Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates

Abstract

Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2'-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB-TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes.

Selected Arylpiperazines Are Capable of Reversing Multidrug Resistance in Escherichia coli Overexpressing RND Efflux Pumps

“…Among gram-negative bacteria, many of these MDR efflux pumps belong to the RND (resistance-nodulation-cell division) type family of tripartite efflux pumps. MDR in selected gram-negative bacteria has been shown to be reversible by using compounds like Phe-Arg-␤-naphthylamide (PA␤N) or other small N-heterocyclic organic compounds thought to inhibit RND type efflux pump activity through unknown mechanisms (4,5,7,9). In this study, we describe another novel type of putative efflux pump inhibitor (EPI) identified through screening of an N-heterocyclic organic compound library for MDR reversal activity in Escherichia coli.…”

Potentiation of Antimicrobial Activity of Aminoglycosides by Carnosol from Salvia officinalis

“…Baicalein potentiated activities of tetracycline and b-lactams against MRSA, 14) 5Ј-methoxyhydonocarpin inhibited NorA pump in S. aureus 15) and MC-207,110 (phenylalanine arginine bnaphthylamide, PAbN) and its relatives potentiated some types of antimicrobials that are substrates of one of multidrug efflux pumps, MexAB-OprM of Pseudomonas aeruginosa [16][17][18][19][20][21] or AcrAB-TolC of Escherichia coli 22) and Enterobacter aerogenes. 23) Regarding to VRE, allicin, which potentiated activity of vancomycin against VRE, 24) and [10]gingerol and some detergents, such as sodium dodecyl sulfate (SDS) and Triton X-100, which potentiated some antimicrobials including aminoglycosides against enterococci 25) have been reported. During the course of our studies, we found that a crude extract from sage leaves reduced the MICs of aminoglycosides (potentiated the antimicrobial activity of aminoglycosides) against VRE.…”

The AcrAB-TolC Pump Is Involved in Macrolide Resistance but Not in Telithromycin Efflux inEnterobacter aerogenesandEscherichia coli

“…The MIC determinations were carried out with or without phenylalanine arginine ␤-naphthylamide (PA␤N) at various concentrations which have no antibacterial effect (4,10). Antibiotic uptake was determined as previously described (4,12,13).…”