抗击MRSA等病原体新法：让RNA再循环系统出岔
http://news.dxy.cn/bbs/topic/19414002 抗击MRSA等病原体新法：让RNA再循环系统出岔译者：Docofsoul
《每日科学》2011年2月12日报道 —— 科学家已发现抗击危险病原体的新方式，使日益升级的人类与细菌之间的战争向人类最终赢得胜利的方向又推进了一步。
http://i.0dxy.cn/upload/2011/02/16/34398051.jpg
放大倍数为9560的扫描电子显微照片（SEM）显示耐甲氧西林金黄色葡萄球菌即MRSA为数众多的丛落。（照片来源：CDC/Janice Haney Carr)
在线发表于《PloS病原体》的一篇论文证实：通过阻挠细菌的RNA降解（对其繁殖至关重要的“家务劳动”过程）能力，科学家成功遏制了实验室与受感染小鼠中耐甲氧西林金黄色葡萄球菌即MRSA的活动。
该研究小组由罗彻斯特大学医学中心的一位微生物学家率队，目前正在开发比本论文所讨论的化合物效力更为强大的密切相关的化合物。
新的方法在抗击大多数毒力最强的MRSA菌株、抗击最严重类型的MRSA感染方面展现了希望，使抗生素能够渗透与生物膜紧密融合的细菌。
罗彻斯特大学医学中心微生物学与免疫学助理教授Paul Dunman（此前在内布拉斯加大学任教）说：“这一方法是向世界上最危险的细菌发动全新攻势的方法。我们希望本研究为开发全新一类抗菌素打开大门。”
本研究小组也包括来自内布拉斯加大学、阿肯色大学、范德比尔特大学与北德州大学健康科学中心的科学家。
MRSA感染属于已知最为致命的感染之一。仅在美国该超级病菌每年就导致五十万人住院、一万九千人死亡，比艾滋病导致的死亡人数还要高。在社区或医院都可能感染该病菌。
MRSA与其它危险的微生物之所以如此致命，主要是因为它们有能力快速适应变化中的环境。细菌适应技能取决于其持续产生新的RNA分子的能力。RNA携带有关键信息，告诉细胞应该生产什么样的蛋白与具体的生产量。
这项新的研究集中于属于该过程一部分的关键的细胞学步骤：RNA降解。当一个RNA分子不再被需要时，就会被沉默与分解，其元件被回收放入原料池，以供细胞建立其它所需的RNA分子。
Dunman说：“对细菌而言，RNA降解是关键。细胞快速复制、对环境变化作出极快的响应。在少于三分钟内，一个新的RNA转录即告完成；蛋白被生产出来了，于是RNA被降解，作为原料供制造其它RNA分子。”
Dunman的研究小组发现，诸如RnpA这种分子在降解过程中起到了核心作用。在明确RnpA的活动意义后，该小组测试了超过二万九千种化合物以寻找抑制其活动的合适人选。他们找到了一种叫做RNAP1000的小分子；该小分子会让MRSA几乎处于静止状态。
向细菌的RNA再循环系统扔进一种破坏性因素（比如说丢进了一个“扳手”）就可能以多种方式损害MRSA。其中一个可能性是：由于信使RNA分子未以应有的方式被毁灭，于是原来应被关闭的一系列混乱的指令弄垮了MRSA；另外一个可能性则是MRSA无法制造新的RNA分子，因为原材料供应已被切断。
Dunman说：“我们相信这足以让超级细菌遭殃。细胞确实在生产着蛋白，只是所生产的蛋白并非其所需，因为它不再有能力生产必需蛋白了。”
该小组发现RNPA1000积极对抗在美国流行的MRSA类型，对万古霉素半成品敏感的金色葡萄球菌（VISA）与耐万古霉素金葡菌（VRSA）。该化合物也显示了对抗一大批其它被测试的病菌（包括表皮葡萄球菌、耐抗生素肺炎链球菌、化脓性链球菌与耐万古霉素屎肠球菌）的显著抗菌活动性。
RNPA1000在对抗MRSA生物膜的活动能力方面尤有前景，此膜的结构是该病菌在医学环境中的毒性表现的核心。目前的抗菌素在突破诸如导管之类设备上的MRSA生物膜方面存在很大难度，但是RNPA1000即使在细菌隐藏于生物膜中也能让其丧失活动性。
但该化合物并不影响用于治疗MRSA感染的其它药物（包括万古霉素、达托霉素或利福平）；它确实影响了苯甲异噁唑青霉素（oxacillin），使之效力更强。这一发现使最终把诸如RNPA1000之类药剂与其它也以此种感染为靶标的药物结合起来具有可行性.
