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Published on: May 21, 2018
Discovery of MurA Inhibitors as Novel Antimicrobials through an Integrated Computational and Experimental Approach
Fangyuan Zhang1, Joshua Graham1, Tianhua Zhai1
1Department of Chemical and Biological Engineering, Villanova University, Villanova, PA 19085, USA.
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 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.
Insights
Researchers identified novel MurA inhibitors to combat bacterial infections. These compounds show potential as new antibiotics and alternatives for fosfomycin-resistant bacteria.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Computational Biology
Background:
- The bacterial cell wall is crucial for bacterial survival and integrity.
- The MurA enzyme is essential for bacterial cell wall synthesis and a potential antibiotic target.
- Fosfomycin is a clinical MurA inhibitor, but antibiotic resistance is a growing concern.
Purpose of the Study:
- To identify novel inhibitors of the MurA enzyme using virtual screening.
- To evaluate the antibacterial activity of identified compounds against Gram-positive and Gram-negative bacteria.
- To discover potential new antibiotics and alternatives for fosfomycin-resistant strains.
Main Methods:
- Utilized molecular docking-based virtual screening of over 1.4 million compounds.
- Experimentally tested 33 top-ranked compounds for antibacterial activity.
- Determined Minimum Inhibitory Concentration (MIC) values for effective compounds.
Main Results:
- Compound S17 (2-Amino-5-bromobenzimidazole) inhibited both *Listeria innocua* and *Escherichia coli* growth (MIC 0.5 mg/mL).
- Compound C1 (2-[4-(dimethylamino)benzylidene]-*n*-nitrohydrazinecarboximidamide) inhibited *L. innocua* growth (MIC 0.5 mg/mL).
- FDA-approved drugs S4 (albendazole) and S8 (diflunisal) inhibited *E. coli* growth (MIC 0.0625 mg/mL).
Conclusions:
- Identified several compounds with MurA inhibitory activity, demonstrating potential as novel antibiotics.
- The discovered inhibitors could serve as alternatives to fosfomycin, particularly against resistant bacterial strains.
- This study highlights the utility of virtual screening in discovering new antibacterial agents.
