Enamide Prodrugs of Acetyl Phosphonate Deoxy- d -xylulose-5-phosphate Synthase Inhibitors as Potent Antibacterial Agents

David Bartee, Sara Sanders, Paul D. Phillips, Mackenzie J. Harrison, Andrew T Koppisch, Caren L. Freel Meyers

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

To fight the growing threat of antibiotic resistance, new antibiotics are required that target essential bacterial processes other than protein, DNA/RNA, and cell wall synthesis, which constitute the majority of currently used antibiotics. 1-Deoxy-d-xylulose-5-phosphate (DXP) synthase is a vital enzyme in bacterial central metabolism, feeding into the de novo synthesis of thiamine diphosphate, pyridoxal phosphate, and essential isoprenoid precursors isopentenyl diphosphate and dimethylallyl diphosphate. While potent and selective inhibitors of DXP synthase in vitro activity have been discovered, their antibacterial activity is modest. To improve the antibacterial activity of selective alkyl acetylphosphonate (alkylAP) inhibitors of DXP synthase, we synthesized peptidic enamide prodrugs of alkylAPs inspired by the natural product dehydrophos, a prodrug of methyl acetylphosphonate. This prodrug strategy achieves dramatic increases in activity against Gram-negative pathogens for two alkylAPs, butyl acetylphosphonate and homopropargyl acetylphosphonate, decreasing minimum inhibitory concentrations against Escherichia coli by 33- and nearly 2000-fold, respectively. Antimicrobial studies and LC-MS/MS analysis of alkylAP-treated E. coli establish that the increased potency of prodrugs is due to increased accumulation of alkylAP inhibitors of DXP synthase via transport of the prodrug through the OppA peptide permease and subsequent amide hydrolysis. This work demonstrates the promise of targeting DXP synthase for the development of novel antibacterial agents.

Original languageEnglish (US)
Pages (from-to)406-417
Number of pages12
JournalACS Infectious Diseases
Volume5
Issue number3
DOIs
StatePublished - Mar 8 2019

Fingerprint

Organophosphonates
Prodrugs
Anti-Bacterial Agents
Bacterial Physiological Phenomena
Thiamine Pyrophosphate
Escherichia coli
Pyridoxal Phosphate
Terpenes
Microbial Sensitivity Tests
Microbial Drug Resistance
Biological Products
Amides
Cell Wall
Hydrolysis
phosphonoacetaldehyde
xylulose-5-phosphate
RNA
DNA
Enzymes
Proteins

Keywords

  • 1-deoxy- d -xylulose-5-phosphate synthase
  • bacterial central metabolism
  • bacterial metabolic branch point
  • dehydrophos
  • OppA peptide permease
  • phosphonate prodrug

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Enamide Prodrugs of Acetyl Phosphonate Deoxy- d -xylulose-5-phosphate Synthase Inhibitors as Potent Antibacterial Agents. / Bartee, David; Sanders, Sara; Phillips, Paul D.; Harrison, Mackenzie J.; Koppisch, Andrew T; Freel Meyers, Caren L.

In: ACS Infectious Diseases, Vol. 5, No. 3, 08.03.2019, p. 406-417.

Research output: Contribution to journalArticle

Bartee, David ; Sanders, Sara ; Phillips, Paul D. ; Harrison, Mackenzie J. ; Koppisch, Andrew T ; Freel Meyers, Caren L. / Enamide Prodrugs of Acetyl Phosphonate Deoxy- d -xylulose-5-phosphate Synthase Inhibitors as Potent Antibacterial Agents. In: ACS Infectious Diseases. 2019 ; Vol. 5, No. 3. pp. 406-417.
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