6YIZ

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with triazolo-pyridine inverse agonist A

6YIZ の概要

• エントリーDOI: 10.2210/pdb6yiz/pdb
• 分子名称: Transcriptional regulator MvfR, 7-oxidanylidene-8-[2-(4-sulfonaphthalen-1-yl)hydrazinyl]-8~{H}-naphthalene-1,3-disulfonic acid, ~{N}-[[1-(4-phenoxyphenyl)-1,2,3-triazol-4-yl]methyl]-2-(trifluoromethyl)pyridin-4-amine, ... (5 entities in total)
• 機能のキーワード: quorum sensing, lysr-type transcriptional regulator, pseudomonas, 2 quinolone signaling system, lttr, dna binding protein
• 由来する生物種: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53328.29

構造登録者

Schmelz, S.,Blankenfeldt, W. (登録日: 2020-04-01, 公開日: 2021-04-14, 最終更新日: 2024-01-24)

主引用文献

Schutz, C.,Ho, D.K.,Hamed, M.M.,Abdelsamie, A.S.,Rohrig, T.,Herr, C.,Kany, A.M.,Rox, K.,Schmelz, S.,Siebenburger, L.,Wirth, M.,Borger, C.,Yahiaoui, S.,Bals, R.,Scrima, A.,Blankenfeldt, W.,Horstmann, J.C.,Christmann, R.,Murgia, X.,Koch, M.,Berwanger, A.,Loretz, B.,Hirsch, A.K.H.,Hartmann, R.W.,Lehr, C.M.,Empting, M.
A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms.
Adv Sci, 8:e2004369-e2004369, 2021

PubMed 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 IC values as low as 200 and 11 × 10 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.

PubMed: 34165899
DOI: 10.1002/advs.202004369

実験手法

X-RAY DIFFRACTION (2.163 Å)