Inhibition of Efflux Pumps by Using NorA Efflux Pump Inhibitors.

One promising approach in treating antibiotic-resistant bacteria is to "break" resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of -overexpressing , were evaluated for their ability to inhibit -mediated efflux in and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline , dihydropyridine and 2-phenyl-4-carboxy-quinoline were considered the best EPIs for . Overall, most of the compounds, except for 2-arylquinoline compound , were able to fully restore the susceptibility of to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for and lay the foundation for further studies on successful EPIs to treat staphylococcal infections.