Sortase A anchoring mechanism

描述(申请人提供)：革兰氏阳性细菌使用细胞壁上显示的表面蛋白附着在动物的特定组织上。这些表面蛋白促进细菌黏附、逃避宿主免疫系统和入侵宿主生物体。负责将这些蛋白质附着在细胞壁上的酶被称为索尔特酶，它们存在于所有革兰氏阳性细菌中。这项建议的重点是研究金黄色葡萄球菌的分解酶A(SrtA)。为了更好地了解索酸酶的普遍锚定机制，我们将设计并测试几种srtA抑制剂的酶活性。我们还建议用核磁共振波谱来阐明SrtA-抑制剂复合体的结构。我们将通过在srtA引入单一氨基酸突变来鉴定对催化和底物结合重要的氨基酸。从这项研究中获得的知识将有望导致禁用这种锚定机制的方法，从而防止细菌感染。特别是在细菌对许多常用抗生素产生抗药性的时代，应优先开发针对病原菌的抗感染剂。

DESCRIPTION (provided by applicant): Gram-positive bacteria adhere to specific tissues in animals using the surface proteins displayed on their cell wall. These surface proteins promote bacterial adhesion, evasion of the host immune system and invasion of the host organism. The enzymes responsible for attaching these proteins to the cell wall are called sortases and they are found in all gram-positive bacteria. The focus of this proposal is to study sortase A (SrtA) from Staphylococcus aureus. To obtain a better understanding of the universal anchoring mechanism of sortases we will design and test the enzymatic effectiveness of several inhibitors of SrtA. We also propose to elucidate the structure of the SrtA-inhibitor complex by using NMR spectroscopy. We will identify the amino acids that are important for catalysis and substrate binding by introducing single amino acid mutations in SrtA. The knowledge gained from this study will hopefully lead to ways of disabling this anchoring mechanism and thereby preventing bacterial infection. Work leading to the creation of anti-infective agents against pathogenic bacteria should be prioritized especially in an era where bacteria have developed a resistance to many commonly used antibiotics.