Investigation of New Inhibitors of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) by Virtual Screening with Antibacterial Assessment

Abstract

Background: View to its interesting role in the peptidoglycan biosynthesis pathway the enzyme UDP-N- acetylglucosamine enolpyruvyl transferase is an attractive target to develop new antibacterial agents, it catalyzes the first key step of this pathway and its inhibition leads to the bacterial cell death. Fosfomycin is known as the natural inhibitor of MurA. Objective: Call new inhibitors of MurA by virtual screening of different chemical compounds libraries, and test the best scored “virtual hits” against three pathogenic bacteria: Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. Methods: A Virtual screening of the structural analogues of fosfomycin downloaded from PubChem database was performed on one side and of the French National Chemical Library as well as using ZINC database to identify new structures different from fosfomycin on the other, FlexX was the software used for this study. The antibacterial testing was divided into methods: disk diffusion and broth dilution. Results: A set of virtual hits was found with better energy score than that of fosfomycin, seven between them were tested in vitro. Therefore, disk diffusion method explored four compounds exhibited antibacterial activity: CID-21680357 (fosfomycin analogue), AB-00005001, ZINC04658565, and ZINC901335. The testing was continued by broth dilution method for both compounds CID-21680357 and ZINC901335 to determine their minimum inhibitory concentrations, and ZINC901335 had the best value with 457µg/ml against Staphylococcus aureus. Conclusion: Four compounds were found and proven in silico and in vitro to have antibacterial activity: CID-21680357, AB-00005001, ZINC04658565, and ZINC901335.

Cell wall thickness and the molecular mechanism of heterogeneous vancomycin‐intermediateStaphylococcus aureus

“…The vraS/R system involves many genes related to cell wall synthesis, including UDP-N-acetylglucosamine enolpyruvyl transferase (murZ) and monofunctional glycosyltransferase (sgtB) (Kuroda et al 2003). murZ and sgtB are involved in the synthesis of cell wall monomer (Karinou et al 2019;Boulhissa et al 2020). The cell wall synthesis of S. aureus is a complex process, and the expression of various related genes is coordinated and inseparable.…”

“…2019; Boulhissa et al . 2020). The cell wall synthesis of S. aureus is a complex process, and the expression of various related genes is coordinated and inseparable.…”

Discovery of a Potential Molluscicide Based on Protein PcRoo in Gill Cilia of Pomacea canaliculata

“…It is a method to screen a small number of potential active compounds from a large number of candidate compounds, which needs to be based on discovered drug targets and relies on the performance of computer high-speed computing. In comparison to other methods in drug development, virtual screening has many advantages, for instance, it can greatly improve the efficiency of drug screening …”

“…In comparison to other methods in drug development, virtual screening has many advantages, for instance, it can greatly improve the efficiency of drug screening. 2 In the field of agriculture and pesticides, the discovery of new pesticides based on target proteins through virtual screening is gradually becoming the most active frontier topic. For example, Zhang et al selected insect chitinase as a template to conduct virtual screening in database SPECS.…”

Synthesis and inhibitory activity against MurA and MurZ enzymes of 4H-pyrano[2,3-d]pyrimidine–1H-1,2,3-triazole hybrid compounds having piperidine and morpholine rings

“…30 Recently, studies on the synthesis of compounds with inhibitory activity for MurA and MurZ enzymes mentioned above have been continued to be published. 4,[8][9][10]31,32 From the above brief reviews of the inhibitory activity of compounds having pyrimidine, 1,2,3-triazole rings as well as the sugar moiety, in this work we devised a design for the target hybrid molecule containing simultaneously 4H-pyrano [2,3-d]pyrimidine, 1H-1,2,3-triazole rings and saturated cyclic amines, including piperidine and morpholine, and it is hoped that they will exhibit activity against E. coli MurA as well as S. aureus enzymes MurA and MurZ.…”