Targeting DXP synthase in human pathogens

Enzyme inhibition and antimicrobial activity of butylacetylphosphonate

Jessica M. Smith, Nicole V. Warrington, Ryan J. Vierling, Misty L. Kuhn, Wayne F. Anderson, Andrew T Koppisch, Caren L. Freel Meyers

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The unique methylerythritol phosphate pathway for isoprenoid biosynthesis is essential in most bacterial pathogens. The first enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes a distinct thiamin diphosphate (ThDP)-dependent reaction to form DXP from D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate and represents a potential anti-infective drug target. We have previously demonstrated that the unnatural bisubstrate analog, butylacetylphosphonate (BAP), exhibits selective inhibition of Escherichia coli DXP synthase over mammalian ThDP-dependent enzymes. Here, we report the selective inhibition by BAP against recombinant DXP synthase homologs from Mycobacterium tuberculosis, Yersinia pestis and Salmonella enterica. We also demonstrate antimicrobial activity of BAP against both Gram-negative and Gram-positive strains (including E. coli, S. enterica and Bacillus anthracis), and several clinically isolated pathogens. Our results suggest a mechanism of action involving inhibition of DXP synthase and show that BAP acts synergistically with established antimicrobial agents, highlighting a potential strategy to combat emerging resistance in bacterial pathogens.

Original languageEnglish (US)
Pages (from-to)77-83
Number of pages7
JournalJournal of Antibiotics
Volume67
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Thiamine Pyrophosphate
Salmonella enterica
Enzymes
Polyisoprenyl Phosphates
Glyceraldehyde 3-Phosphate
Escherichia coli
Yersinia pestis
Bacillus anthracis
Anti-Infective Agents
Pyruvic Acid
Mycobacterium tuberculosis
deoxyxylulose-5-phosphate synthase
butylacetylphosphonate
Pharmaceutical Preparations
1-deoxylulose 5-phosphate

Keywords

  • DXP synthase
  • Isoprenoid biosynthesis
  • Selective inhibitor
  • Thiamin diphosphate

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Smith, J. M., Warrington, N. V., Vierling, R. J., Kuhn, M. L., Anderson, W. F., Koppisch, A. T., & Freel Meyers, C. L. (2014). Targeting DXP synthase in human pathogens: Enzyme inhibition and antimicrobial activity of butylacetylphosphonate. Journal of Antibiotics, 67(1), 77-83. https://doi.org/10.1038/ja.2013.105

Targeting DXP synthase in human pathogens : Enzyme inhibition and antimicrobial activity of butylacetylphosphonate. / Smith, Jessica M.; Warrington, Nicole V.; Vierling, Ryan J.; Kuhn, Misty L.; Anderson, Wayne F.; Koppisch, Andrew T; Freel Meyers, Caren L.

In: Journal of Antibiotics, Vol. 67, No. 1, 01.2014, p. 77-83.

Research output: Contribution to journalArticle

Smith, Jessica M. ; Warrington, Nicole V. ; Vierling, Ryan J. ; Kuhn, Misty L. ; Anderson, Wayne F. ; Koppisch, Andrew T ; Freel Meyers, Caren L. / Targeting DXP synthase in human pathogens : Enzyme inhibition and antimicrobial activity of butylacetylphosphonate. In: Journal of Antibiotics. 2014 ; Vol. 67, No. 1. pp. 77-83.
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