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

doi:10.1016/j.chembiol.2011.05.014

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

^*Corresponding author for this work

CLP - High Throughput Analysis Lab (HTAL)

Research output: Contribution to journal › Article › peer-review

35 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 language	English (US)
Pages (from-to)	1032-1041
Number of pages	10
Journal	Chemistry and Biology
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.chembiol.2011.05.014
State	Published - Aug 26 2011

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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title = "Targeting MgrA-mediated virulence regulation in Staphylococcus aureus",

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.",

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

note = "Funding Information: We thank S. Chiang and other members of The National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Disease (NSRB) for technical assistance during high-throughput screening. We thank Drs. O. Schneewind and D. Missiakas at the University of Chicago for providing transposon mutants. This work was financially supported by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (grant AI074658 to C.H.) and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award (to C.H.). F.S. is a Scholar of the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust. ",

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AU - Yi, Chengqi

AU - Jian, Xing

AU - Song, Chun Xiao

AU - Luan, Chi Hao

AU - Bae, Taeok

AU - Li, Zigang

AU - He, Chuan

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N2 - 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.

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