華東師大生命科學(xué)學(xué)院吳自榮教授指導(dǎo)的博士研究生賴玉平與美國(guó)國(guó)家衛(wèi)生研究所米歇爾·奧托博士合作,，研究發(fā)現(xiàn)了控制革蘭氏陽(yáng)性菌感應(yīng)抗菌肽的三原素感應(yīng)系統(tǒng)。該研究成果以賴玉平為并列第一作者發(fā)表于美國(guó)科學(xué)院院刊PNAS上,。日前,，權(quán)威的《自然微生物學(xué)》雜志將該成果評(píng)為微生物領(lǐng)域2007年上半年的突出研究成果,。
三原素感應(yīng)系統(tǒng)就像一把鑰匙，控制著細(xì)菌細(xì)胞膜表面抗抗菌肽基因（Dlt和mprF）的開(kāi)關(guān),。這項(xiàng)研究成果解答了為什么一些細(xì)菌能生存于人的表皮從而與人共生的機(jī)理,，同時(shí)為開(kāi)發(fā)新型抗菌藥物提供了新的靶點(diǎn)。
據(jù)介紹,，表皮葡萄球菌是人皮膚上的主要共生菌,，通常情況下不會(huì)引起人類疾病。但是一旦附著在一些人造器官上,，當(dāng)這些器官移植入人體后,，就會(huì)使病人產(chǎn)生許多并發(fā)癥。而這些表皮葡萄球菌很難被抗生素殺死,，但其機(jī)理尚不清楚,。
賴玉平利用基因芯片技術(shù)發(fā)現(xiàn)表皮葡萄球菌在被人抗菌肽防御素3刺激后，許多基因的表達(dá)發(fā)生改變,，其中最重要的一個(gè)是ABC轉(zhuǎn)運(yùn)子表達(dá)的上調(diào),。接著，她們又利用基因敲除技術(shù),，證明了三原素的調(diào)節(jié)子是感應(yīng)抗菌肽,、從而調(diào)節(jié)表皮葡萄球菌抗抗菌肽的獨(dú)特調(diào)節(jié)子，而這一調(diào)節(jié)子與目前所發(fā)現(xiàn)的革蘭氏陰性菌抗抗菌肽的二元素調(diào)節(jié)子完全不同,，是革蘭氏陽(yáng)性菌所特有的,。
專家表示，由于長(zhǎng)期抗生素的濫用,，導(dǎo)致許多細(xì)菌,，特別是致病菌產(chǎn)生了耐藥性，這已經(jīng)成為目前醫(yī)學(xué)界一個(gè)世界性難題,。研究致病菌的耐藥機(jī)制以及研發(fā)出新型抗菌藥物迫在眉睫,。美國(guó)國(guó)家衛(wèi)生研究所過(guò)敏與感染所所長(zhǎng)Anthony S.Fauci,M.D高度評(píng)價(jià)了賴玉平等人的此項(xiàng)研究成果，“這為解決抗生素耐藥性問(wèn)題,、設(shè)計(jì)新型抗菌藥物開(kāi)辟了新的道路,。”
原始出處:
Published online before print May 21, 2007, 10.1073/pnas.0702159104
PNAS | May 29, 2007 | vol. 104 | no. 22 | 9469-9474
Gram-positive three-component antimicrobial peptide-sensing system
Min Li*, Yuping Lai*,,, Amer E. Villaruz*, David J. Cha*, Daniel E. Sturdevant, and Michael Otto*,¶
*Laboratory of Human Bacterial Pathogenesis and Research and Technology Branch, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and School of Life Science, East China Normal University, Shanghai 200062, China
Edited by Emil C. Gotschlich, The Rockefeller University, New York, NY, and approved April 19, 2007 (received for review March 8, 2007)
To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human -defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Furthermore, our data indicate that a very short, extracellular loop with a high density of negative charges in the sensor protein is responsible for antimicrobial peptide binding and the observed specificity for cationic antimicrobial peptides. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development.
innate host defense | Staphylococcus epidermidis
