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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
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
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
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