解决困扰科学界50年已久的霍乱难题或许将为新抗生素的开发指明方向
2012-06-04 00:10:46   来源： 丁香园   作者：  评论：0 点击：

1 For 50 years scientists have been unsure how the bacteria that gives humans cholera manages to resist one of our basic innate immune responses. That mystery has now been solved, thanks to research from biologists at The University of Texas at Austin.
50年以来，科学家一直没弄明白引起霍乱的霍乱弧菌是如何抵御人类的固有免疫系统中的某环节的。美国德州大学奥斯丁分校的生物科学家已经成功阐明具体机制。

2 The answers may help clear the way for a new class of antibiotics that don't directly shut down pathogenic bacteria such as V. cholerae, but instead disable their defenses so that our own immune systems can do the killing.
该发现或许将为新抗生素的开发指明方向：不直接对致病菌本身来攻击而是通过瘫痪霍乱弧菌的防御机制以期我们自身的免疫系统将之消灭。

3 Every year cholera afflicts millions of people and kills hundreds of thousands, predominantly in the developing world. The infection causes profuse diarrhea and vomiting. Death comes from severe dehydration.
霍乱会照成严重的腹泻与呕吐，甚至会因严重的脱水而致死。霍乱主要在发展中国家流行，每年都有数百万的人感染此病数十万的人死于此病。

4 "If you understand the mechanism, the bacterial target, you're more likely to be able to design an effective antibiotic," says Stephen Trent, associate professor of molecular genetics and microbiology and lead researcher on the study.
分子遗传学和微生物学副教授以及本研究的主管研究员Stephen Trent表示“如果我们阐明了霍乱抵抗机制我们就更可能设计出更有效的抗生素”

5 The bacterium's defense, which was unmasked this month in the Proceedings of the National Academy of Sciences, involves attaching one or two small amino acids to the large molecules, known as endotoxins, that cover about 75 percent of the bacterium's outer surface.
本月的国家科学研究院会议揭示了霍乱弧菌的防御机制包括细菌如何往大分子上加上几个小分子氨基酸从而组成内毒素，这种占细菌外表面75%的物质。

6 "It's like it's hardening its armor so that our defenses can't get through," says Trent.
Trent解释道“这就好比为细菌安了一层装甲，我们的免疫系统无法对之起效”

7 Trent says these tiny amino acids simply change the electrical charge on that outer surface of the bacteria. It goes from negative to neutral.
Trent说，一旦加上这些小分子氨基酸，细菌外表面的电荷就会由带负电变为电中性。

8 That's important because the molecules we rely on to fight off such bacteria, which are called cationic antimicrobial peptides (CAMPs), are positively charged. They can bind to the negatively charged surface of bacteria, and when they do so, they insert themselves into the bacterial membrane and form a pore. Water then flows through the pore into the bacterium and pops it open from the inside, killing the harmful bacteria.
这一点非常重要，因为我们用来对抗细菌的阳离子抗微生物多肽 (CAMPs)分子是带正电荷的，他们 (CAMPs)会为细菌表面的负电荷吸引进而插入细菌表面，形成孔隙让水流入从而从其内部攻破，杀死细菌。

9 It's an effective defense, which is why these CAMPs are ubiquitous in nature (as well as one of the main ingredients in over-the-counter antibacterial ointments such as Neosporin).
这种杀菌方式是有效的，也是自然界普遍存在的（这也是非处方抗菌药eg:Neosporin这种膏药的主要成分）

10 However, when the positively charged CAMPs come up against the neutral V. cholerae bacteria, they can't bind. They bounce away, and we're left vulnerable.
然而，在霍乱弧菌，因为其表面电荷的改变，CAMPs被弹开，所以细菌无法被消灭，我们也更易被霍乱弧菌感染。

11 V. cholerae can then invade our intestines and turn them into a kind of factory for producing more cholera, in the process rendering us incapable of holding onto fluids or extracting sufficient nutrients from what we eat and drink.
霍乱弧菌的致病机制是其入侵肠道并在肠道大量增殖，进而让我们无法保留足够体液或者无法从食物中吸取足够的营养。

12 "It pretty much takes over your normal flora," says Trent.
Trent说，霍乱弧菌会显著改变你肠道中的正常菌群。

13 Trent says that scientists have known for some time that the strain of V. cholerae responsible for the current pandemic in Haiti and elsewhere is resistant to these CAMPs. It's that resistance that is likely responsible, in part, for why the current strain displaced the strain that was responsible for previous pandemics.
Trent说科学家们现在明白了正是这种耐 CAMPs的新的霍乱弧菌造成了在海地等国霍乱的流行.事实上这也可能是以前的霍乱弧菌不耐CAMPs的原因之一（优胜劣汰）。

14 "It's orders of magnitude more resistant," says Trent.
Trent说这也是现在的霍乱弧菌更耐药的原因所在。

15 Now that Trent and his colleagues understand the mechanism behind this resistance, they hope to use that knowledge to help develop antibiotics that can disable the defense, perhaps by preventing the cholera bacteria from hardening their armor. If that happened, our CAMPs could do the rest of the work.
既然Trent及其同事了解了现今有霍乱弧菌的耐药机制，他们就希望利用该发现开发出新的抗生素以减弱霍乱弧菌的防护层，如果做到了这点，我们自身的CAMPs就又可发挥杀菌作用了。

16 Trent says the benefits of such an antibiotic would be considerable. It might be effective against not just cholera but a range of dangerous bacteria that use similar defenses. And because it disarms but doesn't kill the bacteria outright, as traditional antibiotics do, it might take longer for the bacteria to mutate and evolve resistance in response to it.
Trent说这种新式抗菌素的好处是极大的。他或许对与霍乱弧菌类似的危险细菌也起作用。而且因为新抗生素不像以前的抗生素直接杀灭细菌，这样一来细菌产生变异和耐药的时间也会延长。

17 "If we can go directly at these amino acids that it uses to protect against us, and then allow our own innate immune system to kill the bug, there could be less selection pressure," he says.
他说：如果我们针对改变细菌外膜电荷进而抵御人体自身免疫的氨基酸来设计药物，让我们的固有免疫系统来杀灭细菌，将会有较少的选择压力（细菌产生变异和耐药）

18 Trent's lab is now screening for compounds that would do precisely that.

Trent的研究团队正在筛选合适的分子。