The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI.
Anti-Bacterial Agents
/ metabolism
Binding Sites
/ drug effects
Carbamates
/ metabolism
Crystallography, X-Ray
Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific)
/ antagonists & inhibitors
Enzyme Inhibitors
/ metabolism
Fatty Acids, Unsaturated
/ metabolism
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Point Mutation
Protein Binding
Staphylococcus aureus
/ drug effects
MRSA
antibiotics
inhibitors
natural products
protein structures
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
22 06 2020
22 06 2020
Historique:
received:
15
12
2019
revised:
17
02
2020
pubmed:
26
3
2020
medline:
29
4
2021
entrez:
26
3
2020
Statut:
ppublish
Résumé
The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus. By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development.
Identifiants
pubmed: 32208550
doi: 10.1002/anie.201915407
doi:
Substances chimiques
Anti-Bacterial Agents
0
Carbamates
0
Enzyme Inhibitors
0
Fatty Acids, Unsaturated
0
kalimantacin A
174513-95-2
Enoyl-(Acyl-Carrier Protein) Reductase (NADPH, B-Specific)
EC 1.3.1.10
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10549-10556Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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