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The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl‐Acyl Carrier Protein Binding Site of FabI
Author(s) -
Fage Christopher D.,
Lathouwers Thomas,
Vanmeert Michiel,
Gao LingJie,
Vrancken Kristof,
Lammens EvelineMarie,
Weir Angus N. M.,
Degroote Ruben,
Cuppens Harry,
Kosol Simone,
Simpson Thomas J.,
Crump Matthew P.,
Willis Christine L.,
Herdewijn Piet,
Lescrinier Eveline,
Lavigne Rob,
Anné Jozef,
Masschelein Joleen
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201915407
Subject(s) - polyketide , staphylococcus aureus , antibiotics , biochemistry , biology , enzyme , microbiology and biotechnology , mode of action , acyl carrier protein , biosynthesis , reductase , bacteria , genetics
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.