A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence
A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence
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DOI：
10.1126/science.1153018
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发表时间：
2008-03-07
期刊：
影响因子：
56.9
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Liu, Chia-I;Liu, George Y.;Oldfield, Eric
金黄色葡萄球菌可引起医院和社区获得性感染，其中耐甲氧西林金黄色葡萄球菌对公共健康构成严重威胁。金黄色葡萄球菌的金色类胡萝卜素色素葡萄球菌黄素可促进对活性氧的抵抗并促进对宿主中性粒细胞的杀伤，葡萄球菌黄素生产中的早期酶促步骤类似于胆固醇生物合成的那些步骤。我们以 1.58 埃的分辨率测定了金黄色葡萄球菌脱氢角鲨烯合酶 (CrtM) 的晶体结构，发现与人角鲨烯合酶 (SQS) 的结构相似。我们筛选了九种 SQS 抑制剂，并确定了其中三种与 CrtM 结合的结构。其中一种先前在人体中进行了降低胆固醇活性的测试，可在体外阻断葡萄球菌黄素的生物合成（中位抑制浓度类似于 100 nM），导致无色细菌在小鼠感染模型中更容易被人类血液杀死，并增加先天免疫清除的可能性。这一发现代表了针对金黄色葡萄球菌的基于毒力因子的疗法的原理证明。
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 angstrom 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 ( median inhibitory concentration similar to 100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor - based therapy against S. aureus.