First-in-class inhibitors targeting the interaction between bacterial RNA polymerase and sigma initiation factor affect the viability and toxin release of streptococcus pneumoniae

Jiqing Ye, Adrian Jun Chu, Lin Lin, Xiao Yang, Cong Ma

Research output: Journal article publicationJournal articleAcademic researchpeer-review

6 Citations (Scopus)

Abstract

Novel antimicrobial classes are in desperate need for clinical management of infections caused by increasingly prevalent multi-drug resistant pathogens. The protein-protein interaction between bacterial RNA polymerase (RNAP) and the housekeeping sigma initiation factor is essential to transcription and bacterial viability. It also presents a potential target for antimicrobial discovery, for which a hit compound (C3) was previously identified from a pharmacophore modelbased in silico screen. In this study, the hit compound was experimentally assessed with some rationally designed derivatives for the antimicrobial activities, in particular against Streptococcus pneumoniae and other pathogens. One compound, C3-005, shows dramatically improved activity against pneumococci compared to C3. C3-005 also attenuates S. pneumoniae toxin production more strongly than existing classes of antibiotics tested. Here we demonstrate a newly validated antimicrobial agent to address an overlooked target in the hit-to-lead process, which may pave the way for further antimicrobial development.

Original languageEnglish
Article number2902
JournalMolecules
Volume24
Issue number16
DOIs
Publication statusPublished - 9 Aug 2019

Keywords

  • Antimicrobial discovery
  • Inhibitor
  • RNA polymerase
  • Sigma factor
  • Transcription

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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