The antibiotic dehydrophos is converted to a toxic pyruvate analog by peptide bond cleavage in Salmonella enterica

Benjamin T. Circello, Charles G. Miller, Jin Hee Lee, Wilfred A. Van Der Donk, William W. Metcalf

Research output: Contribution to journalArticlepeer-review

Abstract

The metabolic processing of dehydrophos, a broad-spectrum peptide antibiotic containing an unusual vinyl-phosphonate moiety, was examined by using a panel of Salmonella enterica mutants deficient in peptide uptake and catabolism. Dehydrophos bioactivity is lost in opp tpp double mutants, demonstrating a requirement for uptake via nonspecific oligopeptide permeases. Dehydrophos bioactivity is also abolished in a quadruple Salmonella mutant lacking the genes encoding peptidases A, B, D, and N, showing that hydrolysis of the peptide bond is required for activity. 31P nuclear magnetic resonance spectroscopy was used to assess the fate of dehydrophos following in vitro digestion of the antibiotic with purified PepA. The results suggest that the initial product of peptidase processing is 1-aminovinyl-phosphonate O-methyl ester. This phosphonate analogue of dehydroalanine undergoes rearrangement to the more stable imine, followed by spontaneous hydrolysis to yield O-methyl-acetylphosphonate, a structural analogue of pyruvate. This compound is a known inhibitor of pyruvate dehydrogenase and pyruvate oxidase and is probably the active species responsible for dehydrophos bioactivity.

Original languageEnglish (US)
Pages (from-to)3357-3362
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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