2. Academic Validation
  3. Discovery of Antibacterials That Inhibit Bacterial RNA Polymerase Interactions with Sigma Factors

Discovery of Antibacterials That Inhibit Bacterial RNA Polymerase Interactions with Sigma Factors

  • J Med Chem. 2020 Jul 23;63(14):7695-7720. doi: 10.1021/acs.jmedchem.0c00520.
Jiqing Ye 1,  Adrian Jun Chu 2,  Rachel Harper 2,  Shu Ting Chan 1,  Tsun Lam Shek 3,  Yufeng Zhang 3,  Margaret Ip 2,  Mariya Sambir 4,  Irina Artsimovitch 4,  Zhong Zuo 3,  Xiao Yang 2,  Cong Ma 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, People's Republic of China.
  • 2 Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
  • 3 School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
  • 4 Department of Microbiology and the Center for RNA Biology, The Ohio State University, Columbus, Ohio 43210, United States.
PMID: 32633513 DOI: 10.1021/acs.jmedchem.0c00520
Abstract

Formation of a Bacterial RNA polymerase (RNAP) holoenzyme by a catalytic core RNAP and a sigma (σ) initiation factor is essential for Bacterial viability. As the primary binding site for the housekeeping σ factors, the RNAP clamp helix domain represents an attractive target for novel antimicrobial agent discovery. Previously, we designed a pharmacophore model based on the essential Amino acids of the clamp helix, such as R278, R281, and I291 (Escherichia coli numbering), and identified hit compounds with antimicrobial activity that interfered with the core-σ interactions. In this work, we rationally designed and synthesized a class of triaryl derivatives of one hit compound and succeeded in drastically improving the antimicrobial activity against Streptococcus pneumoniae, with the minimum inhibitory concentration reduced from 256 to 1 μg/mL. Additional characterization of antimicrobial activity, inhibition of transcription, in vitro pharmacological properties, and cytotoxicity of the optimized compounds demonstrated their potential for further development.

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