Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus

Masahiro Kanaida, Aoi Kimishima, Shuhei Eguchi, Masato Iwatsuki, Yoshihiro Watanabe, Masako Honsho, Tomoyasu Hirose, Yoshihiko Noguchi, Kenichi Nonaka, Goh Sennari, Hidehito Matsui, Chikara Kaito, Hideaki Hanaki, Yukihiro Asami, Toshiaki Sunazuka

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2106-2111
Number of pages6
JournalChemMedChem
Volume16
Issue number13
DOIs
Publication statusPublished - Jul 6 2021

Keywords

  • Enzymes
  • Gene expression
  • Natural Products
  • Total Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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