Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins

Yangyi Qiu , Shu Ting Chan , Lin Lin (1) , Tsun Lam Shek , Tsz Fung Tsang , Yufeng Zhang (2) , Margaret Ip , Paul Kay-Sheung Chan , Nicolas Blanchard (3) , Gilles Hanquet (4) , Zhong Zuo , Xiao Yang (5) , Cong Ma

1 Department of Mathematics [Berkeley]
2 HIT - Harbin Institute of Technology
3 LIMA - Laboratoire d'innovation moléculaire et applications
4 Laboratoire de Stéréochimie associé au CNRS
5 DECE

Discovery of antibiotics of a novel mode of action is highly required in the fierce battlefield with multi-drug resistant bacterial infections. Previously we have validated the protein-protein interaction between bacterial NusB and NusE proteins as an unprecedented antimicrobial target and reported the identification of a first-in-class inhibitor of bacterial ribosomal RNA synthesis with antimicrobial activities. In this paper, derivatives of the hit compound were rationally designed based on the pharmacophore model for chemical synthesis, followed by biological evaluations. Some of the derivatives demonstrated the improved antimicrobial activity with the minimum inhibitory concentration (MIC) at 1-2 g/mL against clinically significant bacterial pathogens. Time-kill kinetics, confocal microscope, ATP production, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells of a representative compound were also measured. This series of compounds were named "nusbiarylins" based on their target protein NusB and the biaryl structure and were expected to be further developed towards novel antimicrobial drug candidates in the near future.

Mots clés: bacterial transcription, protein-protein interaction, NusB, inhibitor, antimicrobial activity

Domaines: Chimie

Yangyi Qiu, Shu Ting Chan, Lin Lin, Tsun Lam Shek, Tsz Fung Tsang, et al.. Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins. Bioorganic Chemistry, 2019, 92, pp.103203. ⟨10.1016/j.bioorg.2019.103203⟩. ⟨hal-02323331⟩