Irreversible inhibitors of the proline racemase (PRAC) unveil innovative mechanism of action as antibacterial against Clostridioides difficile - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Chemical Biology and Drug Design Année : 2022

Irreversible inhibitors of the proline racemase (PRAC) unveil innovative mechanism of action as antibacterial against Clostridioides difficile

Résumé

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.
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hal-03504249 , version 1 (15-02-2023)

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Paternité - Pas d'utilisation commerciale

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Cécile Gateau, Guilherme Dias de Melo, Philippe Uriac, Olivier Tasseau, Jacques Renault, et al.. Irreversible inhibitors of the proline racemase (PRAC) unveil innovative mechanism of action as antibacterial against Clostridioides difficile. Chemical Biology and Drug Design, 2022, 99 (4), pp.513-526. ⟨10.1111/cbdd.14005⟩. ⟨hal-03504249⟩
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