The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI

Christopher D Fage, Thomas Lathouwers, Michiel Vanmeert, Ling-Jie Gao, Kristof Vrancken, Eveline-Marie Lammens, Angus N M Weir, Ruben Degroote, Harry Cuppens, Simone Kosol, Thomas J Simpson, Matthew P Crump, Christine L Willis, Piet Herdewijn, Eveline Lescrinier, Rob Lavigne, Jozef Anné, Joleen Masschelein

Research output: Contribution to journalArticle (Academic Journal)

Abstract

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.

Original languageEnglish
Pages (from-to)10549-10556
JournalAngewandte Chemie - International Edition
Volume59
Issue number26
Early online date24 Mar 2020
DOIs
Publication statusE-pub ahead of print - 24 Mar 2020

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    Fage, C. D., Lathouwers, T., Vanmeert, M., Gao, L-J., Vrancken, K., Lammens, E-M., Weir, A. N. M., Degroote, R., Cuppens, H., Kosol, S., Simpson, T. J., Crump, M. P., Willis, C. L., Herdewijn, P., Lescrinier, E., Lavigne, R., Anné, J., & Masschelein, J. (2020). The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI. Angewandte Chemie - International Edition, 59(26), 10549-10556. https://doi.org/10.1002/anie.201915407