该化合物对小鼠也有一定的效力。在一项有关已感染的小鼠的实验中，所有未接受治疗的小鼠均告死亡，而接受大剂量RNPA1000的小鼠有一半生存了下来。该化合物在大剂量应用时对人类细胞也有一定的毒性。这些都表明，RNPA1000本身并不能直接用作抗菌素，从而促使Dunman及其同事去设计更为安全、更为有效的替代物。
Dunman表示：“这是一个了不起的开端。 我们已经确认一种积极对抗RnpA的化合物。现在可以尝试应用化学来成百倍地提高其性能、使其对人类细胞的毒性大为减少。我们已经在药物筛选方面获得了线索，并且我们现在正在构建一种更好的分子。”
Dunman是开发与运用阵列技术来研究微生物及探索开发抗生素的全新方法方面的领军人物。当科学家们广泛运用微阵列来拍照一个细胞内的数千基因活动时，Dunman则别出心裁另辟蹊径。他的研究小组应用该技术持续观察RNA分子被制造出后的发生情况，通常每隔几个小时就拍摄数十张快照，从而获得持续进行的RNA降解详貌。
这篇论文总结了六年来的研究情况；六年前第一作者Patrick Olson还在上高中，在Dunman的内布拉斯加实验室当实习生。Olson现在是华盛顿大学圣路易斯分校的研究生，正在为医学学位与博士学位打拼。
除了Dunman与Olson，论文的其他作者包括（名单翻译从略）。
Dunman与分布全球的二十四个实验室有合作关系，这些与之协同作战的研究者正是这些实验室成员的一部分。他也是Caddis Research LLC的奠基者与所有权人。Caddis Research LLC致力于开发抗菌素对对付对公众健康构成威胁的细菌。Dunman同时也是辉瑞研究顾问。
本计划由国家过敏与感染性疾病研究院、美国心脏协会与内布拉斯加研究计划提供资金。
参考文献：
Patrick D. Olson, Lisa J. Kuechenmeister, Kelsi L. Anderson, Sonja Daily, Karen E. Beenken, Christelle M. Roux, Michelle L. Reniere, Tami L. Lewis, William J. Weiss, Mark Pulse, Phung Nguyen, Jerry W. Simecka, John M. Morrison, Khalid Sayood, Oluwatoyin A. Asojo, Mark S. Smeltzer, Eric P. Skaar, Paul M. Dunman. Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis. PLoS Pathogens, 2011; 7 (2): e1001287 DOI: 10.1371/journal.ppat.1001287
（Docofsoul译于2011-02-16）
译后中文字数为1985个。
原英文报道：
http://www.sciencedaily.com/releases/2011/02/110210184328.htm
论文地址：
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001287
==============================================
New Way to Attack Pathogens: RNA Recycling System Gone Awry Brings MRSA to a Halt
抗击病原体新法：让RNA再循环系统出岔
译者：Docofsoul
ScienceDaily (Feb. 11, 2011) — Scientists have discovered a new way to attack dangerous pathogens, marking a hopeful next step in the ever-escalating battle between man and microbe.
《每日科学》2011年2月12日报道 —— 科学家已发现抗击危险病原体的新方式，使日益升级的人类与细菌之间的战争向人类最终赢得胜利的方向又推进了一步。
http://i.0dxy.cn/upload/2011/02/16/34398051.jpg
Scanning electron micrograph (SEM) depicted numerous clumps of methicillin-resistant Staphylococcus aureus bacteria, commonly referred to by the acronym, MRSA; Magnified 9560x. (Credit: CDC/Janice Haney Carr)
放大倍数为9560的扫描电子显微照片（SEM）显示耐甲氧西林金黄色葡萄球菌即MRSA为数众多的丛落。（照片来源：CDC/Janice Haney Carr)
In a paper published online Feb. 10 in the journal PLoS Pathogens, scientists demonstrate that by stopping bacteria's ability to degrade RNA -- a "housekeeping" process crucial to their ability to thrive -- scientists were able to stop methicillin-resistant Staphylococcus aureus or MRSA both in the laboratory and in infected mice.
