Sun Fei, Zhou Lu, Zhao Bing-Chuan, Deng Xin, Cho Hoonsik, Yi Chengqi, Jian Xing, Song Chun-Xiao, Luan Chi-Hao, Bae Taeok, Li Zigang, He Chuan
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
Chem Biol. 2011 Aug 26;18(8):1032-41. doi: 10.1016/j.chembiol.2011.05.014.
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.
人类病原体中抗生素耐药性不断增加，因此需要开发新的抗感染方法。在转录水平上靶向毒力调节是一种尚未探索的有前景的策略。金黄色葡萄球菌中的全局转录调节因子MgrA先前被鉴定为关键毒力决定因素。我们进行了基于荧光各向异性（FA）的高通量筛选，鉴定出5,5-亚甲基二水杨酸（MDSA），它可阻断MgrA与DNA的结合。MDSA可抑制由MgrA上调的α-毒素的表达，并激活由MgrA下调的蛋白A基因的转录。MDSA通过MgrA依赖性途径改变细菌对抗生素的敏感性。感染小鼠模型表明，MDSA可减弱金黄色葡萄球菌的毒力。这项工作是利用小分子阻断蛋白质-DNA相互作用从而在转录水平调节重要生物调控的罕见例证。
