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

Here, we report on
a potent class of substituted ureidothiophenes
targeting energy-coupling factor (ECF) transporters, an unexplored
target that is not addressed by any antibiotic in the market. Since
the ECF module is crucial for the vitamin transport mechanism, the
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 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.