在线发表于《PloS病原体》的一篇论文证实：通过阻挠细菌的RNA降解（对其繁殖至关重要的“家务劳动”过程）能力，科学家成功遏制了实验室与受感染小鼠中耐甲氧西林金黄色葡萄球菌即MRSA的活动。
The team, headed by a microbiologist at the University of Rochester Medical Center, is now developing closely related compounds designed to be much more potent than the one discussed in the paper.
该研究小组由罗彻斯特大学医学中心的一位微生物学家率队，目前正在开发比本论文所讨论的化合物效力更为强大的密切相关的化合物。
The new approach shows promise against the most severe strains of MRSA as well as the toughest type of MRSA infection for antibiotics to infiltrate -- bacteria enmeshed in biofilms.
新的方法在抗击大多数毒力最强的MRSA菌株、抗击最严重类型的MRSA感染方面展现了希望，使抗生素能够渗透与生物膜紧密融合的细菌。
"This offers a whole new way to go on the offensive against some of the world's most dangerous bugs," said the leader of the group, Paul Dunman, Ph.D., associate professor of Microbiology and Immunology at the University of Rochester Medical Center and formerly of the University of Nebraska. "We're hoping our research opens the door to an entirely new class of antibiotics."
罗彻斯特大学医学中心微生物学与免疫学助理教授Paul Dunman（此前在内布拉斯加大学任教）说：“这一方法是向世界上最危险的细菌发动全新攻势的方法。我们希望本研究为开发全新一类抗菌素打开大门。”
The team also includes scientists from the University of Nebraska, the University of Arkansas, Vanderbilt University, and the University of North Texas Health Science Center.
本研究小组也包括来自内布拉斯加大学、阿肯色大学、范德比尔特大学与北德州大学健康科学中心的科学家。
MRSA infections are among the most virulent infections known. The superbug causes nearly 500,000 hospitalizations and 19,000 deaths in the United States each year -- more deaths than caused by AIDS. The bug can be acquired in the community or in hospitals.
MRSA感染属于已知最为致命的感染之一。仅在美国该超级病菌每年就导致五十万人住院、一万九千人死亡，比艾滋病导致的死亡人数还要高。在社区或医院都可能感染该病菌。
MRSA and other dangerous microbes are so deadly largely because of their ability to adapt quickly to changing conditions. Bacteria's knack for adaptation hinges on their ability to constantly churn out new molecules of RNA, which carry crucial messages that tell a cell what proteins to make and in what quantities.
MRSA与其它危险的微生物之所以如此致命，主要是因为它们有能力快速适应变化中的环境。细菌适应技能取决于其持续产生新的RNA分子的能力。RNA携带有关键信息，告诉细胞应该生产什么样的蛋白与具体的生产量。
The new research focuses on a critical cellular step that is part of the process, known as RNA degradation. Once an RNA molecule is no longer needed, the molecule is sliced and diced up, and its components are returned to the pool of available raw material that the cell taps again and again to construct other RNA molecules as needed.
这项新的研究集中于属于该过程一部分的关键的细胞学步骤：RNA降解。当一个RNA分子不再被需要时，就会被沉默与分解，其元件被回收放入原料池，以供细胞建立其它所需的RNA分子。
"In bacteria, RNA degradation is crucial. The cells are replicating very quickly and responding to environmental changes very rapidly. In less than three minutes, a new RNA transcript is made, the protein is made, and then the RNA is degraded, and that material is made available to make other RNA molecules," Dunman said.
Dunman说：“对细菌而言，RNA降解是关键。细胞快速复制、对环境变化作出极快的响应。在少于三分钟内，一个新的RNA转录即告完成；蛋白被生产出来了，于是RNA被降解，作为原料供制造其它RNA分子。”
Dunman's team discovered that a molecule known as RnpA is central to the degradation process. After nailing down the activity of RnpA, the team tested more than 29,000 compounds in its search for one that inhibits its activity. The team found one, a small molecule called RNPA1000, that brings MRSA nearly to a standstill.
