OpenLB
Open Library of Bioscience
Advanced Search
Communications biology
11 20, 2023;6 (1): 1182.

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

Eleonora Diamanti, Paulo C T Souza, Inda Setyawati, Spyridon Bousis, Leticia Monjas, Lotteke J Y M Swier, Atanaz Shams, Aleksei Tsarenko, Weronika K Stanek, Manuel Jäger, Siewert J Marrink, Dirk J Slotboom, Anna K H Hirsch
Author Information
  1. Eleonora Diamanti: Helmholtz Institute for Pharmaceutical Research (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, D-66123, Saarbrücken, Germany.
  2. Paulo C T Souza: Molecular Microbiology and Structural Biochemistry, UMR 5086 CNRS and University of Lyon, Lyon, France. ORCID
  3. Inda Setyawati: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands. ORCID
  4. Spyridon Bousis: Helmholtz Institute for Pharmaceutical Research (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, D-66123, Saarbrücken, Germany.
  5. Leticia Monjas: Department of Pharmacy, Saarland University, Campus Building E8.1, 66123, Saarbrücken, Germany.
  6. Lotteke J Y M Swier: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands.
  7. Atanaz Shams: Helmholtz Institute for Pharmaceutical Research (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, D-66123, Saarbrücken, Germany.
  8. Aleksei Tsarenko: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands.
  9. Weronika K Stanek: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands. ORCID
  10. Manuel Jäger: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, NL-9747, AG Groningen, the Netherlands.
  11. Siewert J Marrink: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands. ORCID
  12. Dirk J Slotboom: Biomolecular Sciences and Biotechnology Institute University of Groningen Nijenborgh 4, 9747AG, Groningen, The Netherlands. ORCID
  13. Anna K H Hirsch: Helmholtz Institute for Pharmaceutical Research (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, D-66123, Saarbrücken, Germany. Anna.Hirsch@helmholtz-hips.de. ORCID
PMID: 37985798 DOI: 10.1038/s42003-023-05555-x

Abstract

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.

References

  1. Nat Rev Microbiol. 2014 Feb;12(2):79-87 [PMID: 24362466]
  2. Signal Transduct Target Ther. 2020 Sep 23;5(1):213 [PMID: 32968059]
  3. FEMS Microbiol Rev. 2011 Jan;35(1):3-67 [PMID: 20497229]
  4. Sci Rep. 2013 Dec 20;3:3566 [PMID: 24356467]
  5. Cell Res. 2014 Mar;24(3):267-77 [PMID: 24366337]
  6. J Bacteriol. 2009 Jan;191(1):42-51 [PMID: 18931129]
  7. Nat Commun. 2020 Apr 9;11(1):1763 [PMID: 32273501]
  8. Nat Struct Mol Biol. 2011 Jun 26;18(7):755-60 [PMID: 21706007]
  9. Chembiochem. 2015 Mar 23;16(5):819-26 [PMID: 25676607]
  10. Nat Rev Drug Discov. 2016 Aug;15(8):533-50 [PMID: 27050677]
  11. J Med Chem. 2022 Jul 14;65(13):8869-8880 [PMID: 35709475]
  12. Nat Commun. 2016 Mar 30;7:11072 [PMID: 27026363]
  13. J Med Chem. 2010 Apr 8;53(7):2719-40 [PMID: 20131845]
  14. Front Mol Biosci. 2021 Mar 29;8:657222 [PMID: 33855050]
  15. Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18560-5 [PMID: 25512487]
  16. J Mol Graph. 1996 Feb;14(1):33-8, 27-8 [PMID: 8744570]
  17. Elife. 2018 May 29;7: [PMID: 29809140]
  18. Cell Res. 2017 May;27(5):675-687 [PMID: 28322252]
  19. Microbiol Mol Biol Rev. 2008 Jun;72(2):317-64, table of contents [PMID: 18535149]
  20. FEMS Microbiol Rev. 1990 Aug;6(4):429-46 [PMID: 2147378]
  21. J Bacteriol. 2008 Nov;190(22):7591-4 [PMID: 18776013]
  22. Gut Microbes. 2023 Jan-Dec;15(1):2154544 [PMID: 36511640]
  23. Nat Methods. 2021 Apr;18(4):382-388 [PMID: 33782607]
  24. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2534-9 [PMID: 23359690]
  25. Nature. 2013 May 9;497(7448):272-6 [PMID: 23584587]
  26. J Bacteriol. 2013 Sep;195(18):4105-11 [PMID: 23836870]
  27. Nat Commun. 2020 Jul 24;11(1):3714 [PMID: 32709852]
  28. Medchemcomm. 2017 Mar 31;8(5):1121-1130 [PMID: 30108823]
  29. Int J Mol Sci. 2022 Feb 27;23(5): [PMID: 35269783]
  30. Biochemistry. 2015 Aug 11;54(31):4763-6 [PMID: 26217920]
  31. Bioinformatics. 2012 Aug 1;28(15):2074-5 [PMID: 22628523]
  32. J Gen Physiol. 2014 Apr;143(4):419-35 [PMID: 24638992]
  33. Proc Natl Acad Sci U S A. 2021 Aug 24;118(34): [PMID: 34408021]
  34. Annu Rev Cell Biol. 1992;8:67-113 [PMID: 1282354]
  35. J Chem Theory Comput. 2014 Feb 11;10(2):676-90 [PMID: 26580045]
  36. Curr Opin Chem Biol. 2022 Aug;69:102169 [PMID: 35749929]
  37. J Chem Theory Comput. 2015 May 12;11(5):2144-55 [PMID: 26574417]
  38. Elife. 2020 Dec 22;9: [PMID: 33350937]
  39. QRB Discov. 2022 Oct 12;3:e19 [PMID: 37529288]
  40. J Med Chem. 2012 Nov 26;55(22):9763-72 [PMID: 23061697]

MeSH Term

Humans
Bacterial Proteins
ATP-Binding Cassette Transporters
Bacteria
Vitamins
Molecular Dynamics Simulation

Chemicals

Bacterial Proteins
ATP-Binding Cassette Transporters
Vitamins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 5

Word Cloud

Created with Highcharts 10.0.0ECFtransportersenergy-couplingfactorproteinsuptakebacteriavitamintransportinhibitioninhibitorsmechanismfamilytransmembraneinvolvedvitaminswiderangeInhibitionactivityreduceviabilitypathogensdependcentralrolemetabolismabsencehumansmakeattractivetargetselectivechemicalprobesreportidentificationpromisingclassusedcoarse-grainedmoleculardynamicssimulationsLactobacillusdelbrueckiiECF-FolT2ECF-PanTprofilebindingmodenovelchemotyperesultscorroboratepostulatedpavewaydrug-discoveryeffortsIdentificationtargeting

Similar Articles

Cited By (4)