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Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) \u2013 a crucial transcriptional regulator serving major functions in PA virulence \u2013 can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry\u2010driven hit\u2010to\u2010lead optimization and in\u2010depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter\u2010gene with IC<jats:sub>50<\/jats:sub> values as low as 200 and 11\u00a0\u00d7 10<jats:sup>\u22129<\/jats:sup> <jats:sc>m<\/jats:sc>, 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\u2010tobramycin (Tob) combination against PA biofilms using a tailor\u2010made squalene\u2010derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32\u2010fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker\u2010mediated therapy against PA infections opening up avenues for preclinical development.<\/jats:p>","DOI":"10.1002\/advs.202004369","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T23:45:57Z","timestamp":1616111157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate <i>Pseudomonas aeruginosa<\/i> Biofilms"],"prefix":"10.1002","volume":"8","author":[{"given":"Christian","family":"Sch\u00fctz","sequence":"first","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS)\u2010Helmholtz Centre for Infection Research (HZI)  Campus E8.1 Saarbr\u00fccken 66123 Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig  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