Antibacterial activity of 2-amino-4-hydroxypyrimidine-5-carboxylates and binding to Burkholderia pseudomallei 2-C-methyl-d-erythritol-2, 4-cyclodiphosphate synthase. Issue 20 (15th October 2019)

• Record Type: Journal Article
• Authors: Watkins, Sydney M.; Ghose, Debarati; Blain, Joy M.; Grote, Dakota L.; Luan, Chi-Hao; Clare, Michael; Meganathan, R.; Horn, James R.; Hagen, Timothy J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 20(2019)
• Publication Date: 2019-10-15
• Subjects: MEP pathway -- Burkholderia pseudomallei IspF -- Antibacterial activity -- STD-NMR -- Fluorescence-based thermal shift -- Kirby Bauer disk diffusion; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126660
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.