Synthesis and evaluation of PSSRI-based inhibitors of Staphylococcus aureus multidrug efflux pumps

Phenylpiperidine selective serotonin reuptake inhibitors (PSSRIs) block the function of selected multidrug efflux pumps of Staphylococcus aureus. In this study PSSRI-based piperidine derivatives were prepared, evaluated for inhibition of two multidrug resistance (MDR)-conferring efflux pump systems, and tested for potentiation of antimicrobial activity of antibacterial efflux pump substrates. It is demonstrated that the 4-phenyl moiety of PSSRI-based efflux pump inhibitors (EPIs) is not an absolute structural requirement for inhibiting the NorA and MepA MDR efflux pumps. Potency of efflux inhibition is maintained or enhanced by replacing the aryloxymethyl substituent at position-3 of PSSRIs with arylalkene and arylthioether moieties. Novel 3-aryl piperidine EPIs that significantly increase substrate antibiotic activity against strains of S. aureus expressing NorA and MepA are described.