Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired
infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial
therapy involves lower risks and costs compared to de novo development of novel
antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available
anthelmintic drugs. The FDA approved
drug niclosamide and the
veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of
niclosamide and
oxyclozanide were determined against
methicillin,
vancomycin,
linezolid or
daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for
niclosamide and
oxyclozanide respectively. A time-kill study demonstrated that
niclosamide is bacteriostatic, whereas
oxyclozanide is bactericidal. Interestingly,
oxyclozanide permeabilized the bacterial membrane but neither of the
anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes.
Oxyclozanide was non-toxic to HepG2 human liver
carcinoma cells within the range of its in vitro MICs but
niclosamide displayed toxicity even at low concentrations. These data show that the
salicylanilide anthelmintic drugs
niclosamide and
oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of
staphylococcal infections.