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A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

  • 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.

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Document Type:Article
Author:Christian Schütz, Duy-Khiet HoORCiD, Mostafa Mohamed Hamed, Ahmed Saad Abdelsamie, Teresa RöhrigORCiD, Christian HerrORCiD, Andreas Martin KanyORCiD, Katharina RoxORCiD, Stefan SchmelzORCiD, Lorenz SiebenbürgerORCiD, Marius Wirth, Carsten BörgerORCiD, Samir YahiaouiORCiD, Robert BalsORCiD, Andrea ScrimaORCiD, Wulf BlankenfeldtORCiD, Justus Constantin HorstmannORCiD, Rebekka ChristmannORCiD, Xabier MurgiaORCiD, Marcus Koch, Aylin BerwangerORCiD, Brigitta LoretzORCiD, Anna Katharina H. HirschORCiD, Rolf W. Hartmann, Claus-Michael LehrORCiD, Martin EmptingORCiD
Parent Title (English):Advanced Science
First Page:2004369
Year of first Publication:2021
Release Date:2022/08/16
Tag:biofilm inhibition; nanoparticles; pseudomonas aeruginosa; quorum sensing
Impact:17.521 (2021)
Funding Information:H2020 Marie Skłodowska-Curie Actions (Grant Agreement No. 642028); Deutsches Zentrum für Infektionsforschung (Flexible Fund TTU09.908); Helmholtz Association (Helmholtz‐Validation Fonds HVF0054);
Scientific Units:Physical Analytics
DDC classes:500 Naturwissenschaften und Mathematik / 570 Biowissenschaften, Biologie
Open Access:Open Access
Signature:INM 2021/037
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International