Biological and Medicinal Chemistry

Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

Authors

  • Alexander F. Kiefer Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research ,
  • Spyridon Bousis Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University ,
  • Mostafa M. Hamed Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research ,
  • Eleonora Diamanti Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Helmholtz International Lab for Anti-Infectives ,
  • Jörg Haupenthal Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research ,
  • Anna K. H. Hirsch Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & Helmholtz International Lab for Anti-Infectives

Abstract

Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target, which is not addressed by any antibiotic on the market. Since the ECF module is crucial for the vitamin transport mechanism, prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit compound yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects.

Content

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Supplementary material

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Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors targeting the Energy-Coupling Factor Transporters_SI
Table of Contents: Structure-Based Virtual Screening, ECF- inhibition assay, Chemical experimental procedures, Copies of NMR spectra & HPLC purities