Dunman的研究小组发现，诸如RnpA这种分子在降解过程中起到了核心作用。在明确RnpA的活动意义后，该小组测试了超过二万九千种化合物以寻找抑制其活动的合适人选。他们找到了一种叫做RNAP1000的小分子；该小分子会让MRSA几乎处于静止状态。
Throwing a monkey wrench into bacteria's RNA recycling system might harm MRSA in a number of ways. One possibility is that since messenger RNA molecules are not destroyed like they should be, the bacteria are overcome by an array of confusing instructions that should have been turned off. Another possibility is that bacteria are unable to make essential new RNA molecules, since the supply of raw material is not available.
向细菌的RNA再循环系统扔进一种破坏性因素（比如说丢进了一个“扳手”）就可能以多种方式损害MRSA。其中一个可能性是：由于信使RNA分子未以应有的方式被毁灭，于是原来应被关闭的一系列混乱的指令弄垮了MRSA；另外一个可能性则是MRSA无法制造新的RNA分子，因为原材料供应已被切断。
"We believe this basically makes the bacterial cell go haywire. The cell is producing proteins it no longer needs, and it can't produce proteins that it does need," said Dunman.
Dunman说：“我们相信这足以让超级细菌遭殃。细胞确实在生产着蛋白，只是所生产的蛋白并非其所需，因为它不再有能力生产必需蛋白了。”
The team found that RNPA1000 is active against the predominant MRSA types circulating in the United States, vancomycin intermediate susceptible S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). The compound also showed significant antimicrobial activity against a host of other bugs tested, including Staphylococcus epidermidis, antibiotic-resistant Streptococcus pneumoniae, Streptococcus pyogenes, and vancomycin-resistant Enterococcus faecium.
该小组发现RNPA1000积极对抗在美国流行的MRSA类型，对万古霉素半成品敏感的金色葡萄球菌（VISA）与耐万古霉素金葡菌（VRSA）。该化合物也显示了对抗一大批其它被测试的病菌（包括表皮葡萄球菌、耐抗生素肺炎链球菌、化脓性链球菌与耐万古霉素屎肠球菌）的显著抗菌活动性。
Especially promising was its activity against MRSA biofilms, whose formation is central to the bacterium's virulence in medical settings. Today's antibiotics have a tough time breaking through MRSA biofilms on equipment like catheters, but RNPA1000 brought the bacteria to a halt even when they were ensconced within biofilms.
RNPA1000在对抗MRSA生物膜的活动能力方面尤有前景，此膜的结构是该病菌在医学环境中的毒性表现的核心。目前的抗菌素在突破诸如导管之类设备上的MRSA生物膜方面存在很大难度，但是RNPA1000即使在细菌隐藏于生物膜中也能让其丧失活动性。
The agent does not affect other drugs used to treat MRSA infections, including vancomycin, daptomycin, or rifampicin; it does affect oxacillin, making it more potent. That find might make it possible to eventually combine an agent like RNPA1000 with other drugs that also target the infection.
但该化合物并不影响用于治疗MRSA感染的其它药物（包括万古霉素、达托霉素或利福平）；它确实影响了苯甲异噁唑青霉素（oxacillin），使之效力更强。这一发现使最终把诸如RNPA1000之类药剂与其它也以此种感染为靶标的药物结合起来具有可行性.
The compound was also moderately effective in mice. In an experiment with infected mice, all of the untreated mice died from their infection, but half the mice survived when treated with a large dose of RNPA1000. The compound is also somewhat toxic to human cells at the largest doses. Those findings make it unlikely that RNPA1000 itself will end up as an antibiotic and spurred Dunman and colleagues to design safer, more potent alternatives.
该化合物对小鼠也有一定的效力。在一项有关已感染的小鼠的实验中，所有未接受治疗的小鼠均告死亡，而接受大剂量RNPA1000的小鼠有一半生存了下来。该化合物在大剂量应用时对人类细胞也有一定的毒性。这些都表明，RNPA1000本身并不能直接用作抗菌素，从而促使Dunman及其同事去设计更为安全、更为有效的替代物。
"This is a great starting point," said Dunman. "We've identified a compound that is very active against RnpA, and now we can use chemistry to try to increase its potency by hundreds of times, as well as make it less toxic to human cells. We've gotten a lead from the drug screen, and now we're building a better molecule."
