@article{e72ae36fcb934709963ba7c656f67ed1,
title = "Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus",
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.",
keywords = "Enzymes, Gene expression, Natural Products, Total Synthesis",
author = "Masahiro Kanaida and Aoi Kimishima and Shuhei Eguchi and Masato Iwatsuki and Yoshihiro Watanabe and Masako Honsho and Tomoyasu Hirose and Yoshihiko Noguchi and Kenichi Nonaka and Goh Sennari and Hidehito Matsui and Chikara Kaito and Hideaki Hanaki and Yukihiro Asami and Toshiaki Sunazuka",
note = "Funding Information: We are grateful to Distinguished Emeritus Professor Satoshi Ōmura (Kitasato University) for his helpful support and valuable suggestions. We thank Dr. K. Nagai and Ms. N. Sato (School of Pharmacy, Kitasato University) for various instrumental analyses. This study was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency for Medical Research & Development (AMED) under Grant Number JP19am0101096. This research was also partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED under Grant Number JP20am0101096. Moreover, this research was also partly supported by AMED under Grant Number 16ak0101053 h0001 and 20ae0101047. Grant for Doctor 21 to M. Kanaida from the Yoshida Scholarship Foundation. Funding Information: We are grateful to Distinguished Emeritus Professor Satoshi ?mura (Kitasato University) for his helpful support and valuable suggestions. We thank Dr. K. Nagai and Ms. N. Sato (School of Pharmacy, Kitasato University) for various instrumental analyses. This study was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency for Medical Research & Development (AMED) under Grant Number JP19am0101096. This research was also partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED under Grant Number JP20am0101096. Moreover, this research was also partly supported by AMED under Grant Number 16ak0101053 h0001 and 20ae0101047. Grant for Doctor 21 to M. Kanaida from the Yoshida Scholarship Foundation. Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",
year = "2021",
month = jul,
day = "6",
doi = "10.1002/cmdc.202100219",
language = "English",
volume = "16",
pages = "2106--2111",
journal = "Farmaco",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "13",
}