abfR基因的缺失导致细菌的的凝集（A 和 B）及AbfR作用的分子机理（C）
表皮葡萄球菌是引起医院内感染的重要病原菌，其引起败血症、慢性前列腺炎的趋势与日俱增。表皮葡萄球菌因其形成生物膜从而增强了细菌对抗生素和宿主防御体系的抵抗能力，使得临床治疗十分棘手。在感染的过程中，表皮葡萄球菌必须克服人体免疫系统所产生的活性氧(ROS)的杀伤作用从而成功地定植、感染，而人们对表皮葡萄球菌是如何感受、应答氧化胁迫信号，了解的很少。
在中科院上海药物所杨财广研究员和蓝乐夫研究员的联合指导下,药物所博士研究生刘幸等最近在表皮葡萄球菌中发现了一个感受氧化胁迫信号的转录调节因子，并对其命名为AbfR。研究发现AbfR在氧化胁迫信号存在的情况下，形成分子间二硫键从而改变了蛋白质二聚体的构象，促使该蛋白对目的启动子的DNA结合减弱，从而激活谷胱甘肽过氧化物酶基因和2-酮酸脱氢酶基因的表达以增强细菌对氧化胁迫的杀伤的抵抗能力，并导致细菌的聚集和形成生物膜能力的降低。
本研究进一步阐明了表皮葡萄球菌感受氧化胁迫信号的分子机制，并为小分子干预表皮葡萄球菌生物膜的形成提供了潜在的新作用靶点，研究成果于2012年12月27日在线发表于The Journal of Biological Chemistry。
本研究工作是药物所“新类型抗菌物研究交叉与合作团队”所取得的又一项研究进展，得到了复旦大学和南京大学的合作支持。该研究团队不久前相继报道了金黄色葡萄球菌重要功能基因stp1（PNAS. 2012，109:15461-6）和潜在药物作用新靶点革兰氏阳性菌ClpP的作用分子机理（J Biol Chem. 2011，286:37590-601）。
该项工作得到国家自然科学基金委、中科院“百人计划”等资助，以及上海同步辐射光源的支持。(生物谷Bioon.com)
doi: 10.1074/jbc.M112.426205
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PMID:
Oxidation-sensing Regulator AbfR Regulates Oxidative Stress Responses, Bacterial Aggregation, and Biofilm Formation in Staphylococcus epidermidis
Xing Liu1, Xiaoxu Sun1, Youcong Wu2, Cen Xie1, Wenru Zhang1, Dan Wang3, Xiaoyan Chen1, Di Qu2, Jianhua Gan2, Hao Chen3, Hualiang Jiang1, Lefu Lan1 and Cai-Guang Yang1,*
Staphylococcus epidermidis is a notorious human pathogen that is the major cause of infections related to implanted medical devices. Although redox regulation involving reactive oxygen species (ROS) is now recognized as a critical component of bacterial signaling and regulation, the mechanism by which S. epidermidis senses and responds to oxidative stress remains largely unknown. Here, we report a new oxidation-sensing regulator, AbfR (Aggregation and Biofilm Formation Regulator) in S. epidermidis. An environment of oxidative stress mediated by hydrogen peroxide (H2O2) or cumene hydroperoxide (CHP) markedly up-regulates the expression of abfR gene. Similar to Pseudomonas aeruginosa OspR, AbfR is negatively auto-regulated and dissociates from promoter DNA in the presence of oxidants. In vivo and in vitro analyses indicate that Cys-13 and Cys-116 are the key functional residues to form an intersubunit disulphide bond upon oxidation in AbfR. We further show that deletion of abfR leads to a significant induction in H2O2 or CHP resistance, enhanced bacterial aggregation, and reduced biofilm formation. These effects are mediated by de-repression of SERP2195 and gpxA-2 that lie immediately downstream of the abfR gene in the same operon. Thus, oxidative stress likely acts as a signal to modulate S. epidermidis key virulence properties through AbfR.
