Antibacterial activity of 2-amino-4-hydroxypyrimidine-5-carboxylates and binding to Burkholderia pseudomallei 2-C-methyl-d-erythritol-2,4-cyclodiphosphate synthase.

Autor: Watkins SM; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Ghose D; Department of Biological Sciences, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Blain JM; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Grote DL; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Luan CH; High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA., Clare M; Clare Associates LLC, Skokie, IL 60077, USA., Meganathan R; Department of Biological Sciences, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Horn JR; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA., Hagen TJ; Department of Chemistry and Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy., DeKalb, IL 60115, USA. Electronic address: thagen@niu.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Oct 15; Vol. 29 (20), pp. 126660. Date of Electronic Publication: 2019 Sep 03.
DOI: 10.1016/j.bmcl.2019.126660
Abstrakt: Enzymes in the methylerythritol phosphate pathway make attractive targets for antibacterial activity due to their importance in isoprenoid biosynthesis and the absence of the pathway in mammals. The fifth enzyme in the pathway, 2-C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), contains a catalytically important zinc ion in the active site. A series of de novo designed compounds containing a zinc binding group was synthesized and evaluated for antibacterial activity and interaction with IspF from Burkholderia pseudomallei, the causative agent of Whitmore's disease. The series demonstrated antibacterial activity as well as protein stabilization in fluorescence-based thermal shift assays. Finally, the binding of one compound to Burkholderia pseudomallei IspF was evaluated through group epitope mapping by saturation transfer difference NMR.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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