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

08 December 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


energy-coupling factor transporter
transmembrane protein
antimicrobial agent
virtual screening
structure-based drug design
structure–activity relationship

Supplementary materials

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


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