Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus
Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus
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DOI：
10.1002/cmdc.202100219
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发表时间：
2021-05-07
期刊：
影响因子：
3.4
通讯作者：
Sunazuka, Toshiaki
中科院分区：
文献类型：
--
作者：
Kanaida, Masahiro;Kimishima, Aoi;Sunazuka, Toshiaki
Hymeglusin是一种已知的真核羟甲基戊二酰辅酶a （HMG-CoA）合成酶抑制剂，被鉴定为可绕过耐甲氧西林金黄色葡萄球菌（MRSA）的β -内酰胺耐药性。我们描述了一系列天然产物的简明全合成，从而确定了fusarilactone a的绝对构型，并提供了构效关系信息。根据以往的报道，我们推测这种规避作用的靶蛋白可能是MRSA细菌HMG-CoA合成酶（mvaS）。我们发现这种酶被黑胶蛋白剂量依赖性地抑制。此外，MRSA mvaS基因的过表达和位点定向诱变研究提示了其结合位点和作用机制。
Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitor, was identified as circumventing the beta-lactam drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). We describe the concise total syntheses of a series of natural products, which enabled determination of the absolute configuration of fusarilactone A and provided structure-activity relationship information. Based on previous reports, we speculated that the target protein of this circumventing effect may be MRSA bacterial HMG-CoA synthase (mvaS). We found that this enzyme was dose-dependently inhibited by hymeglusin. Furthermore, overexpression of the MRSA mvaS gene and site-directed mutagenesis studies suggested its binding site and the mechanism of action.