Dunman表示：“这是一个了不起的开端。 我们已经确认一种积极对抗RnpA的化合物。现在可以尝试应用化学来成百倍地提高其性能、使其对人类细胞的毒性大为减少。我们已经在药物筛选方面获得了线索，并且我们现在正在构建一种更好的分子。”
Dunman is a leader in the development and use of array technology to study microbes and explore fresh approaches to the development of antibiotics. While microarrays are widely used by scientists to take what amounts to a snapshot of the activity of thousands of genes in a cell, Dunman adds a twist. His team employs the technology constantly to watch what happens to RNA molecules after they've been made, typically taking dozens of snapshots in the span of hours to get an ongoing, intimate look at RNA degradation.
Dunman是开发与运用阵列技术来研究微生物及探索开发抗生素的全新方法方面的领军人物。当科学家们广泛运用微阵列来拍照一个细胞内的数千基因活动时，Dunman则别出心裁另辟蹊径。他的研究小组应用该技术持续观察RNA分子被制造出后的发生情况，通常每隔几个小时就拍摄数十张快照，从而获得持续进行的RNA降解详貌。
The paper caps a six-year effort that began when the first author, Patrick Olson, was a high school student working as an intern in Dunman's laboratory in Nebraska. Olson is now in graduate school at Washington University in St. Louis, working toward both his medical and doctoral degrees.
这篇论文总结了六年来的研究情况；六年前第一作者Patrick Olson还在上高中，在Dunman的内布拉斯加实验室当实习生。Olson现在是华盛顿大学圣路易斯分校的研究生，正在为医学学位与博士学位打拼。
In addition to Dunman and Olson, other authors of the paper include post-doctoral associate Christelle Roux of the University of Rochester; Lisa Kuechenmeister, Kelsi Anderson, Tami Lewis, Oluwatoyin Asojo, and Khalid Sayood of the University of Nebraska; graduate student John Morrison of the University of Nebraska Medical Center, currently a visiting scientist in Dunman's Rochester laboratory; Sonja Daily, Karen Beenken, and Mark Smeltzer of the University of Arkansas; Michelle Reniere and Eric Skaar of Vanderbilt University; and William Weiss, Mark Pulse, Phung Nguyen, and Jerry Simecka of the University of North Texas Health Science Center.
除了Dunman与Olson，论文的其他作者包括（名单翻译从略）。
These researchers are among scientists at two dozen laboratories around the world with which Dunman works. He is also a founder and owner of Caddis Research LLC, which is developing antimicrobial agents that target bacteria that pose a threat to public health, and he is a consultant for Pfizer Research.
Dunman与分布全球的二十四个实验室有合作关系，这些与之协同作战的研究者正是这些实验室成员的一部分。他也是Caddis Research LLC的奠基者与所有权人。Caddis Research LLC致力于开发抗菌素对对付对公众健康构成威胁的细菌。Dunman同时也是辉瑞研究顾问。
The project was funded by the National Institute of Allergy and Infectious Diseases, the American Heart Assn., and the Nebraska Research Initiative.
本计划由国家过敏与感染性疾病研究院、美国心脏协会与内布拉斯加研究计划提供资金。
Journal Reference:
参考文献：
Patrick D. Olson, Lisa J. Kuechenmeister, Kelsi L. Anderson, Sonja Daily, Karen E. Beenken, Christelle M. Roux, Michelle L. Reniere, Tami L. Lewis, William J. Weiss, Mark Pulse, Phung Nguyen, Jerry W. Simecka, John M. Morrison, Khalid Sayood, Oluwatoyin A. Asojo, Mark S. Smeltzer, Eric P. Skaar, Paul M. Dunman. Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis. PLoS Pathogens, 2011; 7 (2): e1001287 DOI: 10.1371/journal.ppat.1001287
（Docofsoul译于2011-02-16） 这真是一个福音啊！盼望试验早日成功 好消息！期待着胜利的果实！ 感谢版主第一手信息的分享！
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