Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β‐Lactam Drug Resistance in Methicillin‐Resistant Staphylococcus aureus. (7th May 2021)

• Record Type: Journal Article
• Authors: Kanaida, Masahiro; Kimishima, Aoi; Eguchi, Shuhei; Iwatsuki, Masato; Watanabe, Yoshihiro; Honsho, Masako; Hirose, Tomoyasu; Noguchi, Yoshihiko; Nonaka, Kenichi; Sennari, Goh; Matsui, Hidehito; Kaito, Chikara; Hanaki, Hideaki; Asami, Yukihiro; Sunazuka, Toshiaki
• Is Part Of: ChemMedChem. Volume 16:Number 13(2021)
• Page Start: 2106
• Page End: 2111
• Publication Date: 2021-05-07
• Subjects: Enzymes -- Gene expression -- Natural Products -- Total Synthesis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100219
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl‐CoA (HMG−CoA) synthase inhibitor, was identified as circumventing the β‐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. Abstract : A comprehensive study of hymeglusin is described. We identified that hymeglusin shows a circumventing effect against β‐lactam drug resistance in methicillin‐resistant Staphylococcus aureus . Our concise total synthetic route contributed to the first total synthesis of the congener, fusarilactone A and synthetic derivatives allowed us to clarify SAR. The enzyme inhibition assay and site‐directed mutagenesis studies suggested the target protein.