TY - JOUR
T1 - Targeting MgrA-Mediated Virulence Regulation in Staphylococcus aureus
AU - Sun, Fei
AU - Zhou, Lu
AU - Zhao, Bing-Chuan
AU - Deng, Xin
AU - Cho, Hoonsik
AU - Yi, Chengqi
AU - Jian, Xing
AU - Song, Chun-Xiao
AU - Luan, Chi-Hao
AU - Bae, Taeok
AU - Li, Zigang
AU - He, Chuan
PY - 2011/8/26
Y1 - 2011/8/26
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052158681&partnerID=8YFLogxK
UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-80052158681&origin=recordpage
U2 - 10.1016/j.chembiol.2011.05.014
DO - 10.1016/j.chembiol.2011.05.014
M3 - RGC 21 - Publication in refereed journal
C2 - 21867918
SN - 1074-5521
VL - 18
SP - 1032
EP - 1041
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 8
ER -
