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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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

Fingerprint

Virulence
Staphylococcus aureus
Anti-Bacterial Agents
Fluorescence Polarization
DNA
Staphylococcal Protein A
Pathogens
Transcription
Microbial Drug Resistance
Infection
Anisotropy
Demonstrations
Tuning
Genes
Fluorescence
Throughput
Molecules
5,5'-methylenedisalicylic acid
Proteins

ASJC Scopus subject areas

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

Cite this

Sun, F., Zhou, L., Zhao, B. C., Deng, X., Cho, H., Yi, C., ... 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

Targeting MgrA-mediated virulence regulation in Staphylococcus aureus. / Sun, Fei; Zhou, Lu; Zhao, Bing Chuan; Deng, Xin; Cho, Hoonsik; Yi, Chengqi; Jian, Xing; Song, Chun Xiao; Luan, Chi Hao; Bae, Taeok; Li, Zigang; He, Chuan.

In: Chemistry and Biology, Vol. 18, No. 8, 26.08.2011, p. 1032-1041.

Research output: Contribution to journalArticle

Sun, F, Zhou, L, Zhao, BC, Deng, X, Cho, H, Yi, C, Jian, X, Song, CX, Luan, CH, Bae, T, Li, Z & He, C 2011, 'Targeting MgrA-mediated virulence regulation in Staphylococcus aureus', Chemistry and Biology, vol. 18, no. 8, pp. 1032-1041. https://doi.org/10.1016/j.chembiol.2011.05.014
Sun, Fei ; Zhou, Lu ; Zhao, Bing Chuan ; Deng, Xin ; Cho, Hoonsik ; Yi, Chengqi ; Jian, Xing ; Song, Chun Xiao ; Luan, Chi Hao ; Bae, Taeok ; Li, Zigang ; He, Chuan. / Targeting MgrA-mediated virulence regulation in Staphylococcus aureus. In: Chemistry and Biology. 2011 ; Vol. 18, No. 8. pp. 1032-1041.
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