Targeting MgrA-mediated virulence regulation in Staphylococcus aureus

Fei Sun, Lu Zhou, Bing Chuan Zhao, Xin Deng, Hoonsik Cho, Chengqi Yi, Xing Jian, Chun Xiao Song, Chi Hao Luan, Taeok Bae, Zigang Li, Chuan He

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33 Scopus citations

Abstract

Increasing antibiotic resistance in human pathogens necessitates the development of new approaches against infections. Targeting virulence regulation at the transcriptional level represents a promising strategy yet to be explored. A global transcriptional regulator, MgrA in Staphylococcus aureus, was identified previously as a key virulence determinant. We have performed a fluorescence anisotropy (FA)-based high-throughput screen that identified 5, 5-methylenedisalicylic acid (MDSA), which blocks the DNA binding of MgrA. MDSA represses the expression of α-toxin that is up-regulated by MgrA and activates the transcription of protein A, a gene down-regulated by MgrA. MDSA alters bacterial antibiotic susceptibilities via an MgrA-dependent pathway. A mouse model of infection indicated that MDSA could attenuate S. aureus virulence. This work is a rare demonstration of utilizing small molecules to block protein-DNA interaction, thus tuning important biological regulation at the transcriptional level.

Original languageEnglish (US)
Pages (from-to)1032-1041
Number of pages10
JournalChemistry and Biology
Volume18
Issue number8
DOIs
StatePublished - Aug 26 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Sun, F., Zhou, L., Zhao, B. C., Deng, X., Cho, H., Yi, C., Jian, X., Song, C. X., Luan, C. H., Bae, T., Li, Z., & He, C. (2011). Targeting MgrA-mediated virulence regulation in Staphylococcus aureus. Chemistry and Biology, 18(8), 1032-1041. https://doi.org/10.1016/j.chembiol.2011.05.014