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
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:
Link to this record: urn:nbn:de:bsz:291--ds-367563
ISSN: 2198-3844
Date of registration: 11-Jul-2022
Description of the related object: Supporting Information
Related object:
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

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