Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis

Proj, Matic (author), Hrast, Martina (author), Bajc, Gregor (author), Frlan, Rok (author), Meden, Anže (author), Butala, Matej (author), Gobec, Stanislav (author)

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.

• Language: English
• Keywords: fragment-based drug discovery, hit triage, inhibitors, antibacterial agents
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 387-397
• Numbering: Vol. 38, no. 11
• PID: 20.500.12556/RUL-142961
• UDC: 615.4:54:615.015.8
• ISSN on article: 1475-6374
• DOI: 10.1080/14756366.2022.2149745
• COBISS.SI-ID: 132472579
• Publication date in RUL: 06.12.2022

Record is a part of a journal

• Title: Journal of enzyme inhibition and medicinal chemistry
• Shortened title: J. enzyme inhib. med. chem.
• Publisher: Taylor & Francis
• ISSN: 1475-6374
• COBISS.SI-ID: 22763225

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: zaviralci, antibakterijska sredstva, odkrivanje zdravil na osnovi fragmentov, triaža zadetkov, bakterijska rezistenca