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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 publication




Journal article


Chem Biol

Publication Date





1032 - 1041


Animals, Anti-Bacterial Agents, Bacterial Proteins, Drug Resistance, Bacterial, Gene Expression Regulation, Bacterial, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Salicylates, Staphylococcal Infections, Staphylococcal Protein A, Staphylococcus aureus, Transcription Factors, Transcriptional Activation, Virulence, Virulence Factors