A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms
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Authors
Schütz, ChristianHo, 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
Issue Date
2021-03-18
Metadata
Show full item recordAbstract
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.Citation
Adv. Sci. 2021, 2004369. https://doi.org/10.1002/advs.202004369.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
Wiley and Sons Inc.Journal
Advanced ScienceType
ArticleLanguage
enISSN
2198-3844EISSN
2198-3844Sponsors
H2020 Marie Skłodowska-Curie Actionsae974a485f413a2113503eed53cd6c53
10.1002/advs.202004369
Scopus Count
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- Creative Commons