中科院上海藥物所藍(lán)樂夫課題組、蔣華良課題組與芝加哥大學(xué)何川教授課題組等合作，在金黃色葡萄球菌致病性及耐藥性的調(diào)節(jié)機(jī)制研究方面獲得新進(jìn)展,。研究論文于8月27日在線發(fā)表于美國科學(xué)院院刊PNAS (Proceedings of the National Academy of Sciences)。
金黃色葡萄球菌是一種重要的院內(nèi)感染細(xì)菌?？股氐氖褂靡约盀E用催生并富集了耐藥性菌株，耐甲氧西林的金黃色葡萄球菌(MRSA)的感染已成為最難解決的感染性疾患,。目前,，細(xì)菌毒力因子的表達(dá)調(diào)控正在成為病原細(xì)菌學(xué)研究的熱點(diǎn)，研究的深入將會給新型的抗細(xì)菌感染策略—抗毒力治療（Anti-virulence therapies）提供理論基礎(chǔ)和切入點(diǎn),。
研究發(fā)現(xiàn),，在金黃色葡萄球菌細(xì)菌毒力調(diào)節(jié)因子SarA蛋白家族中存在一種新的蛋白質(zhì)修飾—半胱氨酸的磷酸化，并由一對蛋白激酶-蛋白磷酸酯酶（Stk1-Stp1）所控制,。細(xì)菌的毒力調(diào)節(jié)因子SarA家族蛋白包括MgA,、SarA和SarZ等蛋白分子中半胱氨酸的磷酸化修飾引起了蛋白質(zhì)構(gòu)象的變化從而調(diào)節(jié)了金黃色葡萄球菌毒力因子的產(chǎn)生以及細(xì)菌對萬古霉素的抗性。靶向細(xì)菌細(xì)胞壁的抗生素如萬古霉素及頭孢曲松能夠抑制蛋白激酶Stk1的活性,。stp1基因的缺失導(dǎo)致了SarA/MgrA蛋白半胱氨酸的磷酸化水平的增加,、細(xì)菌產(chǎn)生毒力因子溶血素的能力減弱并使得細(xì)菌喪失在小鼠體內(nèi)的致病能力。這些研究為進(jìn)一步闡明金黃色葡萄球毒力因子表達(dá)的調(diào)控機(jī)制,，并為靶向蛋白磷酸酯酶Stp1,，開發(fā)高效特異的小分子抑制劑提供了理論基礎(chǔ)。
該研究工作得到了NIH、中國科學(xué)院百人計(jì)劃,、上海市科委,、863項(xiàng)目等基金的資助。（生物谷Bioon.com）
doi: 10.1073/pnas.1205952109
PMC:
PMID:
Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance
Fei Sun,Yue Ding, Quanjiang Ji, Zhongjie Liang, Xin Deng, Catherine C. L. Wong, Chengqi Yi, Liang Zhang, Sherrie Xie, Sophie Alvarez,Leslie M. Hicks,Cheng Luo, Hualiang Jiang, Lefu Lan and Chuan He
Protein posttranslational modifications (PTMs), particularly phosphorylation, dramatically expand the complexity of cellular regulatory networks. Although cysteine (Cys) in various proteins can be subject to multiple PTMs, its phosphorylation was previously considered a rare PTM with almost no regulatory role assigned. We report here that phosphorylation occurs to a reactive cysteine residue conserved in the staphylococcal accessary regulator A (SarA)/MarR family global transcriptional regulator A (MgrA) family of proteins, and is mediated by the eukaryotic-like kinase-phosphatase pair Stk1-Stp1 in Staphylococcus aureus. Cys-phosphorylation is crucial in regulating virulence determinant production and bacterial resistance to vancomycin. Cell wall-targeting antibiotics, such as vancomycin and ceftriaxone, inhibit the kinase activity of Stk1 and lead to decreased Cys-phosphorylation of SarA and MgrA. An in vivo mouse model of infection established that the absence of stp1, which results in elevated protein Cys-phosphorylation, significantly reduces staphylococcal virulence. Our data indicate that Cys-phosphorylation is a unique PTM that can play crucial roles in bacterial signaling and regulation.
