降胆固醇的药物BPH-652可使致病金黄色葡萄球菌变的无害

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New Approach May Render Disease-causing Staph Harmless

Researchers at the University of Illinois helped lead a collaborative effort to uncover a completely new treatment strategy for serious Staphylococcus aureus ("Staph") infections. The research, published Feb. 14 online in Science, comes at a time when strains of antibiotic-resistant Staph (known as MRSA, for methicillin-resistant S. aureus) are spreading in epidemic proportions in hospital and community settings.

Among the deadliest of all disease-causing organisms, Staph is the leading cause of human infections in the skin, soft tissues, bones, joints and bloodstream, and drug-resistant Staph infections are a growing threat. By federal estimates, more than 94,000 people develop serious MRSA infections and about 19,000 people die from MRSA in the U.S. every year. MRSA is believed to cause more deaths in the U.S. than HIV/AIDS.

The multi-institutional team exploited a chemical pathway that allows the Staph bacterium to defend itself against an immune response. The researchers showed that a compound (BPH-652) originally designed to lower cholesterol blocks a key enzyme in that pathway, weakening the organism's defenses and allowing the body's immune cells to prevail against the infection.

A golden-colored pigment called a carotenoid gives the S. aureus bacterium its edge. "Aureus" is Latin for "golden." The carotenoid acts as an antioxidant for the bacterium, allowing it to evade attack by the body's immune cells. By crippling production of the carotenoid, the compound strips Staph of one of its key defenses.

The new research builds on a recent discovery by scientists at the University of California, San Diego. The UCSD team, led by Dr. Victor Nizet, a professor of pediatrics and pharmacy, showed that knocking out a gene for an enzyme in the chemical pathway that produced the Staph carotenoid reduced its virulence.

When he read about this finding, University of Illinois chemistry professor Eric Oldfield realized that the chemical precursors of the Staph carotenoid were identical to those that led to production of cholesterol in humans. Oldfield, who is the senior author of the paper, had spent decades exploring this pathway, which has implications for the treatment of some cancers, as well as fungal and parasitic diseases. He noted that an enzyme in the human pathway, squalene synthase, was strikingly similar to one that led to the production of the carotenoid in Staph. He also knew that many compounds already had been developed to block the human enzyme.

"I thought there was a good chance that squalene synthase inhibitors developed early on as cholesterol lowering agents might also work on this other pathway," he said. "Current cholesterol-lowering drugs like statins work in a completely different way and would be ineffective."

The researchers began by testing dozens of new compounds for their activity against the Staph enzyme. This allowed them to narrow the field of potential candidates to eight. When they tested these drugs on Staph cells, they found that BPH-652 was the most effective at getting into the cells. A tiny dose impaired the cells' ability to produce the carotenoid. The cells, once golden, turned white.

"We have found that the same golden armor used by Staph to thwart our immune system can also be its Achilles' heel," said Nizet, a study co-author, who is affiliated with the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD.

Preliminary studies were conducted in the laboratories of Nizet and Dr. George Liu, a professor of pediatrics at Cedar-Sinai Medical Center. Exposure to BPH-652 also markedly reduced bacterial levels in a mouse model of severe Staph infection.

Because the approach reduces the virulence of the bacteria by stopping pigment production, it may not cause selective pressures on the population, which can lead to antibiotic resistance. It also targets only S. aureus, possibly reducing side effects.

The key to the compound's success is that the human and bacterial enzymes it targets are so similar. Andrew Wang and his colleagues at Academia Sinica and the National Taiwan University, both in Taipei, used X-ray crystallography to determine the structure of the enzyme and how it interacts with the inhibitors.

"Our structural studies pinpointed how these drug candidates bound to the bacterial enzyme to shut off pigment production," Wang said.

