2. Academic Validation
  3. Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction

Benzyl and benzoyl benzoic acid inhibitors of bacterial RNA polymerase-sigma factor interaction

  • Eur J Med Chem. 2020 Dec 15;208:112671. doi: 10.1016/j.ejmech.2020.112671.
Jiqing Ye 1,  Adrian Jun Chu 2,  Lin Lin 2,  Shu Ting Chan 1,  Rachel Harper 2,  Min Xiao 3,  Irina Artsimovitch 4,  Zhong Zuo 3,  Cong Ma 5,  Xiao Yang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • 2 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
  • 3 School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 4 Department of Microbiology and the Center for RNA Biology, The Ohio State University, Columbus, OH, 43210, USA.
  • 5 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China. Electronic address: cong.ma@polyu.edu.hk.
  • 6 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. Electronic address: xiaoyang@cuhk.edu.hk.
PMID: 32920341 DOI: 10.1016/j.ejmech.2020.112671
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.

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