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Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2-Epimerase as Potent Antibacterial Agents.
Xu, Yong; Brenning, Benjamin; Clifford, Adrianne; Vollmer, David; Bearss, Jared; Jones, Carissa; McCarthy, Virgil; Shi, Chongtie; Wolfe, Bradley; Aavula, Bhasker; Warner, Steve; Bearss, David J; McCullar, Michael V; Schuch, Raymond; Pelzek, Adam; Bhaskaran, Shyam S; Stebbins, C Erec; Goldberg, Allan R; Fischetti, Vincent A; Vankayalapati, Hariprasad.
Afiliación
  • Xu Y; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Brenning B; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Clifford A; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Vollmer D; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Bearss J; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A ; Division of Oncology of School of Medicine and Center for Investigational Therapeutics at Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT
  • Jones C; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • McCarthy V; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Shi C; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Wolfe B; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Aavula B; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Warner S; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Bearss DJ; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A ; Division of Oncology of School of Medicine and Center for Investigational Therapeutics at Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT
  • McCullar MV; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
  • Schuch R; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
  • Pelzek A; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
  • Bhaskaran SS; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
  • Stebbins CE; Laboratory of Structural Microbiology, The Rockefeller University, New York, NY, U.S.A.
  • Goldberg AR; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A ; Avacyn Pharmaceuticals, Inc., Teaneck, NJ, U.S.A. (Current Address).
  • Fischetti VA; Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
  • Vankayalapati H; Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A ; Division of Oncology of School of Medicine and Center for Investigational Therapeutics at Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT
ACS Med Chem Lett ; 4(12): 1142-1147, 2013 Dec 12.
Article en En | MEDLINE | ID: mdl-24443700
We present the discovery and optimization of a novel series of inhibitors of bacterial UDP-N-acetylglucosamine 2-epimerase (called 2-epimerase in this paper). Starting from virtual screening hits, the activity of various inhibitory molecules was optimized using a combination of structure-based and rational design approaches. We successfully designed and identified a 2-epimerase inhibitor (compound 12-ES-Na, that we named Epimerox) which blocked the growth of methicillin-resistant Staphylococcus aureus (MRSA) at 3.9 µM MIC (minimum inhibitory concentration) and showed potent broad-range activity against all Gram-positive bacteria that were tested. Additionally a microplate coupled assay was performed to further confirm that the 2-epimerase inhibition of Epimerox was through a target-specific mechanism. Furthermore, Epimerox demonstrated in vivo efficacy and had a pharmacokinetic profile that is consonant with it being developed into a promising new antibiotic agent for treatment of infections caused by Gram-positive bacteria.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos