Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening
Di Zhu, Sandra Johannsen, Tiziana Masini, Céline Simonin, Jörg Haupenthal, Boris A. Illarionov, Anastasia Andreas, Mahendra Awale, Robin Matthias Gierse, Tridia van der Laan, Ramon van der Vlag, Rita Nasti, Mael Poizat, Eric Buhler, Norbert Reiling, Rolf Müller, Markus J. Fischer, Jean‐Louis Reymond, Anna K. H. Hirsch · Chemical Science · 2022
. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.