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

Sydney M. Watkins, Debarati Ghose, Joy M. Blain, Dakota L. Grote, Chi-Hao Luan, Michael Clare, R. Meganathan, James R. Horn, Timothy J. Hagen*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number126660
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number20
DOIs
StatePublished - Oct 15 2019

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Burkholderia pseudomallei
Zinc
Epitope Mapping
Mammals
Biosynthesis
Terpenes
Enzymes
Epitopes
Assays
Catalytic Domain
Stabilization
Hot Temperature
Fluorescence
Phosphates
Nuclear magnetic resonance
Ions
Proteins
methyl-D-erythritol 2,4-cyclodiphosphate
4-hydroxypyrimidine

Keywords

  • Antibacterial activity
  • Burkholderia pseudomallei IspF
  • Fluorescence-based thermal shift
  • Kirby Bauer disk diffusion
  • MEP pathway
  • STD-NMR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Watkins, Sydney M. ; Ghose, Debarati ; Blain, Joy M. ; Grote, Dakota L. ; Luan, Chi-Hao ; Clare, Michael ; Meganathan, R. ; Horn, James R. ; Hagen, Timothy J. / Antibacterial activity of 2-amino-4-hydroxypyrimidine-5-carboxylates and binding to Burkholderia pseudomallei 2-C-methyl-D-erythritol-2,4-cyclodiphosphate synthase. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 20.
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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.",
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Antibacterial activity of 2-amino-4-hydroxypyrimidine-5-carboxylates and binding to Burkholderia pseudomallei 2-C-methyl-D-erythritol-2,4-cyclodiphosphate synthase. / Watkins, Sydney M.; Ghose, Debarati; Blain, Joy M.; Grote, Dakota L.; Luan, Chi-Hao; Clare, Michael; Meganathan, R.; Horn, James R.; Hagen, Timothy J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 20, 126660, 15.10.2019.

Research output: Contribution to journalArticle

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AU - Ghose, Debarati

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AU - Grote, Dakota L.

AU - Luan, Chi-Hao

AU - Clare, Michael

AU - Meganathan, R.

AU - Horn, James R.

AU - Hagen, Timothy J.

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