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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 ?-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.

SUBMITTER: Sun F 

PROVIDER: S-EPMC3163066 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Targeting MgrA-mediated virulence regulation in Staphylococcus aureus.

Sun Fei F   Zhou Lu L   Zhao Bing-Chuan BC   Deng Xin X   Cho Hoonsik H   Yi Chengqi C   Jian Xing X   Song Chun-Xiao CX   Luan Chi-Hao CH   Bae Taeok T   Li Zigang Z   He Chuan C  

Chemistry & biology 20110801 8


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 block  ...[more]

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