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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

DOI: 10.1002/anie.201915407 DOI Help

Authors: Christopher D. Fage (University of Warwick) , Thomas Lathouwers (Katholieke Universiteit Leuven) , Michiel Vanmeert (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Ling-Jie Gao (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Kristof Vrancken (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Eveline-Marie Lammens (Katholieke Universiteit Leuven) , Angus Weir (University of Bristol) , Ruben Degroote (Katholieke Universiteit Leuven) , Harry Cuppens (Katholieke Universiteit Leuven) , Simone Kosol (University of Warwick) , Thomas J. Simpson (University of Bristol) , Matthew P. Crump (University of Bristol) , Christine L. Willis (University of Bristol) , Piet Herdewijn (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Eveline Lescrinier (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Rob Lavigne (Katholieke Universiteit Leuven) , Jozef Anné (Katholieke Universiteit Leuven Rega Institute for Medical Research) , Joleen Masschelein (KU Leuven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 14692

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.

Journal Keywords: Antibiotics; Inhibitors; Natural products; Methicillin-resistant Staphylococcus aureus (MRSA); protein structures

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 01/04/2020 10:20

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)