The mammalian efflux pump inhibitor Valspodar (PSC833) improves susceptibility of MRSA to antibiotics

Aim: Inhibitors of mammalian efflux pumps are known to potentiate antibiotic susceptibility in bacteria by inhibiting bacterial efflux pumps as well.  In this study the effect of 2nd generation mammalian efflux pump inhibitor PSC 833 on inhibition of efflux pumps in bacteria is tested. Methods : Disc diffusion assay for several antimicrobial agents such as cefoxitine, oxacillin, gentamicin, ticarcillin-clavulanate norfloxacin and ofloxacin was performed in the presence and absence of PSC 833 in culture media of Gram positive and Gram negative bacteria and zones of inhibition were compared. Accumulation of the universal efflux pump substrate ethidium bromide in test organisms was measured in the presence and absence of PSC 833. Results : PSC833 at concentrations starting from  62.5 µg/ml downwards till 3.12 µg/ml have significantly improved and restored  the sensitivity of S.aureus and MRSA towards all tested antibiotics and  resulted in highest accumulation of ethidium bromide within the cells, when compared to the other mammalian efflux inhibitors, verapamil and reserpine. However no effect was observed on the Gram negative P. aeruginosa and vancomycin resistant Enterococci (VRE). Conclusions : The results of this study indicate that PSC 833 represents a good candidate for use in combination with examined antibiotics to restore their clinical efficacy.