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

• DOI: 10.1111/cbdd.14005
• Publication Date: 2021-12-17T09:30:09Z
• Authors: Cécile Gateau; Guilherme D. Melo; Philippe Uriac; Olivier Tasseau; Jacques Renault; Arnaud Blondel; Nicolas Gouault; Frédéric Barbut; Paola Minoprio
• Keywords: 0301 basic medicine; Proline; Clostridioides difficile; enzyme inhibitors; structure-activity relationship; Anti-Bacterial Agents; 3. Good health; antibacterial; 03 medical and health sciences; 0302 clinical medicine; proline racemase; [CHIM] Chemical Sciences; [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology; Amino Acid Isomerases

AbstractProline 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.