Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis. (31st December 2023)

• Record Type: Journal Article
• Authors: Proj, Matic; Hrast, Martina; Bajc, Gregor; Frlan, Rok; Meden, Anže; Butala, Matej; Gobec, Stanislav
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Page Start: 387
• Page End: 397
• Publication Date: 2023-12-31
• Subjects: Fragment-based drug discovery -- hit triage -- inhibitors -- antibacterial agents; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2149745
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Bacterial resistance is an increasing threat to healthcare systems, highlighting the need for discovering new antibacterial agents. An established technique, fragment-based drug discovery, was used to target a bacterial enzyme Ddl involved in the biosynthesis of peptidoglycan. We assembled general and focused fragment libraries that were screened in a biochemical inhibition assay. Screening revealed a new fragment-hit inhibitor of DdlB with a Ki value of 20.7 ± 4.5 µM. Binding to the enzyme was confirmed by an orthogonal biophysical method, surface plasmon resonance, making the hit a promising starting point for fragment development. Graphical Abstract: UF0001