Irreversible inhibitors of the proline racemase unveil innovative mechanism of action as antibacterial agents against Clostridioides difficile

Autor: Cécile Gateau, Guilherme D. Melo, Philippe Uriac, Olivier Tasseau, Jacques Renault, Arnaud Blondel, Nicolas Gouault, Frédéric Barbut, Paola Minoprio
Přispěvatelé: Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Processus infectieux à Trypanosomatidés - Trypanosomatids Infectious Processes, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Carnot Pasteur Microbes & Santé CARNOT/MS (ANR-16-CARN-0023-01 - non référencé dans AuréHAL), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Carnot Pasteur Microbes & Santé CARNOT/MS (ARN-16-CARN-0023-01 - non référencé dans AuréHAL)
Rok vydání: 2021
Předmět:
Zdroj: Chemical Biology and Drug Design
Chemical Biology and Drug Design, Wiley, 2021, ⟨10.1111/cbdd.14005⟩
Chemical Biology and Drug Design, 2022, 99 (4), pp.513-526. ⟨10.1111/cbdd.14005⟩
Chemical Biology and Drug Design, Wiley, 2022, ⟨10.1111/cbdd.14005⟩
ISSN: 1747-0285
1747-0277
Popis: International audience; Proline racemases (PRAC), catalyzing the l-proline and d-proline interconversion, are essential factors in eukaryotic pathogens such as Trypanosoma cruzi, Trypanosoma vivax, and Clostridioides difficile. If the discovery of irreversible inhibitors of T. cruzi PRAC (TcPRAC) led to innovative therapy of the Chagas disease, no inhibitors of CdPRAC have been discovered to date. However, C. difficile, due to an increased incidence in recent years, is considered as a major cause of health threat. In this work, we have taken into account the similarity between TcPRAC and CdPRAC enzymes to design new inhibitors of CdPRAC. Starting from (E) 4-oxopent-2-enoic acid TcPRAC irreversible inhibitors, we synthesized 4-aryl substituted analogs and evaluated their CdPRAC enzymatic inhibition against eleven strains of C. difficile. This study resulted in promising candidates and allowed for identification of (E)-4-(3-bromothiophen-2-yl)-4-oxobut-2-enoic acid 20 that was chosen for complementary in vivo studies and did not reveal in vivo toxicity.
Databáze: OpenAIRE
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