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JAC Advance Access originally published online on July 2, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):502-509; doi:10.1093/jac/dkm229
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Potent and selective inhibitors of Staphylococcus epidermidis tryptophanyl-tRNA synthetase

Yang Wu1,{dagger}, Kunqian Yu2,{dagger}, Bin Xu1, Lili Chen2, Xianglong Chen3, Jialing Mao1, Antoine Danchin4, Xu Shen2, Di Qu1,* and Hualiang Jiang2

1 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 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 3 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China 4 Genetics of Bacterial Genomes, CNRS URA 2171, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France

Received 8 March 2007; returned 5 April 2007; revised 29 April 2007; accepted 29 May 2007

* Corresponding author. Fax: +86-21-54237603; E-mail: dqu{at}shmu.edu.cn

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.

Keywords: WRS , virtual screening , S. epidermidis , antibacterials

{dagger} Both authors contributed equally to this work.


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