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journal article·2023-02Open access

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

Mostafa M. Hamed, Ahmed S. Abdelsamie, Katharina Rox, Christian Schütz, Andreas M. Kany, Teresa Röhrig, Stefan Schmelz, Wulf Blankenfeldt, Alejandro Arce‐Rodriguez, José Manuel Borrero‐de Acuña, Dieter Jahn, Jessica Rademacher, Felix C. Ringshausen, Nina Cramer, Burkhard Tümmler, Anna K. H. Hirsch, Rolf W. Hartmann, Martin Empting

Advanced Science· Volume 10· Issue 5
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Bacterial biofilms and quorum sensing · Antibiotic Resistance in Bacteria · Antimicrobial Resistance in Staphylococcus

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

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