Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus.
Humans
Anti-Bacterial Agents
/ chemical synthesis
beta-Lactam Resistance
/ drug effects
Dose-Response Relationship, Drug
Methicillin-Resistant Staphylococcus aureus
/ drug effects
Microbial Sensitivity Tests
Molecular Structure
Pyrones
/ chemical synthesis
Structure-Activity Relationship
Fatty Acids
/ chemical synthesis
Enzymes
Gene expression
Natural Products
Total Synthesis
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
received:
29
03
2021
pubmed:
31
3
2021
medline:
17
2
2022
entrez:
30
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33783142
doi: 10.1002/cmdc.202100219
doi:
Substances chimiques
Anti-Bacterial Agents
0
fusarilactone A
0
Pyrones
0
hymeglusin
0
Fatty Acids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2106-2111Subventions
Organisme : Platform Project for Supporting Drug Discovery and Life Science Research
Organisme : Japan Agency for Medical Research & Development (AMED)
ID : JP19am0101096
Organisme : Platform Project for Supporting Drug Discovery and Life Science Research
ID : JP20am0101096
Organisme : AMED
ID : 16ak0101053 h0001
Organisme : AMED
ID : 20ae0101047
Organisme : Yoshida Scholarship Foundation
Informations de copyright
© 2021 Wiley-VCH GmbH.
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