6yiz
Crystal structure of PqsR (MvfR) ligand-binding domain in complex with triazolo-pyridine inverse agonist A
Structural highlights
FunctionMVFR_PSEAE Transcription regulator that plays a critical role in virulence by positively regulating the expression of multiple quorum sensing (QS)-regulated virulence factors, genes involved in protein secretion, translation, response to oxidative stress and the phnAB operon (PubMed:11724939, PubMed:27678057, PubMed:17083468). At the stationary phase, negatively autoregulates its function through cleavage and translocation to the extracellular space (PubMed:11724939).[1] [2] [3] Publication Abstract from PubMedPseudomonas 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 x 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. A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms.,Schutz C, Ho DK, Hamed MM, Abdelsamie AS, Rohrig T, Herr C, Kany AM, Rox K, Schmelz S, Siebenburger L, Wirth M, Borger C, Yahiaoui S, Bals R, Scrima A, Blankenfeldt W, Horstmann JC, Christmann R, Murgia X, Koch M, Berwanger A, Loretz B, Hirsch AKH, Hartmann RW, Lehr CM, Empting M Adv Sci (Weinh). 2021 Jun;8(12):e2004369. doi: 10.1002/advs.202004369. Epub 2021 , Mar 18. PMID:34165899[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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