Irreversible inhibitors of the proline racemase unveil innovative mechanism of action as antibacterial agents against Clostridioides difficile. (5th January 2022)

• Record Type: Journal Article
• Authors: Gateau, Cécile; Melo, Guilherme D.; Uriac, Philippe; Tasseau, Olivier; Renault, Jacques; Blondel, Arnaud; Gouault, Nicolas; Barbut, Frédéric; Minoprio, Paola
• Is Part Of: Chemical biology & drug design. Volume 99:Number 4(2022)
• Page Start: 513
• Page End: 526
• Publication Date: 2022-01-05
• Subjects: antibacterial -- Clostridioides difficile -- enzyme inhibitors -- proline racemase -- structure‐activity relationship; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.14005
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: 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 Cd PRAC 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 Tc PRAC and Cd PRAC enzymes to design new inhibitors of Cd PRAC. Starting from ( E ) 4‐oxopent‐2‐enoic acid Tc PRAC irreversible inhibitors, we synthesized 4‐aryl substituted analogs and evaluated their Cd PRAC 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. Abstract : ( E )‐4‐oxo‐4‐arylpent‐2‐enoic acids 1 –20 were designed and evaluated against Clostridium difficile . Some compounds revealed in vitro and in vivo promising activities on Cd PRAC.