Identification of inhibitors targeting the energy-coupling factor (ECF) transporters

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. The central role of vitamin transpo...

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Bibliographic Details
Published in:Communications biology 2023-11, Vol.6 (1), p.1182-1182, Article 1182
Main Authors: Diamanti, Eleonora, Souza, Paulo C. T., Setyawati, Inda, Bousis, Spyridon, Monjas, Leticia, Swier, Lotteke J.Y.M., Shams, Atanaz, Tsarenko, Aleksei, Stanek, Weronika K., Jäger, Manuel, Marrink, Siewert J., Slotboom, Dirk J., Hirsch, Anna K. H.
Format: Article
Language:English
Subjects:
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ATP-Binding Cassette Transporters - metabolism
Bacteria - metabolism
Bacterial Proteins - metabolism
Bacteriology
Biochemistry, Molecular Biology
Biology
Biomedical and Life Sciences
Chemical Sciences
Drug discovery
Humans
Life Sciences
Medicinal Chemistry
Membrane proteins
Microbiology and Parasitology
Molecular Dynamics Simulation
Structural Biology
Vitamins
Vitamins - metabolism
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Summary: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. The central role of vitamin transport in the metabolism of bacteria and absence from humans make the ECF transporters an attractive target for inhibition with selective chemical probes. Here, we report on the identification of a promising class of inhibitors of the ECF transporters. We used coarse-grained molecular dynamics simulations on Lactobacillus delbrueckii ECF-FolT2 and ECF-PanT to profile the binding mode and mechanism of inhibition of this novel chemotype. The results corroborate the postulated mechanism of transport and pave the way for further drug-discovery efforts. Virtual screening, biochemical assays, and coarse-grained simulations identify an inhibitor of energy-coupling factor transporters and its potential mechanism of action.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-023-05555-x