Targeting MgrA-Mediated Virulence Regulation in Staphylococcus aureus

SummaryIncreasing 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.

► A high-throughput screen identified compounds targeting virulence regulation in S. aureus
► A small molecule MDSA efficiently disrupts the DNA binding of MgrA
► MDSA represses the transcriptional expression of virulence factors hla and spa
► MDSA attenuates the infectivity of S. aureus in the mouse model