Targeting the Energy-Coupling Factor Transporters: A Novel Antibiotic Drug Target in <i> <i>Streptococcus pneumoniae</i> </i>
High Resolution Image Download MS PowerPoint Slide Energy-Coupling Factor (ECF) transporters are a hitherto underexplored target involved in the uptake of several micronutrients in bacteria and are absent in humans. Here, in Streptococcus pneumoniae, we demonstrate that the genes encoding ECF transporters are highly conserved and their expression is crucial for causing bacterial infection in both murine ( in vivo ) and human ( ex vivo ) infection models. Next, we demonstrated that the antimicrobial activity of our inhibitors against S. pneumoniae is related to the level of the ECF transporter expressed by the bacterium, confirming the target engagement of this chemical class in S. pneumoniae . The pharmacokinetic studies conducted revealed high peroral bioavailability for 4, which was also assessed in a murine neutropenic lung-infection model with S. pneumoniae, and observed a one log 10 reduction in bacterial load compared to vehicle. This work sets the stage for an innovative approach to combat S. pneumonia -derived infections by targeting the ECF transporters with the novel chemotype reported.
Authors
- Inda Setyawati (ORCID: https://orcid.org/0000-0001-9861-1755)
- Mostafa M. Hamed (ORCID: https://orcid.org/0000-0002-7374-6992)
- Eleonora Diamanti (ORCID: https://orcid.org/0000-0001-8392-5575)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Amelieke J. H. Cremers (ORCID: https://orcid.org/0000-0003-4704-4978)
- Matthias Witschel (ORCID: https://orcid.org/0000-0003-0537-5146)
- Rouven Becker (ORCID: https://orcid.org/0000-0002-6493-0413)
- Atanaz Shams (ORCID: https://orcid.org/0000-0002-7352-2876)
- Jörg Haupenthal (ORCID: https://orcid.org/0000-0003-3991-2800)
- Dirk Jan Slotboom (ORCID: https://orcid.org/0000-0002-5804-9689)
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
- Jennifer E. Herrmann (ORCID: https://orcid.org/0000-0003-3398-9938)
- Paddy Gibson
- Carole Baumann
- Lucie Zeimetz
- Ioulia Exapicheidou
- Yue Li
- Louise Martin
- Jan-Willem Veening
Institutions
- University of Groningen (NL)
- BASF (United States) (US)
- Institute of Chemical Biology and Fundamental Medicine (RU)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Robert Bosch (Germany) (DE)
- Saarland University (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03638
- Primary Topic
- Pneumonia and Respiratory Infections
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Zentrum für Infektionsforschung
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Rijksuniversiteit Groningen
- Universität des Saarlandes
- Université de Lausanne
- Helmholtz Association