Identification and dynamic modeling of biomarkers for bacterial uptake and effect of sulfonamide antimicrobials

The effects of sulfathiazole (STA) on Escherichia coli   with glucose as a growth substrate was investigated to elucidate the effect-based reaction of sulfonamides in bacteria and to identify biomarkers for bacterial uptake and effect. The predominant metabolite was identified as pterine-sulfathiazole by LC-high resolution mass spectrometry. The formation of pterine-sulfathiazole per cell was constant and independent of the extracellular STA concentrations, as they exceeded the modeled half-saturation concentration KMS of 0.011 μmol L−1. The concentration of the dihydrofolic acid precursor para-aminobenzoic acid (pABA) increased with growth and with concentrations of the competitor STA. This increase was counteracted for higher STA concentrations by growth inhibition as verified by model simulation of pABA dynamics. The EC value for the inhibition of pABA increase was 6.9 ± 0.7 μmol L−1 STA, which is similar to that calculated from optical density dynamics indicating that pABA is a direct biomarker for the SA effect.

► Elucidation of the effect-based reaction of sulfonamides in bacteria.
► Identification of a biomarker for uptake and effect-based reaction of sulfonamides.
► Investigation of a biomarker for the bacterial growth inhibition by sulfonamides.
► Quantitative mechanistic modeling of biomarker dynamics using enzyme kinetics.
► Mechanistic quantitative linking of sulfonamide concentrations and effects.