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dc.contributor.authorKiefer, Alexander F.
dc.contributor.authorBousis, Spyridon
dc.contributor.authorHamed, Mostafa M.
dc.contributor.authorDiamanti, Eleonora
dc.contributor.authorHaupenthal, Jörg
dc.contributor.authorHirsch, Anna K.H.
dc.date.accessioned2022-10-05T08:40:03Z
dc.date.available2022-10-05T08:40:03Z
dc.date.issued2022-07-14
dc.date.submitted2021-12-10
dc.identifier.citationKiefer AF, Bousis S, Hamed MM, Diamanti E, Haupenthal J, Hirsch AKH. Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters. J Med Chem. 2022 Jul 14;65(13):8869-8880. doi: 10.1021/acs.jmedchem.1c02114. Epub 2022 Jun 16. PMID: 35709475; PMCID: PMC9289886.en_US
dc.identifier.issn00222623
dc.identifier.doi10.1021/acs.jmedchem.1c02114
dc.identifier.urihttp://hdl.handle.net/10033/623250
dc.description.abstractHere, 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. © 2022 American Chemical Society.en_US
dc.description.sponsorshipHorizon 2020 Framework Programme, ERC starting grant 757913, Marie Skłodowska Curie grant agreement no. 665250en_US
dc.publisherACS/ American Chemical Societyen_US
dc.relationhttp://cordis.europa.eu/projects/757913en_US
dc.relation.ispartofseriesVolume 65, Issue 13en_US
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/pmc9289886/en_US
dc.relation.urlhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02114#article_content-righten_US
dc.rightsopenAccessen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshBacterial Proteinsen_US
dc.subject.meshBiological Transporten_US
dc.subject.meshCell Membraneen_US
dc.subject.meshFolic Aciden_US
dc.subject.meshMembrane Proteinsen_US
dc.subject.meshmolecular model;en_US
dc.titleStructure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transportersen_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.eissn15204804
dc.contributor.departmenta Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8.1, Saarbrücken, 66123, Germany b Department of Pharmacy, Saarland University, Campus E8.1, Saarbrücken, 66123, Germany c Helmholtz International Lab for Anti-Infectives, Campus E8.1, Saarbrücken, 66123, Germanyen_US
dc.identifier.journalJournal of Medicinal Chemistryen_US
dc.identifier.eid2-s2.0-85134010866
dc.identifier.scopusidSCOPUS_ID:85134010866
dc.source.volume65
dc.source.issue13
dc.source.beginpage8869
dc.source.endpage8880
refterms.dateFOA2022-10-05T08:40:04Z
dc.source.journaltitleJournal of Medicinal Chemistry


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