From Bones to Bugs: Structure-Based Development of Raloxifene-Derived Pathoblockers That Inhibit Pyocyanin Production in <i>Pseudomonas aeruginosa</i>
The human pathogen <i>Pseudomonas aeruginosa</i> is particularly notorious for its multiple resistance mechanisms. A new concept for anti-infectives is the "pathoblocker" approach, which targets virulence factors to disarm rather than kill pathogens and thus attenuates the development of resistance. Based on the estrogen receptor modulator raloxifene, which had previously been identified as a potential biosynthesis inhibitor of the virulence factor pyocyanin <i>via in silico</i> screening, analogues have been developed as pathoblockers against <i>P. aeruginosa</i>. These compounds reduce the production of pyocyanin by binding to the phenazine biosynthesis enzyme PhzB. Structure-activity relationships (SAR) were explored using nano differential scanning fluorimetry, isothermal titration calorimetry, and 12 X-ray cocrystal structures. Compared to raloxifene, congener <b>20c</b> shows a 60-fold lower affinity for the human estrogen receptor with a 15-fold increase in pyocyanin inhibitory activity. The comprehensive structural information gathered in this study paves the way for the development of improved pathoblockers with increased potency and selectivity.
Authors
- Mikhail O. Lebedev (ORCID: https://orcid.org/0000-0001-7461-0977)
- Matthias Schiedel (ORCID: https://orcid.org/0000-0001-7365-3617)
- Wulf Blankenfeldt (ORCID: https://orcid.org/0000-0001-9886-9668)
- M. Handke (ORCID: https://orcid.org/0009-0007-7175-3615)
- Martin Empting (ORCID: https://orcid.org/0000-0002-0503-5830)
- Conrad Kunick (ORCID: https://orcid.org/0000-0001-7041-5322)
- Esther Zanin (ORCID: https://orcid.org/0000-0003-1450-8684)
- Mathias Müsken (ORCID: https://orcid.org/0000-0002-5624-1378)
- Christina Diederich (ORCID: https://orcid.org/0000-0002-6932-4754)
- Gabriela Krasteva‐Christ (ORCID: https://orcid.org/0000-0002-0113-521X)
- Jakob Pletz
- Rolf Breinbauer (ORCID: https://orcid.org/0000-0001-6009-7359)
- M. Thiemann (ORCID: https://orcid.org/0009-0009-1111-0671)
- Janosch Baumgarten
- Moritz Zimmermann (ORCID: https://orcid.org/0009-0005-8293-7255)
- Huilin Zhan
Institutions
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Graz University of Technology (AT)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Saarland University (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03065
- Citations
- 2
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- European Commission
- Studienstiftung des Deutschen Volkes
- Niedersächsisches Ministerium für Wissenschaft und Kultur