| Summary: | 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 <i>norA</i>-overexpressing <i>Staphylococcus aureus</i>, were evaluated for their ability to inhibit <i>norA</i>-mediated efflux in <i>Staphylococcus pseudintermedius</i> and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on <i>S. pseudintermedius</i> 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 <b>1</b>, dihydropyridine <b>6,</b> and 2-phenyl-4-carboxy-quinoline <b>8</b> were considered the best EPIs for <i>S. pseudintermedius</i>. Overall, most of the compounds, except for 2-arylquinoline compound <b>2</b>, were able to fully restore the susceptibility of <i>S. pseudintermedius</i> 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 <i>S. pseudintermedius</i> and lay the foundation for further studies on successful EPIs to treat staphylococcal infections.
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