The Antibiotic Dehydrophos Is Converted to a Toxic Pyruvate Analog by Peptide Bond Cleavage in Salmonella enterica

Abstract

ABSTRACTThe metabolic processing of dehydrophos, a broad-spectrum peptide antibiotic containing an unusual vinyl-phosphonate moiety, was examined by using a panel ofSalmonella entericamutants deficient in peptide uptake and catabolism. Dehydrophos bioactivity is lost inopptppdouble mutants, demonstrating a requirement for uptake via nonspecific oligopeptide permeases. Dehydrophos bioactivity is also abolished in a quadrupleSalmonellamutant 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 followingin vitrodigestion of the antibiotic with purified PepA. The results suggest that the initial product of peptidase processing is 1-aminovinyl-phosphonateO-methyl ester. This phosphonate analogue of dehydroalanine undergoes rearrangement to the more stable imine, followed by spontaneous hydrolysis to yieldO-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.