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2. Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2-Epimerase as Potent Antibacterial Agents

Author

Steve Warner, C. Erec Stebbins, Bhasker Aavula, Adam J. Pelzek, Vincent A. Fischetti, Bhaskaran Shyam S, Michael V. McCullar, Chongtie Shi, Yong Xu, Jared Bearss, David J. Bearss, Allan R. Goldberg, Adrianne Clifford, Bradley Wolfe, Carissa Jones, David Vollmer, Hariprasad Vankayalapati, Virgil McCarthy, Raymond Schuch, and Benjamin Brenning

Subjects
Virtual screening, biology, business.industry, medicine.drug_class, Gram-positive bacteria, Organic Chemistry, Antibiotics, Rational design, Epimerox, biology.organism_classification, Biochemistry, Microbiology, chemistry.chemical_compound, Minimum inhibitory concentration, chemistry, In vivo, Drug Discovery, Medicine, business, Antibacterial agent
Abstract

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.

Published
2013

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