期刊
CHEMISTRY & BIOLOGY
卷 18, 期 8, 页码 1032-1041出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2011.05.014
关键词
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资金
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases [AI074658]
- Burroughs Wellcome Fund
- Chicago Community Trust
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 a-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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