Potent and selective inhibitors of Staphylococcus epidermidis tryptophanyl-tRNA synthetase.

ABSTRACT

OBJECTIVES: The skin commensal and opportunistic pathogen Staphylococcus epidermidis is one of the leading causes of nosocomial and biofilm-associated infections, which urgently requires discovery of new antibiotics. We decided to find new leads that target the S. epidermidis tryptophanyl-tRNA synthetase (SeWRS), which is essential for translation. METHODS: We applied an approach combining structure-based discovery in silico with biochemical and biological experiments in vitro to screen SeWRS inhibitors. RESULTS: Three compounds have an inhibitory effect on enzymatic activities of SeWRS, of which two show low inhibition of the human tryptophanyl-tRNA synthetase. Binding of these compounds to bacterially expressed SeWRS was demonstrated by surface plasmon resonance technology. These three compounds can also obviously inhibit growth of S. epidermidis in vitro and displayed low cytotoxicity to mammalian cells. CONCLUSIONS: These compounds are good leads to develop new antibiotics.