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

Jiqing Ye, Adrian Jun Chu, Lin Lin, Shu Ting Chan, Rachel Harper, Min Xiao, Irina Artsimovitch, Zhong Zuo, Cong Ma (Corresponding Author), Xiao Yang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number112671
JournalEuropean Journal of Medicinal Chemistry
Volume208
DOIs
Publication statusPublished - 15 Dec 2020

Keywords

  • Antimicrobial
  • Bacterial transcription
  • Inhibitor
  • RNA polymerase
  • Sigma factor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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