In an attempt to find new antibiotics, novel ways of interfering with important biological functions should be explored, especially with those which are necessary or even irreplaceable for bacterial survival, growth, and virulence. The purpose of this review is to highlight B-type vitamin transporters from the energy-coupling factor (ECF) family, which are not present in humans, as potential antimicrobial targets. In addition, a druggability analysis of an ECF transporter for folic acid and sequence-conservation studies in seven prominent pathogens revealed new druggable pockets. Evaluation of the presence of de novo biosynthetic routes for the vitamins in question in the seven pathogens confirmed that this target class holds promise for the discovery of antimicrobial drugs with a new mechanism of action, possibly on a broad-spectrum level.
The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Their central role in the metabolism of bacteria and absence in humans make the ECF transporters a potential antibacterial target, which can be further investigated making use of a selective chemical probe. Here, we report on the virtual screening, design, synthesis, structure–activity relationships (SARs) and coarse-grained molecular dynamics simulations of the first class of inhibitors of the ECF transporters. We investigated the mechanism of action of this chemical class and profiled the best hit compounds regarding their pharmaceutical properties. The optimized hit has a minimum inhibitory concentration (MIC) value of 2 µg/mL against Streptococcus pneumoniae, which opens up the possibility to use this chemical class to investigate the role of the ECF transporters in health and disease.
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