Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases

Journal of Enzyme Inhibition and Medicinal Chemistry

Martina Hrast¹  Veronika Škedelj¹  Matej Sova¹  Anamarija Zega¹  Stanislav Gobec¹  Kaja Rožman²  Delphine Patin³  Hélène Barreteau³  Iza Ogris⁴  Simona Golič Grdadolnik⁴ 

[1] Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia;Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia;Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA;Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, Gif-Sur-Yvette Cedex, Franc;Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Ljubljana, Slovenia;

关键词: Bacterial Mur (MurC–MurF) ligases;    published kinase inhibitor set;    steady-state kinetics measurements;    NMR studies;    antibacterial agents;   

DOI  :  10.1080/14756366.2019.1608981

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY