abfR基因的缺失導(dǎo)致細菌的的凝集（A 和 B）及AbfR作用的分子機理（C）
表皮葡萄球菌是引起醫(yī)院內(nèi)感染的重要病原菌，其引起敗血癥,、慢性前列腺炎的趨勢與日俱增,。表皮葡萄球菌因其形成生物膜從而增強了細菌對抗生素和宿主防御體系的抵抗能力，使得臨床治療十分棘手,。在感染的過程中,，表皮葡萄球菌必須克服人體免疫系統(tǒng)所產(chǎn)生的活性氧(ROS)的殺傷作用從而成功地定植、感染，而人們對表皮葡萄球菌是如何感受,、應(yīng)答氧化脅迫信號,，了解的很少。
在中科院上海藥物所楊財廣研究員和藍樂夫研究員的聯(lián)合指導(dǎo)下,藥物所博士研究生劉幸等最近在表皮葡萄球菌中發(fā)現(xiàn)了一個感受氧化脅迫信號的轉(zhuǎn)錄調(diào)節(jié)因子,，并對其命名為AbfR,。研究發(fā)現(xiàn)AbfR在氧化脅迫信號存在的情況下,，形成分子間二硫鍵從而改變了蛋白質(zhì)二聚體的構(gòu)象,，促使該蛋白對目的啟動子的DNA結(jié)合減弱，從而激活谷胱甘肽過氧化物酶基因和2-酮酸脫氫酶基因的表達以增強細菌對氧化脅迫的殺傷的抵抗能力,，并導(dǎo)致細菌的聚集和形成生物膜能力的降低,。
本研究進一步闡明了表皮葡萄球菌感受氧化脅迫信號的分子機制，并為小分子干預(yù)表皮葡萄球菌生物膜的形成提供了潛在的新作用靶點,，研究成果于2012年12月27日在線發(fā)表于The Journal of Biological Chemistry,。
本研究工作是藥物所“新類型抗菌物研究交叉與合作團隊”所取得的又一項研究進展，得到了復(fù)旦大學(xué)和南京大學(xué)的合作支持,。該研究團隊不久前相繼報道了金黃色葡萄球菌重要功能基因stp1（PNAS. 2012,，109:15461-6）和潛在藥物作用新靶點革蘭氏陽性菌ClpP的作用分子機理（J Biol Chem. 2011，286:37590-601）,。
該項工作得到國家自然科學(xué)基金委,、中科院“百人計劃”等資助，以及上海同步輻射光源的支持,。(生物谷Bioon.com)
doi: 10.1074/jbc.M112.426205
PMC:
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.
