Repositioning of Disulfiram in Association with Vancomycin Against Enterococcus spp. MDR and XDR

Abstract

The identification of molecules that exhibit potent antibacterial activity and are capable of circumventing resistance mechanisms is an unmet need. The repositioning of approved drugs is considered an advantageous alternative in this case, and has gained prominence. In addition, drug synergism can reduce morbidity and mortality in the treatment of nosocomial infections caused by multi-drug resistant microorganisms (MDR). Whole cell growth inhibition assays were used to define the in vitro antibacterial activity of disulfiram against two standard American Type Culture Collection (ATCC) strains and 35 clinical isolates of vancomycin-resistant enterococci (VRE). The ability of disulfiram to synergize with vancomycin was determined by fractional inhibitory concentration index, preceded by the checkerboard test. The cytotoxicity of drugs alone and in combination was tested against Raw 264.7 cells. Disulfiram exhibited potent antibacterial activity against VRE (MIC 16-64 µg mL^-1). Results: Associated with vancomycin, disulfiram it had a reduction in MIC of up to 64 times, with values of 0.5-4 µg mL^-1. Vancomycin had a MIC of 128-1024 µg mL^-1; combined, reduced this value by up to 124 times (8 µg mL^-1), with synergy occurring against all strains. Disulfiram and vancomycin alone and in combination did not show cytotoxicity against the eukaryotic cell line. Based on these results, we suggest that the redirection of disulfiram may be promising in the treatment of infections caused by VRE, since it was able to potentiate the activity of vancomycin against the strains, being able to act as an adjuvant in cases of serious infections caused by Enterococcus.