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Current Computer-Aided Drug Design

Author(s): Ilham Boulhissa*, Abdelouahab Chikhi, Abderrahmane Bensegueni, Mohammad A. Ghattas, El H. Mokrani, Sara Alrawashdeh and Dana E.E. Obaid

DOI: 10.2174/1573409916666200213124929

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

Page: [214 - 224] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Considering the 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 bacterial cell death. Fosfomycin is known as the natural inhibitor of MurA.

Objective: The study aimed to introduce 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 the Pub- Chem database was performed. Moreover, French National Chemical Library and ZINC database were also utilized to identify new structures different from fosfomycin. FlexX was the software used for this study. The antibacterial testing was divided into two methods: disk diffusion and broth dilution.

Results: A set of virtual hits was found to have better energy score than that of fosfomycin, seven of them were tested in vitro. In addition, the disk diffusion method explored four compounds that 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, namely CID-21680357, AB-00005001, ZINC04658565, and ZINC901335.

Keywords: MurA, antibacterial agents, fosfomycin, virtual screening, FlexX, in silico.

Graphical Abstract

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