The new findings are particularly promising because BPH-652 already has been used (as a cholesterol-lowering agent) in human clinical trials, reducing the cost and time for development.
降胆固醇的药物BPH-652可使致病金黄色葡萄球菌变的无害

伊利诺州大学的研究者们在致力于研究一种新的治疗金黄色葡萄球菌感染的对策。这项发表在2月14日的《Science》网络版上的研究，是在当前医院和社区内如MRSA等金葡菌耐药率不断升高的背景下开展的。

在所有导致死亡的疾病中，金黄色葡萄球菌是皮肤、软组织、骨、关节、及血液系统感染的主要病原菌，并且人们还不得不面对日益增多的药物耐药的考验。据联邦政府估计，在美国每年超过94,000的人罹患严重的MRSA感染，其中大约19,000人死亡。在美国，MRSA感染所导致的死亡人数被认为比HIV/AIDS引起的死亡人数还要多。

这个联合小组发现了一条金黄色葡萄球菌使自己免受免疫反应伤害的化学通路。研究表明，之前被设计用来降低胆固醇称为BPH-652的化合物，会影响这条通路中的一个关键酶，从而削弱细菌的防御能力，并让人体的免疫细胞战胜感染。

一种叫做类胡萝卜素的金色色素帮助了金黄色葡萄球菌。“Aureus”在拉丁语中是金色的意思。类胡萝卜素是细菌中的抗氧化剂，这会使细菌逃避机体免疫细胞的攻击。通过减少类胡萝卜素的产生，这种化合物就削弱了对于金黄色葡萄球菌来说十分关键的抵抗力。

这项新的研究是建立在一个由加利福尼亚大学圣迭戈分校的科学家们最近发现基础之上的。在儿科学和药学教授Victor Nizet博士领导下的研究小组，敲除了在产生类胡萝卜素的化学通路中的关键酶基因，从而使葡萄球菌降低其毒力。

当读到这一发现，美国伊利诺斯大学化学教授Eric Oldfield意识到葡萄球菌类胡萝卜素的化学前体与那些在人体中生产胆固醇的前体是相同的。 作为本文的主要作者之一，Eric Oldfield曾花了数十年来探讨这个路径，这已影响到某些癌症以及真菌和寄生虫病的治疗。他指出，在人体通路中的一种酶，即角鲨烯合酶，与葡萄球菌生产类胡萝卜素过程中的一种酶有惊人的相似之处。他也知道，许多化合物已被开发用来阻止这种体内的酶。

他说："我认为，作为降低胆固醇因子鲨烯合酶抑制剂的开发是一个很好的开端，当然它有可能也有其它的作用机制。目前，如他汀类的降胆固醇药物的作用机制是完全不同的，并且可能是无效的" 。

研究人员测试了可以抑制金黄色葡萄球菌的酶几十个新的化合物。这使他们的潜在候选药物减少到八个。当他们测试，这些药物对葡萄球菌细胞时，他们发现在进入细胞方面BPH-652是最有效的。小剂量就能损伤细胞产生类胡萝卜素的能力。那些曾经金黄色的细胞，马上就变成了白色。

研究的共同作者，UCSD附属Skaggs药学院的Nizet说：“我们发现，金黄色葡萄球菌用来阻止我们免疫系统的黄金铠甲，同样存在致命的弱点。”

初步研究是在Cedar-Sinai医学中心儿科学教授George Liu博士和Nizet的实验室进行的。实验显示BPH-652也显着降低严重葡萄球菌感染的小鼠模型的细菌水平。

由于该方法通过阻止致病细菌产生色素而减轻毒力，它可能不会对细菌产生选择性压力，这会导致细菌对抗生素耐药。它也只针对金黄色葡萄球菌，并可能减少副作用。

化合物能否成功的关键是：无论人还是细菌，它对于酶作用的靶位如此相似。Andrew Wang和他的在台北的中央研究院和国立台湾大学同事们用X(射)线衍射晶体分析法，以确定酶的结构以及和它如何与抑制剂相互作用。

王说："我们对于（化合物）结构的研究是要明确这些候选药物是如何与细菌的酶结合从而关闭色素生产的 。"

作为一种降低胆固醇的药物，BPH-652已应用于临床，这在临床试验中可以减少成本和时间，因此，这项新发现有很光明的前景。

摘自丁香园

[ 本帖最后由 潮水 于 2008-2-27 19:58 编辑 ]