PqsR 反向激动剂的转化：从体外功效优化到体内原理验证,Advanced Science

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PqsR 反向激动剂的转化：从体外功效优化到体内原理验证
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-03 , DOI: 10.1002/advs.202204443
Mostafa M Hamed _{1,

2} , Ahmed S Abdelsamie _{1,

2,

3} , Katharina Rox _{2,

4} , Christian Schütz _{1,

2} , Andreas M Kany _{1,

2} , Teresa Röhrig _{1,

2} , Stefan Schmelz ₅ , Wulf Blankenfeldt _{5,

6} , Alejandro Arce-Rodriguez ₇ , José Manuel Borrero-de Acuña _{7,

8,

9} , Dieter Jahn _{7,

8} , Jessica Rademacher _{10,

11} , Felix C Ringshausen _{10,

11,

12} , Nina Cramer ₁₃ , Burkhard Tümmler _{11,

13} , Anna K H Hirsch _{1,

2,

14} , Rolf W Hartmann _{1,

2,

14} , Martin Empting _{1,

2,

14}

Affiliation

Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) Campus E8.1, 66123, Saarbrücken, Germany.
German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig Saarbrücken, 66123, Saarbrücken, Germany.
Department of Chemistry of Natural and Microbial Products, Institute of Pharmaceutical and Drug Industries Research, National Research Centre, El-Buhouth St., Dokki, Cairo, 12622, Egypt.
Department of Chemical Biology (CBIO), Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7 Braunschweig, 38124, Saarbrücken, Germany.
Department of Structure and Function of Proteins (SFPR), Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7 Braunschweig, 38124, Saarbrücken, Germany.
Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany.
Institute of Microbiology, Technische Universität Braunschweig, 38106, Braunschweig, Germany.
Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, 38106, Braunschweig, Germany.
Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Av. de la Reina Mercedes, no. 6, Sevilla, CP 41012, Spain.
Department for Respiratory Medicine, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), 30625, Hannover, Germany.
European Reference Network on Rare and Complex Respiratory Diseases (ERN- LUNG), Frankfurt, Germany.
Department for Pediatric Pneumology, Allergology and Neonatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Department of Pharmacy, Saarland University Campus E8.1, 66123, Saarbrücken, Germany.

铜绿假单胞菌(PA) 是一种机会性人类病原体，涉及范围广泛的危险感染。它对抗生素治疗产生了惊人的耐药性。因此，非常需要抑制致病性或与抗生素治疗协同作用的替代策略来更有效地对抗这些感染。一种有前途的方法是通过干扰细菌的群体感应 (QS) 系统来解除细菌的武装，该系统调节各种毒力因子的释放以及生物膜的形成。在此，这项工作报告了一类新的假单胞菌的合理设计、优化和深入分析喹诺酮信号受体 (PqsR) 反向激动剂。由此产生的领先化合物具有基于嘧啶的支架、高体外和体内疗效、良好的药代动力学以及清洁安全的药理学特征，为潜在的肺部和全身给药途径提供了基础。与 PqsR 复合的 X 射线晶体结构促进了进一步的结构引导先导优化。该化合物显示出有效的绿脓素抑制作用，与氨基糖苷类抗生素妥布霉素协同作用对抗 PA 生物膜，并且对一组来自支气管扩张患者的临床分离株具有活性。重要的是，这种体外效应转化为小鼠中性粒细胞减少性大腿感染模型的体内疗效，为辅助治疗方案提供了原理验证。

"点击查看英文标题和摘要"

Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof-of-Principle

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.

更新日期：2023-01-03

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