Conception de nouveaux inhibiteurs de la N-acétylglucosamine-3-oenolpyruvyltransferase par criblage virtuel et applications sur certaines bactéries pathogènes.

Abstract

The enzyme UDP-N-acetylglucosamine enolpyruvyl transferase or MurA is an attractive target to develop new antibacterial agents; it catalyzes the first step of peptidoglycan biosynthesis of the bacterial wall. In this study, we were interested in the inhibition of this enzyme by a computational approach, virtual screening, followed by an in vitro test of the best molecules with high affinities for the enzyme on four pathogenic bacteria: Escherichia coli ATCC25922, Bacillus subtilis ATCC6633, Staphylococcus aureus ATCC25923, and Methicillin resistant Staphylococcus aureus ATCC33591. We searched for new inhibitors of MurA among the analogues of its substrates and its inhibitors mentioned in the PDB and in the literature and also from new structures using different libraries of chemical compounds, ZINC database, PubChem, and French national chemical library. After this in silico study, we selected from the best results seven molecules whose inhibitory activity was tested by the disk diffusion method, followed for some of them by the dilution method. As a result, we identified four MurA inhibitors with antibacterial activity: a fosfomycin analogue CID21680357 which acted on all tested Gram (-) and Gram (+) strains: E. coli, B. subtilis, S. aureus, and S. aureus methicillin resistant (MRSA), and three other new structures: AB-00005001, ZINC04658565 and ZINC901335 which were only active against tested Gram (+) bacteria. These molecules can be a starting point for developing new antibacterial agents in further work.