IN-VITRO AND IN-VIVO SYNERGISM BETWEEN VALSPODAR (PSC833) AND ANTIBIOTICS AGAINST STAPHYLOCOCCUS AUREUS STRAINS

Here, we report the in-vitro and in-vivo effects of Valspodar (PSC833), a second-generation mammalian efflux pump inhibitor on the susceptibility of methicillin-resistant and methicillin-sensitive Staphylo-coccus aureus (MRSA and MSSA) towards two antibiotics, Oxacillin (OX) and Cefoxitin (FOX). Checkerboard microdilution assays revealed various degrees of strain-dependent synergy demonstrated in the form of major reductions in antibiotic Minimum Inhibitory Concentrations (MIC) and Valspodar Minimum Effective Concentration (MEC). Fractional Inhibitory Concentration (FIC) for OX-PSC833 tested against MRSA and MSSA were 0.125 and 0.048, respectively, and for FOX-PSC833 was 0.5 for the MSSA. In-vivo studies showed that using a combination of an antibiotic and Valspodar to treat bacteremia induced by the different strains of S. aureus in a mouse model did not achieve complete killing of the MRSA strains, but resulted in a significant reduction in bacterial counts. MEC of PSC833 achieving synergy with antibiotics was as low as 5.2 µg/ml. Valspodar is a good candidate for antibiotic combination therapy at concentrations that are considered safe for human application.