Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases. (1st January 2019)

• Record Type: Journal Article
• Authors: Hrast, Martina; Rožman, Kaja; Ogris, Iza; Škedelj, Veronika; Patin, Delphine; Sova, Matej; Barreteau, Hélène; Gobec, Stanislav; Grdadolnik, Simona Golič; Zega, Anamarija
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 1010
• Page End: 1017
• Publication Date: 2019-01-01
• Subjects: Bacterial Mur (MurC–MurF) ligases -- published kinase inhibitor set -- steady-state kinetics measurements -- NMR studies -- antibacterial agents; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1608981
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32–368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP.