Rational design of a global inhibitor of the virulence response in Staphylococcus aureus, based in part on localization of the site of inhibition to the receptor-histidine kinase, AgrC
Rational design of a global inhibitor of the virulence response in Staphylococcus aureus, based in part on localization of the site of inhibition to the receptor-histidine kinase, AgrC
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DOI：
10.1073/pnas.97.24.13330
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发表时间：
2000-11-21
影响因子：
11.1
通讯作者：
Novick, RP
中科院分区：
文献类型：
--
作者：
Lyon, GJ;Mayville, P;Novick, RP
涉及受体组氨酸激酶的双组分信号系统在细菌中普遍存在，在酵母和植物中也发现了。这些系统提供了细菌相互交流和与外界交流的主要手段。值得注意的是，关于可能与受体组氨酸激酶结合以启动信号传递的细胞外配体，人们知之甚少。金黄色葡萄球菌中的两组分AGR信号通路是一个配体化学细节已知的系统，从而为详细的结构-活性关系研究打开了大门。这些配体是含有硫代内酯结构的短(8-到9-AA)肽，其中C端氨基酸的α-羧基连接到半胱氨酸的巯基，半胱氨酸总是从C端开始的第五个氨基酸。AGR系统的一个独特方面是，激活一组金黄色葡萄球菌毒力表达的多肽也抑制其他组金黄色葡萄球菌的毒力表达。在这里，通过在不同AGR特异性类型的菌株之间切换受体组氨酸激酶，证明了组内激活和组间抑制都是由相同的组特异性受体介导的。这些结果促进了金黄色葡萄球菌毒力全球抑制物的发展，该抑制物由一种自然产生的硫代内酯多肽的截短版本组成。
Two-component signaling systems involving receptor-histidine kinases are ubiquitous in bacteria and have been found in yeast and plants. These systems provide the major means by which bacteria communicate with each other and the outside world. Remarkably, very little is known concerning the extracellular ligands that presumably bind to receptor-histidine kinases to initiate signaling. The two-component agr signaling circuit in Staphylococcus aureus is one system where the ligands are known in chemical detail, thus opening the door for detailed structure-activity relationship studies. These ligands are short (8- to 9-aa) peptides containing a thiolactone structure, in which the alpha -carboxyl group of the C-terminal amino acid is linked to the sulfhydryl group of a cysteine, which is always the fifth amino acid from the C terminus of the peptide. One unique aspect of the agr system is that peptides that activate virulence expression in one group of S. aureus strains also inhibit virulence expression in other groups of S. aureus strains. Herein, it is demonstrated by switching the receptor-histidine kinase, AgrC, between strains of different agr specificity types, that intragroup activation and intergroup inhibition are both mediated by the same group-specific receptors. These results have facilitated the development of a global inhibitor of virulence in S. aureus, which consists of a truncated version of one of the naturally occurring thiolactone peptides.