title: Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Rajamuthiah
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Beth Burgwyn
authors.initials: BB
authors.lastname: Fuchs
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Conery
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Elamparithi
authors.initials: E
authors.lastname: Jayamani
authors.affiliation: Division of Neurology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Bumsup
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D058492:Drug Repositioning; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects / Q000254:growth & development; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D056945:Hep G2 Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009534:Niclosamide / Q000494:pharmacology*; D010097:Oxyclozanide / Q000494:pharmacology*; D012756:Sheep
chemical_list: D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D010097:Oxyclozanide; D009534:Niclosamide