Please use this identifier to cite or link to this item:
doi:10.22028/D291-36756
Title: | A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms |
Author(s): | Schütz, Christian Ho, Duy-Khiet Hamed, Mostafa Mohamed Abdelsamie, Ahmed Saad Röhrig, Teresa Herr, Christian Kany, Andreas Martin Rox, Katharina Schmelz, Stefan Siebenbürger, Lorenz Wirth, Marius Börger, Carsten Yahiaoui, Samir Bals, Robert Scrima, Andrea Blankenfeldt, Wulf Horstmann, Justus Constantin Christmann, Rebekka Murgia, Xabier Koch, Marcus Berwanger, Aylin Loretz, Brigitta Hirsch, Anna Katharina Herta Hartmann, Rolf Wolfgang Lehr, Claus-Michael Empting, Martin |
Language: | English |
Title: | Advanced Science |
Volume: | 8 |
Issue: | 12 |
Publisher/Platform: | Wiley |
Year of Publication: | 2021 |
Free key words: | biofilm inhibition nanoparticles Pseudomonas aeruginosa quorum sensing |
DDC notations: | 500 Science 610 Medicine and health |
Publikation type: | Journal Article |
Abstract: | Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development. |
DOI of the first publication: | 10.1002/advs.202004369 |
URL of the first publication: | https://onlinelibrary.wiley.com/doi/10.1002/advs.202004369 |
Link to this record: | urn:nbn:de:bsz:291--ds-367563 hdl:20.500.11880/33398 http://dx.doi.org/10.22028/D291-36756 |
ISSN: | 2198-3844 |
Date of registration: | 11-Jul-2022 |
Description of the related object: | Supporting Information |
Related object: | https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fadvs.202004369&file=advs2512-sup-0001-SuppMat.pdf |
Faculty: | M - Medizinische Fakultät NT - Naturwissenschaftlich- Technische Fakultät |
Department: | M - Innere Medizin NT - Pharmazie |
Professorship: | M - Prof. Dr. Robert Bals NT - Prof. Dr. Rolf W. Hartmann NT - Prof. Dr. Anna Hirsch NT - Prof. Dr. Claus-Michael Lehr |
Collections: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Files for this record:
File | Description | Size | Format | |
---|---|---|---|---|
Advanced Science - 2021 - Sch tz - A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas.pdf | 2,96 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License