Staphylococcus aureus accounts for 16% of hospital-acquired infections in the U.S. annually leading to $9.5 billion in healthcare costs. Strains of S. aureus have become increasingly resistant to several currently available antibiotics including methicillin, vancomycin and fluoroquinolones. As resistance and virulence continues to increase there is a concurrent decrease in the number of novel chemical scaffolds in the antibiotic drug discovery pipeline and according to the Infectious Disease Society of America the problem is only worsening. Utilizing a �drug repurposing� strategy our group has discovered the antihistamine terfenadine to possess previously unreported anti-staphylococcal properties. Given this information the mechanism of action was sought and a structure-activity relationship optimization campaign undertaken. The minimum inhibitory concentration of terfenadine analogs versus wild type and resistant strains of S. aureuswas improved up to 16-fold and a mechanism of action identified. This data suggests terfenadine analogs have promise as potential novel chemical scaffolds possessing antimicrobial activity.

Repurposing the antimistamine terfenadine as an antibiotic

248th National Meeting (2014)

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