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Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach

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...

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Autores principales: Zhang, Fangyuan, Graham, Joshua, Zhai, Tianhua, Liu, Yanhong, Huang, Zuyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031695/
https://www.ncbi.nlm.nih.gov/pubmed/35453279
http://dx.doi.org/10.3390/antibiotics11040528
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author Zhang, Fangyuan
Graham, Joshua
Zhai, Tianhua
Liu, Yanhong
Huang, Zuyi
author_facet Zhang, Fangyuan
Graham, Joshua
Zhai, Tianhua
Liu, Yanhong
Huang, Zuyi
author_sort Zhang, Fangyuan
collection PubMed
description 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 approaches to identify potential MurA inhibitors from 1.412 million compounds from three databases. Thirty-three top compounds from virtual screening were experimentally tested in Listeria innocua (Gram-positive bacterium) and Escherichia coli (Gram-negative bacterium). Compound 2-Amino-5-bromobenzimidazole (S17) showed growth inhibition effect in both L. innocua and E. coli, with the same Minimum Inhibitory Concentration (MIC) value of 0.5 mg/mL. Compound 2-[4-(dimethylamino)benzylidene]-n-nitrohydrazinecarboximidamide (C1) had growth inhibition effect only in L. innocua, with a MIC value of 0.5 mg/mL. Two FDA-approved drugs, albendazole (S4) and diflunisal (S8), had a growth inhibition effect only in E. coli, with a MIC value of 0.0625 mg/mL. The identified MurA inhibitors could be potential novel antibiotics. Furthermore, they could be potential fosfomycin substitutes for the fosfomycin-resistant strains.
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spelling pubmed-90316952022-04-23 Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach Zhang, Fangyuan Graham, Joshua Zhai, Tianhua Liu, Yanhong Huang, Zuyi Antibiotics (Basel) Article 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 approaches to identify potential MurA inhibitors from 1.412 million compounds from three databases. Thirty-three top compounds from virtual screening were experimentally tested in Listeria innocua (Gram-positive bacterium) and Escherichia coli (Gram-negative bacterium). Compound 2-Amino-5-bromobenzimidazole (S17) showed growth inhibition effect in both L. innocua and E. coli, with the same Minimum Inhibitory Concentration (MIC) value of 0.5 mg/mL. Compound 2-[4-(dimethylamino)benzylidene]-n-nitrohydrazinecarboximidamide (C1) had growth inhibition effect only in L. innocua, with a MIC value of 0.5 mg/mL. Two FDA-approved drugs, albendazole (S4) and diflunisal (S8), had a growth inhibition effect only in E. coli, with a MIC value of 0.0625 mg/mL. The identified MurA inhibitors could be potential novel antibiotics. Furthermore, they could be potential fosfomycin substitutes for the fosfomycin-resistant strains. MDPI 2022-04-14 /pmc/articles/PMC9031695/ /pubmed/35453279 http://dx.doi.org/10.3390/antibiotics11040528 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Fangyuan
Graham, Joshua
Zhai, Tianhua
Liu, Yanhong
Huang, Zuyi
Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title_full Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title_fullStr Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title_full_unstemmed Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title_short Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
title_sort discovery of mura inhibitors as novel antimicrobials through an integrated computational and experimental approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031695/
https://www.ncbi.nlm.nih.gov/pubmed/35453279
http://dx.doi.org/10.3390/antibiotics11040528
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