title: 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 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.
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Bing-Chuan
authors.initials: BC
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.forename: Hoonsik
authors.initials: H
authors.lastname: Cho
authors.forename: Chengqi
authors.initials: C
authors.lastname: Yi
authors.forename: Xing
authors.initials: X
authors.lastname: Jian
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.forename: Taeok
authors.initials: T
authors.lastname: Bae
authors.forename: Zigang
authors.initials: Z
authors.lastname: Li
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013205:Staphylococcal Protein A / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012459:Salicylates; D013205:Staphylococcal Protein A; D014157:Transcription Factors; D037521:Virulence Factors; C026816:5,5'-methylenedisalicylic acid