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http://hdl.handle.net/10397/89325
| Title: | Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction | Authors: | Ye, J Chu, AJ Lin, L Chan, ST Harper, R Xiao, M Artsimovitch, I Zuo, Z Ma, C Yang, X |
Issue Date: | 15-Dec-2020 | Source: | European journal of medicinal chemistry, 15 Dec. 2020, v. 208, 112671 | Abstract: | Transcription is an essential biological process in bacteria requiring a core enzyme, RNA polymerase (RNAP). Bacterial RNAP is catalytically active but requires sigma (σ) factors for transcription of natural DNA templates. σ factor binds to RNAP to form a holoenzyme which specifically recognizes a promoter, melts the DNA duplex, and commences RNA synthesis. Inhibiting the binding of σ to RNAP is expected to inhibit bacterial transcription and growth. We previously identified a triaryl hit compound that mimics σ at its major binding site of RNAP, thereby inhibiting the RNAP holoenzyme formation. In this study, we modified this scaffold to provide a series of benzyl and benzoyl benzoic acid derivatives possessing improved antimicrobial activity. A representative compound demonstrated excellent activity against Staphylococcus epidermidis with minimum inhibitory concentrations reduced to 0.5 μg/mL, matching that of vancomycin. The molecular mechanism of inhibition was confirmed using biochemical and cellular assays. Low cytotoxicity and metabolic stability of compounds demonstrated the potential for further studies. | Keywords: | Antimicrobial Bacterial transcription Inhibitor RNA polymerase Sigma factor |
Publisher: | Elsevier Masson | Journal: | European journal of medicinal chemistry | ISSN: | 0223-5234 | EISSN: | 1768-3254 | DOI: | 10.1016/j.ejmech.2020.112671 | Rights: | © 2020 Elsevier Masson SAS. All rights reserved. © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. The following publication Ye, J., Chu, A. J., Lin, L., Chan, S. T., Harper, R., Xiao, M., Artsimovitch, I., Zuo, Z., Ma, C., & Yang, X. (2020). Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction. European Journal of Medicinal Chemistry, 208, 112671 is available at https://dx.doi.org/10.1016/j.ejmech.2020.112671. |
| Appears in Collections: | Journal/Magazine Article |
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| Ye_Benzyl_Benzoyl_Benzoic.pdf | Pre-Published version | 2.02 MB | Adobe PDF | View/Open |
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