Discovery of MurA Inhibitors as novel antimicrobials through an integrated computational and experimental approach

Authors: ZHANG, FANGYUAN - Villanova University; GRAHAM, JOSHUA - Villanova University; ZHAI, TIANHUA - Villanova University; Liu, Yanhong; HUANG, ZUYI - Villanova University

Submitted to: Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/12/2022
Publication Date: 4/14/2022
Citation: Zhang, F., Graham, J., Zhai, T., Liu, Y., Huang, Z. 2022. Discovery of MurA Inhibitors as novel antimicrobials through an integrated computational and experimental approach. Antibiotics. Available online in Antibiotics 2022, 11, 528.. https://doi.org/10.3390/antibiotics11040528.
DOI: https://doi.org/10.3390/antibiotics11040528

Interpretive Summary: Antibiotics are used to treat bacterial infections. The enzyme known as MurA that is produced by bacteria is important for the formation of the cell wall of bacteria. For this reason, it could serve as a good drug target for antibiotics. The antibiotic known as fosfomycin is one such inhibitor of MurA, and it has been used for treatment of an illness known as listeriosis, caused by a bacterium known as Listeria monocytogenes. However, L. monocytogenes can develop resistance to fosfomycin, resulting in loss of effectiveness against the pathogen. In this study, a computational-based approach was developed to identify other potential inhibitors to the action of MurA. Two compounds that inhibited growth of bacteria known as Listeria innocua and Escherichia coli were identified through this approach. Thus, these two compounds have the potential to be developed as new antibiotics. Furthermore, they could be potential fosfomycin substitutes to treat infections caused by fosfomycin resistant bacterial strains. This work provides an innovative approach for identifying novel antibiotics to treat bacterial infections.

Technical Abstract: The bacterial cell wall is essential for protecting bacteria from the surrounding environment and maintaining the integrity of bacteria cells. The MurA enzyme, which is an essential enzyme involved in bacterial cell wall synthesis could be a good drug target for antibiotics. Although fosfomycin is used clinically as a MurA inhibitor, resistance to this antibiotic is a concern. Here we used molecular docking-based virtual screening to identify potential MurA inhibitors from 0.4 million compounds from three databases. Thirty-three compounds from the hit compounds selected from virtual screening were experimentally tested in Listeria innocua (gram-positive bacterium) and Escherichia coli (gram-negative bacterium). The compound 2-amino-5-bromobenzimidazole (S17) showed a growth inhibition effect in both L. innocua and E. coli, with the same Minimal Inhibition Concentration (MIC) value of 0.5mg/ml. The compound 2-[4-(dimethylamino) benzylidene]-N-nitrohydrazinecarboximidamide (C1) had a growth inhibition effect only in L. innocua, with a MIC value of 0.5mg/ml. Two FDA-approved drugs, Albendazole (S4) and Diflunisal (S8) had a growth inhibition effect only in E. coli, with a MIC value of 0.0625mg/ml. The identified MurA inhibitors could be potential novel antibiotics. Furthermore, they could be potential fosfomycin substitutes for fosfomycin resistant strains.