根據(jù)美國PhysOrg網(wǎng)2012年1月4日的報(bào)道,，在一年內(nèi)被單核細(xì)胞增生性李斯特菌(Listeria monocytogenes)污染的甜瓜殺死30個(gè)人的歲月里，發(fā)現(xiàn)一種控制這種致命性細(xì)菌---可能還有其他的細(xì)菌---的化合物是一個(gè)好消息,。
美國康奈爾大學(xué)研究人員鑒定出一種稱作氟-苯基-苯乙烯磺酰胺(fluoro-phenyl-styrene-sulfonamide, FPSS)的化合物,，它對(duì)哺乳動(dòng)物無害,，但能夠當(dāng)場阻止李斯特菌。當(dāng)這種細(xì)菌經(jīng)歷快速變化的環(huán)境時(shí),，它會(huì)表達(dá)一些基因,。該化合物阻斷控制這些基因表達(dá)的機(jī)制。
這一發(fā)現(xiàn)發(fā)表在美國微生物協(xié)會(huì)2011年11月/12月那期的《mBio》期刊上,，為關(guān)于單核細(xì)胞增生性李斯特菌和其他細(xì)菌在大量快速變化的惡劣環(huán)境---人胃中發(fā)現(xiàn)的從波動(dòng)起伏的溫度到低pH值---下存活方面的基礎(chǔ)研究提供新的方向,。此外，人們極有可能最終將FPSS開發(fā)為一種對(duì)抗李斯特菌病(listeriosis)和其他細(xì)菌感染的藥物,。
康奈爾大學(xué)食品科學(xué)教授Kathryn Boor,，也是這篇論文的通信作者，他說,，“迄今為止,，這特別是我職業(yè)生涯最為激動(dòng)人心的研究。”Mary Elizabeth Palmer是論文的第一作者,。
食物來源的病原菌要能夠感染人,，它必須需能夠在快速變化的環(huán)境中存活，這些環(huán)境包括冰箱的冰冷條件,，烹調(diào)時(shí)的加熱條件，胃中高度酸性的條件以及小腸中滲透性和厭氧性條件,。根據(jù)該研究結(jié)果,，單核細(xì)胞增生性李斯特菌和某些其他細(xì)菌為了達(dá)到感染的目的就利用一種稱作σB的“應(yīng)激反應(yīng)選擇性σ因子(stress-responsive alternative sigma factor)”，該因子控制著150多種基因,，包括那些在宿主相關(guān)的應(yīng)激條件下有助于細(xì)菌毒力和存活的基因,，也包括一些讓細(xì)菌跨越胃腸道所必需的基因,。
Boor說，“我們是第一次描述單核細(xì)胞增生性李斯特菌σB因子,。它是這種細(xì)菌從一種無害的環(huán)境細(xì)菌轉(zhuǎn)變?yōu)橐环N人類致病菌的關(guān)鍵,。它允許這種單細(xì)胞致病菌在食物傳送過程中變化的環(huán)境造成殺傷下存活下來，隨后在人體完成這一轉(zhuǎn)變,。”
Boor和同事們一鑒定出σB因子,，他們就尋找可能阻止它發(fā)揮作用的化合物。通過對(duì)來自美國哈佛大學(xué)和麻省理工學(xué)院布羅德研究所(Broad Institute)多套文庫中的57000種自然和人工合成的小分子化合物進(jìn)行計(jì)算機(jī)自動(dòng)控制的篩選,，研究人員最初發(fā)現(xiàn)了41種抑制σB因子的小分子化合物,。在這些當(dāng)中，他們發(fā)現(xiàn)FPSS對(duì)哺乳細(xì)胞沒有毒性,，但能夠抑制單核細(xì)胞增生性李斯特菌和枯草芽孢桿菌(Bacillus subtilis)---一種土壤細(xì)菌和食品污染菌,，能夠在高熱環(huán)境中存活---的σB因子。
Boor補(bǔ)充道,，“在搜索對(duì)哺乳動(dòng)物無害但是又能阻止諸如李斯特菌之類的致病菌的抗生素過程中,，這是一種新出現(xiàn)的方法，很可能作為一種可行的治療方法來對(duì)抗其他微生物,。”
她說仍然需要更多的研究以便更好地理解FPSS如何控制σB因子活性以及這種化合物在諸如蠟樣芽胞桿菌(B. cereus, 導(dǎo)致食源性疾病),、金黃色葡萄球菌(Staphylococcus aureus, 導(dǎo)致痤瘡和肺炎)和炭疽桿菌(Bacillus anthracis, 導(dǎo)致炭疽熱)之類的致病菌中是否也影響同樣的機(jī)制。(生物谷：towersimper編譯)
doi:10.1128/mBio.00241-11
PMC:
PMID:22128349
The Listeria monocytogenes σB Regulon and Its Virulence-Associated Functions Are Inhibited by a Small Molecule
M. Elizabeth Palmer, Soraya Chaturongakul, Martin Wiedmann, and Kathryn J. Boor
The stress-responsive alternative sigma factor σB is conserved across diverse Gram-positive bacterial genera. In Listeria monocytogenes, σB regulates transcription of >150 genes, including genes contributing to virulence and to bacterial survival under host-associated stress conditions, such as those encountered in the human gastrointestinal lumen. An inhibitor of L. monocytogenes σB activity was identified by screening ~57,000 natural and synthesized small molecules using a high-throughput cell-based assay. The compound fluoro-phenyl-styrene-sulfonamide (FPSS) (IC50 = 3.5 µM) downregulated the majority of genes previously identified as members of the σB regulon in L. monocytogenes 10403S, thus generating a transcriptional profile comparable to that of a 10403S ΔsigB strain. Specifically, of the 208 genes downregulated by FPSS, 75% had been identified previously as positively regulated by σB. Downregulated genes included key virulence and stress response genes, such as inlA, inlB, bsh, hfq, opuC, and bilE. From a functional perspective, FPSS also inhibited L. monocytogenes invasion of human intestinal epithelial cells and bile salt hydrolase activity. The ability of FPSS to inhibit σB activity in both L. monocytogenes and Bacillus subtilis indicates its utility as a specific inhibitor of σB across multiple Gram-positive genera.
IMPORTANCE The σB transcription factor regulates expression of genes responsible for bacterial survival under changing environmental conditions and for virulence; therefore, this alternative sigma factor is important for transmission of L. monocytogenes and other Gram-positive bacteria. Regulation of σB activity is complex and tightly controlled, reflecting the key role of this factor in bacterial metabolism. We present multiple lines of evidence indicating that fluoro-phenyl-styrene-sulfonamide (FPSS) specifically inhibits activity of σB across Gram-positive bacterial genera, i.e., in both Listeria monocytogenes and Bacillus subtilis. Therefore, FPSS is an important new tool that will enable novel approaches for exploring complex regulatory networks in L. monocytogenes and other Gram-positive pathogens and for investigating small-molecule applications for controlling pathogen transmission.
