Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2-Epimerase as Potent Antibacterial Agents.
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 (compound12-ES-Na,that we named Epimerox) which blocked the growth of methicillin-resistantStaphylococcus 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 demonstratedin vivoefficacy 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.
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Yong
Y
Xu
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Benjamin
B
Brenning
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Adrianne
A
Clifford
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
David
D
Vollmer
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 84112 U.S.A (Current Address).
Jared
J
Bearss
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Carissa
C
Jones
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Virgil
V
McCarthy
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Chongtie
C
Shi
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Bradley
B
Wolfe
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Bhasker
B
Aavula
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Steve
S
Warner
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 84112 U.S.A (Current Address).
David J
DJ
Bearss
Astex Pharmaceuticals, Inc. (formerly known as SuperGen, Inc.), 4140 Dublin Boulevard, Suite 200, Dublin, CA 94568, U.S.A.
Michael V
MV
McCullar
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
Raymond
R
Schuch
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
Adam
A
Pelzek
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
Shyam S
SS
Bhaskaran
Laboratory of Structural Microbiology, The Rockefeller University, New York, NY, U.S.A.
C Erec
CE
Stebbins
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).
Allan R
AR
Goldberg
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY 10065, U.S.A.
Vincent A
VA
Fischetti
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 84112 U.S.A (Current Address).
Hariprasad
H
Vankayalapati
2-epimerase inhibitor; Gram-positive bacteria; antibacterial agent; antibiotic-resistant pathogens; stereo-isomers