Rugulactone and its Analogues Exert Antibacterial Effects through Multiple Mechanisms Including Inhibition of Thiamine Biosynthesis
Rugulactone and its Analogues Exert Antibacterial Effects through Multiple Mechanisms Including Inhibition of Thiamine Biosynthesis
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胡古内酯及其类似物通过多种机制（包括抑制硫胺素生物合成）发挥抗菌作用
DOI：
10.1002/cbic.201200265
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发表时间：
2012
期刊：
影响因子：
3.2
通讯作者：
Nodwell M.B
中科院分区：
文献类型：
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作者：
Nodwell M.B
rugulacone是一种二氢α吡咯酮，于2009年从植物cryptocarya rugulosain中分离得到。据报道，它显示IkB激酶（IKK）抑制活性，以及对几种病原菌的抗生素活性。然而，其在细菌中的生物学靶点和作用方式尚未探索。在这里，我们提出了规则内酯的对映选择性合成和一些相应的基于活性的蛋白质谱（ABPP）探针。我们发现，在本研究中，ABPP探针对金黄色葡萄球菌nct8325，S的抑制作用比规则内酯更强。金黄色葡萄球菌mu50，威尔士李斯特菌islcc 5334和单核增生李斯特菌egd‐e，这类分子可能通过结合靶点发挥其抗菌作用。这些靶点包括共价抑制4 -氨基- 5 -羟甲基- 2 -甲基嘧啶磷酸（HMPP）激酶（ThiD），这是细菌中硫胺素生物合成途径的重要组成部分。这是第一个小分子ThiD抑制剂的例子。
Rugulactone is a dihydro‐α‐pyrone isolated from the plantCryptocarya rugulosain 2009. It has been reported to display IkB kinase (IKK) inhibitory activity, as well as antibiotic activity in several strains of pathogenic bacteria. However, its biological targets and mode of action in bacteria have not yet been explored. Here we present enantioselective syntheses of rugulactone and of some corresponding activity‐based protein profiling (ABPP) probes. We found that the ABPP probes in this study are more potent than rugulactone againstStaphyloccocus aureusNCTC 8325,S. aureusMu50,Listeria welshimeriSLCC 5334 andListeria monocytogenesEGD‐e, and that molecules of this class probably exert their antibacterial effect through a combination of targets. These targets include covalent inhibition of 4‐amino‐5‐hydroxymethyl‐2‐methylpyrimidine phosphate (HMPP) kinase (ThiD), which is an essential component of the thiamine biosynthesis pathway in bacteria. This represents the first example of a small‐molecule inhibitor of ThiD.