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

Kiefer, Alexander F.
; 
Bousis, Spyridon
; 
Hamed, Mostafa M.
; 
Diamanti, Eleonora
; 
Haupenthal, Jörg
; 
Hirsch, Anna K.H.
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Issue Date
2022-07-14
Submitted date
2021-12-10
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Abstract
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. © 2022 American Chemical Society.
Citation
Kiefer 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.
Affiliation
a 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, Germany
Publisher
ACS/ American Chemical Society
Journal
Journal of Medicinal Chemistry
URI
http://hdl.handle.net/10033/623250
DOI
10.1021/acs.jmedchem.1c02114
PubMed ID
PubMed Central ID
Additional Links
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc9289886/
 https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02114#article_content-right
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Article
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Description
Series/Report no.
Volume 65, Issue 13
ISSN
00222623
EISSN
15204804
ISBN
ISMN
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Sponsors
Horizon 2020 Framework Programme, ERC starting grant 757913, Marie Skłodowska Curie grant agreement no. 665250
License
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
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Collections
publications of the research group drug design and optimization(HIPS]DDOP)