pumps as one of the major cause of resistance to many classes of antibiotics78. Another challenge is to kill the biofilm-associated cells which shows activated efflux and have specific stress responses that contribute to the occurrence of persister cells9101112.…”

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

“…The altered efflux regulation can result in resistance to a whole spectrum of antibiotics, and efflux pump inhibitors are an active area of investigation in the research efforts to overcome antibiotic resistance [53][54][55][56]. Quinolone efflux pumps are also found on certain plasmids that mediate quinolone resistance [45,46,57].…”

Antibacterial photodynamic therapy: overview of a promising approach to fight antibiotic-resistant bacterial infections

“…It is noteworthy that this effect was more prominent when the EPI was administered before adding toluidine blue O than after, indicating that toluidine blue O competitively binds the pump binding site of EPI and therefore blocks its access when the EPI inhibitor is administered after incubation with toluidine blue O. Nevertheless this approach must be further investigated given that EPIs have not yet reached clinical development due to their high toxicity [26,28,29].…”