7P4U

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE

7P4U の概要

• エントリーDOI: 10.2210/pdb7p4u/pdb
• 分子名称: Transcriptional regulator MvfR, ~{N}-[[2-(3-chloranyl-4-propan-2-yloxy-phenyl)pyrimidin-5-yl]methyl]-2-(trifluoromethyl)pyridin-4-amine (3 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, gene regulation
• 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: 1
• 化学式量合計: 26122.90

構造登録者

Schmelz, S.,Blankenfeldt, W. (登録日: 2021-07-13, 公開日: 2022-07-27, 最終更新日: 2024-01-31)

主引用文献

Hamed, M.M.,Abdelsamie, A.S.,Rox, K.,Schutz, C.,Kany, A.M.,Rohrig, T.,Schmelz, S.,Blankenfeldt, W.,Arce-Rodriguez, A.,Borrero-de Acuna, J.M.,Jahn, D.,Rademacher, J.,Ringshausen, F.C.,Cramer, N.,Tummler, B.,Hirsch, A.K.H.,Hartmann, R.W.,Empting, M.
Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof-of-Principle.
Adv Sci, 10:e2204443-e2204443, 2023

PubMed Abstract: Pseudomonas aeruginosa (PA) is an opportunistic human pathogen, which is involved in a wide range of dangerous infections. It develops alarming resistances toward antibiotic treatment. Therefore, alternative strategies, which suppress pathogenicity or synergize with antibiotic treatments are in great need to combat these infections more effectively. One promising approach is to disarm the bacteria by interfering with their quorum sensing (QS) system, which regulates the release of various virulence factors as well as biofilm formation. Herein, this work reports the rational design, optimization, and in-depth profiling of a new class of Pseudomonas quinolone signaling receptor (PqsR) inverse agonists. The resulting frontrunner compound features a pyrimidine-based scaffold, high in vitro and in vivo efficacy, favorable pharmacokinetics as well as clean safety pharmacology characteristics, which provide the basis for potential pulmonary as well as systemic routes of administration. An X-ray crystal structure in complex with PqsR facilitated further structure-guided lead optimization. The compound demonstrates potent pyocyanin suppression, synergizes with aminoglycoside antibiotic tobramycin against PA biofilms, and is active against a panel of clinical isolates from bronchiectasis patients. Importantly, this in vitro effect translated into in vivo efficacy in a neutropenic thigh infection model in mice providing a proof-of-principle for adjunctive treatment scenarios.

PubMed: 36596691
DOI: 10.1002/advs.202204443

実験手法

X-RAY DIFFRACTION (2.74 Å)