Science：金黄葡萄球菌的全新治疗方法

对付抗药性金黄色葡萄球菌有了新突破。台湾“中央研究院”找到全新的治疗方法，利用降胆固醇药与金黄色葡萄球菌的酵素结合，就能快速杀死细菌，而不产生抗药性。

据台湾东森新闻报道，这项崭新发现是由“中研院”生物化学研究所特聘研究员王惠钧与美国学者共同合作，整合了化学、微生物学、以及结构生物学等跨领域的研究团队，成功研发出针对金黄葡萄球菌的全新治疗方法。相关的研究论文已于台湾时间15日凌晨刊登于《科学》期刊(Science Xpress)上。

参与此项研究的美国圣地亚哥加州大学(UCSD) 教授Victor Nizet过去曾研究指出，金黄色葡萄球菌的致病关键因素之一，就是金黄色葡萄球菌会利用它的葡萄金黄色素将自己粉饰成金黄色，藉此逃脱人体白血球免疫系统的猎杀行动。

据台大生化科学研究所博士生刘佳宜表示，这个研究中最大的发现是降胆固醇药物中的首要合成的前鲛鲨烯合酶酵素，与人体内合成人体胆固醇的鲛鲨烯合酶非常类似，两者结合后能抑制金黄色葡萄球菌的黄色色素形成。

研究中明确发现此葡萄金黄色素合成酵素的两个受质结合位置确实定位，“利用两者合成酵素的结合作用，可以让金黄色葡萄球菌的金黄色立即转为白色，换言之，破坏金黄色葡萄球菌的盔甲形成，却不直接杀死细菌，就可以让细菌轻易被人体的白血球的免疫系统吞噬，不致产生抗药性。”刘佳宜说，以注射金黄色葡萄球菌的老鼠做试验，发现有高达98%的清除率。

王惠钧则指出，这个新发现除能提供未来降低胆固醇药物设计的重要指标外，接下来更可应用于受到MRSA感染难以治疗的人体临床试验上，未来广泛运用将指日可待。（中新网）

生物谷推荐原始出处：

Published Online February 14, 2008
Science DOI: 10.1126/science.1153018

Submitted on November 15, 2007
Accepted on January 28, 2008

A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence

Chia-I Liu 1 {dagger} , George Y. Liu 2, Yongcheng Song 3, Fenglin Yin 4, Mary E. Hensler 5, Wen-Yih Jeng 6, Victor Nizet 7*, Andrew H.-J. Wang 1*, Eric Oldfield 8*

1 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 10098, Taiwan.
2 Division of Pediatric Infectious Diseases and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
3 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
4 Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.
5 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
6 Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan. ; National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Nankang, Taipei 11529, Taiwan.
7 Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
8 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.; Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA.

* To whom correspondence should be addressed.
Victor Nizet , E-mail: vnizet@ucsd.edu
Andrew H.-J. Wang , E-mail: ahjwang@gate.sinica.edu.tw
Eric Oldfield , E-mail: eo@chad.scs.uiuc.edu

{dagger} These authors contributed equally to this work.

Staphylococcus aureus produces hospital and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 Å resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (IC50 ~100 nM), resulting in colorless bacteria with diminished virulence that were cleared in vivo by the innate immune system, providing proof-of-principle for a virulence factor-based therapy against S. aureus.