Potent and selective inhibitors of Staphylococcus epidermidis tryptophanyl-tRNA synthetase.
OBJECTIVE
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.
Wu
Yang
Y
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institute of Medical Microbiology and Institutes of Biomedical Sciences, Shanghai Medical School of Fudan University, Shanghai 200032, China.
Yu
Kunqian
K
Xu
Bin
B
Chen
Lili
L
Chen
Xianglong
X
Mao
Jialing
J
Danchin
Antoine
A
Shen
Xu
X
Qu
Di
D
Jiang
Hualiang
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D009391:Nephelometry and Turbidimetry; D011994:Recombinant Proteins / Q000737:chemistry; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D020349:Surface Plasmon Resonance; D014369:Tryptophan-tRNA Ligase / Q000037:antagonists & inhibitors*; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D003470:Culture Media; D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D014369:Tryptophan-tRNA Ligase