|
|||||
|
|
The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI |
|
| Authors: | Dr Christopher D Fage Dr Thomas Lathouwers Michiel Vanmeert Dr Ling-Jie Gao Dr Kristof Vrancken Eveline-Marie Lammens Angus N M Weir Ruben Degroote Prof Harry Cuppens Dr Simone Kosol Prof Thomas J Simpson Prof Matthew P Crump Prof Christine L Willis Prof Piet Herdewijn Prof Eveline Lescrinier Prof Rob Lavigne Prof Jozef Anné Dr Joleen Masschelein |
| Institution: | 1. Department of Chemistry, University of Warwick, Coventry, CV4 7AL UK
These authors contributed equally to this work.;2. Laboratory of Gene Technology, KU Leuven, Kasteelpark Arenberg 21, PO Box 2462, 3001 Heverlee, Belgium These authors contributed equally to this work.;3. Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Herestraat 49, PO Box 1041, 3000 Leuven, Belgium;4. Laboratory of Molecular Bacteriology, Rega Institute for Medical Research, Herestraat 49, PO Box 1037, 3000 Leuven, Belgium;5. Laboratory of Gene Technology, KU Leuven, Kasteelpark Arenberg 21, PO Box 2462, 3001 Heverlee, Belgium;6. School of Chemistry, Cantock's Close, University of Bristol, Bristol, BS8 1TS UK;7. Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;8. Department of Chemistry, University of Warwick, Coventry, CV4 7AL UK |
| 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. |
| Keywords: | antibiotics inhibitors MRSA natural products protein structures |